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Objectives: The aim of this study was to evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) for heavily pretreated metastatic gastric cancer from the perspective of the Chinese healthcare system., Designs: Based on the overall survival and progression-free survival (PFS) data from the Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS) trial (NCT02500043), a three-state Markov model (PFS, progressed disease and death) was constructed to analyse the cost-effectiveness of FTD/TPI compared with the placebo in heavily pretreated metastatic gastric cancer. Cost and utility were from pricing records and the literature. The model was simulated for 5 years with monthly cycles. Costs and health outcomes were discounted by 5%. We then conducted sensitivity analyses to evaluate the robustness of the parameters. The model results were from the Chinese healthcare system., Outcome Measures: The output results were the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER)., Results: According to the model results, FTD/TPI generated an additional cost of US$26 855.66 and 0.88 QALYs compared with the placebo. ICER of FTD/TPI compared with the placebo was US$30 494.89 per QALY. Sensitivity analyses revealed that the utility value of the PFS stage and FTD/TPI adverse event costs were the main influencing parameters, and the results were stable. At a threshold of three times per capita gross domestic product of China (US$35 559.34 in 2022), the probability of FTD/TPI being cost-effective compared with placebo was 99.2%., Conclusion: From the perspective of the Chinese healthcare system, FTD/TPI is a more cost-effective option compared with the placebo for the treatment of heavily pretreated metastatic gastric cancer in patients who have received at least two prior advanced treatment regimens., Trial Registration Number: The Chinese population registered in the Chinese Clinical Trial Registry (ChiCTR2400080940) and clinical trial (NCT05029102)., Competing Interests: Competing interests: None declared., (© 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.)

Opinion Statement: Recommended first and second line treatments for unresectable metastatic colorectal cancer (mCRC) include fluorouracil-based chemotherapy, anti-vascular endothelial growth factor (VEGF)-based therapy, and anti-epidermal growth factor receptor-targeted therapies. In third line, the SUNLIGHT trial showed that trifluridine/tipiracil + bevacizumab (FTD/TPI + BEV) provided significant survival benefits and as such is now a recommended third line regimen in patients with refractory mCRC, irrespective of RAS mutational status and previous anti-VEGF treatment. Some patients are not candidates for intensive combination chemotherapy as first-line therapy due to age, low tumor burden, performance status and/or comorbidities. Capecitabine (CAP) + BEV is recommended in these patients. In the SOLSTICE trial, FTD/TPI + BEV as a first line regimen in patients not eligible for intensive therapy was not superior to CAP + BEV in terms of progression-free survival (PFS). However, in SOLSTICE, FTD/TPI + BEV resulted in similar PFS, overall survival, and maintenance of quality of life as CAP + BEV, with a different safety profile. FTD/TPI + BEV offers a possible first line alternative in patients for whom CAP + BEV is an unsuitable treatment. This narrative review explores and summarizes the clinical trial data on FTD/TPI + BEV., (© 2024. The Author(s).)

Background: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment., Methods: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L., Conclusion: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC., Competing Interests: Declaration of Competing Interest Benoist Chibaudel reports consulting and advisory role from Amgen, Bayer, Beigine, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Revolution Medicines, Roche, SeqOne, Sanofi, Servier, Takeda. Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Qian Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution). Thierry Andre reports attending advisory board meetings and receiving consulting fees from Abbvie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen, Servier, Takeda and Transgène and honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. John Zalcberg reports leadership from ICON Group, Lipotek, PRAXIS; Stock from Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, Teladoc; Honoraria from Gilead Sciences, MSD Oncology, Viatris; Consulting & Advisory Role from Merck Sharp & Dohme, Specialized Therapeutics, CEND, Deciphera, REVOLUTION MEDICINE, FivePHusion, Genorbio, 1Global, Novatech, Alloplex Biotherapeutics Inc, Oncology Republic; Research Funding from BMS, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology, Servier; Travel from MSD Oncology, ICON Group, PRAXIS.Eric Van Cutsem repors participation to advisory boards for Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier paid to his institution. Takayuki Yoshino reports honoraria from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K.; consulting fee from Sumitomo Corp.; research grant from Amgen K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd, FALCO biosystems Ltd., Genomedia Inc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Merus N.V., Molecular Health GmbH, MSD K.K., Nippon Boehringer Ingelheim Co ., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc.,Roche Diagnostics K.K., Sanofi K.K., Sysmex Corp., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Richard Adams reports receiving consulting fees from Takeda, Bayer, GSK; honoraria from Amgen, Bayer, Seagen; Support for attending meetings and/or travel from Servier, Takeda; Participation on Advisory Board from Takeda, Seagen. Carsten Bokemeyer repors receiving consulting fees as advisory boards from Astra Zeneca, Bayer Healthcare, BioNTech, Heaxal, Lindis Biotech, and Sanofi Aventis; as Invited Speaker from AOK Germany, med update, and Roche Pharma; reports honoraria from DGHO, Hamburg Cancer Society, National Network of German Cancer Centers (DKH), Northern German Society of Internal Medicine, DGHO, German Cancer Society. Cornelis J. A. Punt repors receiving consulting fees as advisory boards from Nordic Pharma. Richard M Goldberg receiving consulting fees as advisory boards from Fight for Colorectal Cancer, US NCI. Volker Heinemann repors receiving consulting fees from Merck, Amgen, Roche, AstraZeneca, Celgene, Servier, Novartis, Pierre-Fabre, Halozyme, MSD, BMS, GSK, Janssen, Terumo, Sirtex, Oncosil, Nordic, Boehringer-Ingelheim; honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer-Ingelheim, Celgene, Sirtex, Seagen, GSK; support for attending from Merck, Amgen, MSD, Nordic, AstraZeneca, Servier: reports stock from BionTech. Chiara Cremolini repors receiving consulting fees from Nordic Pharma, Merck, Pierre Fabre, Servier, Takeda; reports honoraria from Takeda, MSD, Amgen, Merck, Pierre Fabre, Servier, Bayer; participation to advisory board from Mirat. Miriam Koopman repors receiving consulting fees from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, Servier and PI participation from the international cohort study PROMETCO with Servier as sponsor; participation to advisory board from Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, Servier; as leadership or fiduciary role in Chair ESMO RWDD working group, co-chair DCCG, PI PLCRC (national observational cohort study), involved in several clinical trials as PI or co-investigator in CRC. Alan Venook repors receiving consulting fees from Amgen, Genentech/Roche, Deciphera; participation on Advisory Board in Amgen, Agenus. Timothy Maughan repors receiving consulting fees from Merck KGAa, Cancer Research UK, Astrazeneca, Ground Truth Laboratories, Perspectum, Nordin Pharma; participation on Advisory Board and leadership in Cancer Research UK, National Cancer Research Institute-University of Liverpool. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.

Purpose: The optimal drug regimen and sequence are still unknown for patients with metastatic colorectal cancer (mCRC) who are candidates for third-line (3L) or subsequent treatment. The aim of this study is to know the opinion of experts on the most appropriate treatment options for mCRC in 3L and to clarify certain clinical decisions in Spain., Methods: Using a modified Delphi method, a group of experts discussed the treatment in 3L of patients with mCRC and developed a questionnaire with 21 items divided into 5 sections., Results: After 2 rounds, the 67 panelists consulted agreed on 17 items (81%). They considered that the main objective of 3L is to equally increase survival and improve patients' quality of life (QoL), but preferably the QoL. It was agreed that patients with mCRC in 3L prefer to receive active versus symptomatic treatment. Panelists considered trifluridine/tipiracil (FTD/TPI) to be the best oral treatment available to them in 3L. In patients with MSI-H or dMMR and BRAF V600E, the panelists mostly prefer targeted treatments. Panelists agreed the use of a therapeutic sequence that not only increases outcomes but also allows patients to be treated later. Finally, it was agreed that FTD/TPI has a mechanism of action that allows it to be used in patients refractory to previous treatment with 5-fluorouracil., Conclusion: The experts agreed with most of the proposed items on 3L treatment of mCRC, prioritizing therapeutic options that increase survival and preserve QoL, while facilitating the possibility that patients can continue to be treated later., (© 2024. The Author(s).)

The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation., (© The Author(s) 2024. Published by Oxford University Press.)

Background: There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data., Objective: We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both., Patients and Methods: This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012-2022). Extended RAS analysis, involving KRAS exon 2-4 and NRAS exon 2-4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation)., Results: Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003)., Conclusions: Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded., (© 2024. The Author(s).)

What Is This Summary About?: This is a summary describing the results from a phase 3 clinical trial called SUNLIGHT. The study looked at treatment with orally administered trifluridine/tipiracil plus intravenously administered bevacizumab in people with metastatic colorectal cancer (mCRC) that is refractory to treatment.This study included people whose cancer had grown or spread beyond its original location after no more than two previous treatments. People in the study received either the combination of trifluridine/tipiracil plus bevacizumab or they received trifluridine/tipiracil alone. The aims of the study were to see how long people lived after treatment with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil alone and to find out how well the combination of trifluridine/tipiracil plus bevacizumab worked at slowing down the spread of the cancer. Researchers also looked at side effects from taking the medicines and at how treatment affected people's physical functioning., What Are the Key Takeaways?: People in the combination group lived longer (a median of 10.8 months) than people who received trifluridine/tipiracil alone (7.5 months). In addition, the time it took for the cancer to worsen was longer for those who received the combination treatment (a median of 5.6 months) compared with those who received trifluridine/tipiracil alone (2.4 months). People's physical functioning took longer to worsen with combination therapy (a median of 9.3 months) than it did with trifluridine/tipiracil alone (6.3 months), as measured by the impact of treatment on people's ability to carry out daily living activities. The most common side effects in both treatment groups were low levels of white blood cells, known as neutrophils (neutropenia), nausea, and low levels of healthy red blood cells (anemia)., What Were the Main Conclusions Reported by the Researchers?: The results from the study suggest that treatment with oral trifluridine/tipiracil plus intravenous (IV) bevacizumab could help people with refractory mCRC live longer and maintain good physical functioning, and it could slow the worsening of their cancer. Clinical Trial Registration: NCT04737187 (SUNLIGHT) (ClinicalTrials.gov).

2', 3'-cGAMP (CDN) as cGAS-STING pathway agonist is extensively used in tumor treatment. However, due to its negatively charged nature (containing two phosphate groups) and high hydrophilicity, CDN faces challenges in crossing cell membranes, resulting in reduced efficiency of its use. Additionally, CDN is susceptible to inactivation through phosphodiesterase hydrolysis. Therefore, the development of a new drug delivery system for CDN is necessary to prevent hydrolysis and enhance targeted accumulation in tumors, as well as improve cellular uptake for STING activation. In this study, we have developed peptide-polymer nanofibers (PEG-Q11) that incorporate thymine (T) and arginine (R) residues to facilitate complexation with CDN through the principles of Watson-Crick base pairing with thymine and favorable electrostatic interactions and bidentate hydrogen bonding with arginine side chains. The entrapment efficiency (EE) of PEG-Q11T3R4@CDN was found to be 51% higher than that of PEG-Q11@CDN. Due to its favorable biocompatibility, PEG-Q11T3R4@CDN was employed for immunotherapy in mouse CT26 tumors. In local tumor treatment, the administration of PEG-Q11T3R4@CDN at a low dose and through a single injection exhibited inhibitory effects. Furthermore, the local injection of PEG-Q11T3R4@CDN resulted in systemic therapeutic responses, effectively suppressing tumor metastasis by activating CD8 + T cells to target distant tumors. This research not only underscores the potential of PEG-Q11T3R4@CDN as an efficient therapeutic agent but also highlights its ability to achieve long-lasting systemic therapeutic outcomes following local treatment. Consequently, PEG-Q11T3R4@CDN represents a promising strategy for immunization., 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 © 2023 Elsevier B.V. All rights reserved.)

Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit., (© 2023. Springer Nature Limited.)

Background: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC)., Methods: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m 2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33., Results: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; P noninferiority  = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%)., Conclusions: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC., Clinical Trial Registration: JapicCTI-173618, jRCTs031180122., (© 2023. The Author(s).)

Manganese oxide nanomaterials (MONs) are emerging as a type of highly promising nanomaterials for diseases diagnosis, and surface modification is the basis for colloidal stability and targeting delivery of the nanomaterials. Here, we report the in-situ functionalization of MnO 2 with DNA through a biomineralization process. Using adsorption-oxidation method, DNA templated Mn 2+ precursor to biomineralize into nano-cubic seed, followed by the growth of MnO 2 to form cube/nanosheet hybrid nanostructure. Among four types of DNA homopolymers, poly-thymine (poly-T) was found to stably attach on MnO 2 surface to resist various biological displacements (phosphate, serum, and complementary DNA). Capitalized on this finding, a di-block DNA was rationally designed, in which the poly-T block stably anchored on MnO 2 surface, while the AS1411 aptamer block was not only an active ligand for tumor targeting delivery, but also a carrier for photosensitizer (Ce6) loading. Upon targeting delivery into tumor cells, the MnO 2 acted as catalase-mimic nanozyme for oxygenation to sensitize photodynamic therapy, and the released Mn 2+ triggered chemodynamic therapy via Fenton-like reaction, achieving synergistic anti-tumor effect with full biocompatibility. This work provides a simple yet robust strategy to functionalize metal oxides nanomaterials for biological applications via DNA-templated biomineralization., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: The current work was designed to estimate the cost-effectiveness of trifluridine/tipiracil (T/T) versus best supportive care (BSC) for patients with advanced stage or metastatic gastroesophageal cancer (mGC) from a UK perspective. Materials & methods: A partitioned survival analysis was undertaken using data from the phase III TAGS trial. A jointly fitted lognormal model was selected for overall survival and individual generalized gamma models were chosen for progression-free survival and time-to-treatment-discontinuation. The primary outcome was the cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were undertaken to investigate uncertainty. Results: Compared with BSC, T/T was associated with a cost per QALY gained of £37,907. Conclusion: T/T provides a cost-effective treatment option for mGC in the UK setting.

Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed., (© 2023. The Author(s).)

Background: The emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates., Results: A total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC 50  and MIC 90  for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene., Conclusion: REMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively., (© 2022. The Author(s).)

Background: The efficacy and safety of trifluridine/tipiracil (FTD/TPI) for third-line treatment of metastatic colorectal cancer have been demonstrated. The authors present the Turkish post hoc analysis of the PRECONNECT study. Methods: An international, multicenter, single-arm, open-label, phase IIIb trial evaluating FTD/TPI in patients with ≥2 previous lines of chemotherapy for metastatic colorectal cancer was conducted. The primary end point was safety. Results: In this Turkish cohort (n = 100; eight centers), the most frequent treatment-emergent adverse event was neutropenia (48%). Median progression-free survival was 3.0 months; disease control rate was 36%; quality of life remained stable. Conclusion: Outcomes with FTD/TPI in Turkey are consistent with previous studies and confirm the efficacy and safety of FTD/TPI treatment in the third-line setting. Clinical Trial Registration: NCT03306394 (ClinicalTrials.gov).

Cancer response to chemotherapeutic agents and its side effects remain a challenge for the development of new anticancer compounds. Dates are consumed worldwide due to their high nutritional value. We investigated the cytotoxicity and expression of the proapoptotic BAX gene in human hepatocellular carcinoma (HepG2) cells treated with Ruthana date ethanolic extract (RDE). The RDE ingredients analyzed by GC/MS and HepG2 cells were treated with different concentrations of RDE for 24, 48, and 72 h. Cytotoxicity, cell viability, DNA fragmentation, and BAX expression were determined. The GC/MS analysis of RDE showed its high content of quercetin, myricetin kaempferol, thymine, and catechol as the most active ingredients. HepG2 treated with RDE showed a significant change in morphological characteristics related to cell death. The antiproliferative activity determined by WST-1 demonstrated that RDE significantly reduced cell viability. Cells treated with RDE (10-60 mg) showed gradual DNA fragmentation in a dose-dependent manner. Gene expression analysis showed upregulation of BAX at 30 mg/ml of RDE (p < 0.001). However, it showed downregulation at (40-60 mg/ml) as compared to control. Our findings indicated that RDE exert cytotoxicity against HepG2 cells due to its high content of flavonoids. This effect through DNA fragmentation and activation of the proapoptotic BAX gene., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses., (© 2022. The Author(s).)

TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25 mg/m 2 twice daily on days 1 to 5 with irinotecan 180 mg/m 2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6 months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3 months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage < 30%). The disease control rate was 75%. In exploratory analyses, mutations in homologous recombination deficiency genes were associated with inferior PFS (P < 0.03). The most common any grade (G) treatment-related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS., (Copyright © 2021. Published by Elsevier Inc.)

Trifluridine/tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers, after the phase III RECOURSE trial demonstrated significant benefit. Another phase III trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the EU in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.

Background/aim: Recently, trifluridine/tipiracil (FTD/TPI) treatment was established as a later-line treatment for metastatic colorectal cancer (mCRC). However, FTD/TPI treatment is frequently associated with hematological toxicity. The aim of this study was to evaluate the efficacy and safety of FTD/TPI in elderly patients with mCRC in a real-world setting., Patients and Methods: We retrospectively reviewed the medical records of 74 patients with mCRC who were treated with FTD/TPI., Results: The treatment effect of the elderly patient group was not inferior to that of the younger patient group. Although the incidence of hematological toxicity in the elderly patient group was higher than that in the younger patient group, there were no significant differences in the rate of treatment discontinuation due to adverse events between the two groups., Conclusion: In elderly patients with mCRC, FTD/TPI treatment was effective for prolonging survival. However, it should be noted that elderly patients showed a higher rate of hematological toxicity than younger patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3-4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model's bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636-0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series., (© 2021. The Author(s).)

Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here., Methods: Pa tients with mGC/mGEJC treated with  ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC)., Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received  ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI., Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.

Pseudomyxoma peritonei is a rare disease with a reported prevalence of about 1-3 per million people annually. Cytoreductive surgery and perioperative hyperthermic intraperitoneal chemotherapy are considered as treatment options improving disease control or long-term survival. However, for patients with incomplete cytoreduction or debulking surgery, outcomes are significantly poorer compared with patients who have obtained complete or optimal cytoreduction. In cases of high-grade pseudomyxoma peritonei that are considered inoperable and/or unresectable, combination chemotherapy regimen with a neo-angiogenesis inhibitor such as bevacizumab is recommended. In this report, a 62-year-old Japanese man presented with abdominal distention. Examination of ascites demonstrated a jelly-like consistency and peritoneal pseudomyxoma was suspected. To relieve progressive symptoms, palliative debulking surgery with total colectomy was performed. Postoperative pathology confirmed high-grade appendiceal mucinous neoplasm with high-grade pseudomyxoma peritonei. In our case, combination chemotherapy with trifluridine/tipiracil (TAS-102) and bevacizumab was initiated after palliative debulking surgery. As a result, carcinoembryonic antigen level was kept stable and the volume of ascites remained almost the same as at the beginning of treatment for more than 2 years. In conclusion, combination chemotherapy comprising TAS-102 and bevacizumab in patients with palliative debulking could be a useful option for patients with high-grade mucinous appendiceal neoplasm and high-grade pseudomyxoma peritonei.

Background/aim: Our multicenter phase II TAS-CC3 study demonstrated favorable median progression-free survival (PFS) and overall survival (OS) of 32 metastatic colorectal cancer (mCRC) patients treated with TAS-102 + bevacizumab as 3 rd -line treatment., Patients and Methods: We investigated the predictive and prognostic values of pre-treatment blood inflammation-based scores, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte ratio (LMR) on disease-control (DC), PFS and OS by a post-hoc analysis., Results: Receiver operating characteristic curve analyses of the 3 inflammation-based scores versus DC showed the best predictive performance for LMR, followed by NLR and PLR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). The high-LMR group showed significantly longer survival than the low group (4.9 vs. 2.3 m for median PFS) (21.0 vs. 6.1 m for median OS)., Conclusion: The pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients undergoing TAS-102 and bevacizumab treatment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0-1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients.

Background: The novel oral nucleoside antineoplastic agent trifluridine/tipiracil was approved for metastatic colorectal cancer in Japan in March 2014. In this post-marketing surveillance study, we investigated the safety and efficacy of trifluridine/tipiracil in a real-world setting, particularly haematological drug reactions classified according to the baseline renal and hepatic functions., Methods: We investigated patients with metastatic colorectal cancer who received trifluridine/tipiracil during the first four treatment cycles prospectively. The patients typically received 35 mg/m2 trifluridine/tipiracil twice daily on days 1-5 and 8-12 every 28 days. The primary objective was to assess the safety of trifluridine/tipiracil, but its efficacy was also evaluated., Results: Between July 2014 and June 2016, 860 patients were enrolled in the study, and the safety and efficacy of trifluridine/tipiracil were evaluated in 823 patients. Adverse drug reactions occurred in 89.7% of the patients. The most common adverse drug reactions were decreased white blood cell count (67.0%) and neutrophil count (63.9%). Haematological drug reactions of grade ≥3 were observed in 41.7% of the patients with normal renal function; 50.3, 65.6 and 78.9% of the patients had mild, moderate and severe renal impairments, respectively. Hepatic impairment was not associated with a higher incidence of haematological drug reactions. The median overall survival was 8.4 months, with a 1-year survival rate of 33.7%., Conclusion: This post-marketing surveillance study further confirmed the safety and tolerability profile of trifluridine/tipiracil observed in a clinical study setting., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: TAS-102 plus bevacizumab is an anticipated combination regimen for patients who have metastatic colorectal cancer. However, evidence supporting its use for this indication is limited. We compared the cost-effectiveness of TAS-102 plus bevacizumab combination therapy with TAS-102 monotherapy for patients with chemorefractory metastatic colorectal cancer., Method: Markov decision modeling using treatment costs, disease-free survival, and overall survival was performed to examine the cost-effectiveness of TAS-102 plus bevacizumab combination therapy and TAS-102 monotherapy. The Japanese health care payer's perspective was adopted. The outcomes were modeled on the basis of published literature. The incremental cost-effectiveness ratio (ICER) between the two treatment regimens was the primary outcome. Sensitivity analysis was performed and the effect of uncertainty on the model parameters were investigated., Results: TAS-102 plus bevacizumab had an ICER of $21,534 per quality-adjusted life-year (QALY) gained compared with TAS-102 monotherapy. Sensitivity analysis demonstrated that TAS-102 monotherapy was more cost-effective than TAS-102 and bevacizumab combination therapy at a willingness-to-pay of under $50,000 per QALY gained., Conclusions: TAS-102 and bevacizumab combination therapy is a cost-effective option for patients who have metastatic colorectal cancer in the Japanese health care system.

Background/aim: In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear., Patients and Methods: The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities., Results: Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed., Conclusion: Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer., Methods: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m 2 ) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting., Findings: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort., Interpretation: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure., Funding: Taiho Pharmaceutical and Eli Lilly., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nivolumab is an increasingly used standard care treatment for heavily pretreated patients with advanced gastric cancer, with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown the objective response rate to cytotoxic chemotherapy potentially improves after an exposure to immune checkpoint inhibitors. Based on these data, we conducted the multicenter observational REVIVE study to evaluate the efficacy and safety of cytotoxic chemotherapy in nivolumab-refractory or nivolumab-intolerant patients with advanced gastric cancer. Patients who are refractory or intolerant to nivolumab and scheduled to receive irinotecan monotherapy, oxaliplatin combination treatment or oral trifluridine/tipiracil hydrochloride therapy will be included. The primary end point is overall survival of nivolumab-pretreated patients with advanced gastric cancer after the cytotoxic chemotherapy. Clinical trial registration: UMIN000032182 (umin.ac.jp).

Background/aim: This study aimed to describe the chemotherapy effects after trifluridine/tipiracil (TFTD) and/or regorafenib treatment in colorectal cancer (CRC) patients., Patients and Methods: Patients receiving regorafenib or TFTD for metastatic CRC during 2013-2018 were selected and divided into two groups: one with additional chemotherapy after regorafenib or TFTD (CTX group) and one without additional chemotherapy (Non-CTX group). Patients were followed up from a landmark point (90 days from the last day of administration of regorafenib or TFTD). We compared overall survival (OS) between the groups., Results: The median OS was 7.7 months in the CTX group and 4.1 months in the non-CTX groups. Several sensitivity analyses did not negate the survival advantage detected in the CTX group., Conclusion: The chemotherapy after regorafenib or TFTD was associated with prolonged OS in advanced CRC patients. Further study is required to determine appropriate treatment choice., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Gastric cancer is a global health problem with high incidence rate and mortality rate. Due to the limitations of traditional chemotherapy drugs, such as patient intolerance, low efficacies and serious adverse effects, trifluridine/tipiracil has been considered to be a promising treatment for patients with heavily pretreated metastatic gastric cancer. However, the relevant systematic review has not been occurring. The presentation of this protocol is to scientifically evaluate the efficacy and safety of trifluridine/tipiracil in patients with highly pretreated metastatic gastric cancer., Methods: The protocol followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will systematically search MEDLINE, PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database (CNKI), VIP Chinese Science and Technology Periodical Database (VIP), Wan Fang Database up to November 1, 2020 to identify published articles. Using the Cochrane risk assessment tool to assess the methodological quality of the RCTs, and all included studies will be analyzed according to the criteria in the Cochrane Handbook. Review Manager 5.3 software will be used for literature quality evaluation and data analysis., Results: Objective to evaluate the efficacy and safety of trifluridine/tipiracil in patients with heavily pretreated metastatic gastric cancer by analyzing the eligible data extracted under limited conditions., Conclusion: This study provides clear evidence to evaluate the effectiveness and safety of trifluridine/tipiracil for patients with highly pretreated metastatic gastric cancer, and the findings will also be published in a peer-reviewed journal., Ethics and Dissemination: No ethical statement will be required for this study because there is no direct involvement of human. This review will be published in a peer-reviewed journal as a conference report or an article., Registration: OSF registration number: DOI 10.17605/OSF.IO/6MF5U., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Evaluate tryptophan and thymine (TT) impact on carcinogenesis and intravesical BCG bladder cancer treatment., Methods: After identification of TT in vitro inhibitory effect in multiple cancer cell cultures, bladder cancer animal model was induced by MNU intravesical instillations and randomized into four groups: Control ( n  = 9), BCG ( n  = 9), TT ( n  = 7), and BCG + TT ( n  = 8). BCG groups received intravesical 10 6 CFU BCG in 0.2 ml saline for 6 consecutive weeks and TT groups received 1 g/kg (1:1) of TT via daily gavage. After 15 wk of protocol, animals were euthanized and the urinary bladders submitted to histopathology, immunohistochemistry, and Western blotting., Results: Urothelial cancer was identified in 100%, 85.7%, 44.5%, and 37.5% of Control, TT, BCG, and BCG + TT groups, respectively. Cell proliferation marked by nuclear Ki-67 was higher in the Control compared to animals in the other groups ( P  = 0.03). BCG, TT, and BCG + TT groups showed proliferative cell decline and TLR4/5 labeling increase in the urothelium. BCG decreased the urothelial VEGF labeling, even in TT association., Conclusion: TT inhibit urothelial carcinogenesis and potentiate the intravesical BCG in the treatment of bladder cancer by reducing cell proliferation and activating TLRs.

In the setting of metastatic colorectal cancer, many gains in patient outcomes have been achieved throughout the last 2 decades. A primary driver of these gains is access to more lines of therapy. In the palliative metastatic setting, all patients ultimately progress and require continued treatment sequencing. The goal is to expose patients to all lines of available therapies. It is now possible to better select patients for each therapy. Treatment selection algorithms encompass disease factors and patient characteristics, such as overall condition and age. Appropriate molecular profiling assessments should be available early in the treatment course, to drive decision-making and allow use of alternative therapies when possible. The transition to third-line therapy can be prompted by changes in imaging scans or laboratory tests, as well as changes in the patient's symptom burden. It can be problematic to delay initiation of third-line therapy when it is clinically indicated. Many oncologists will consider rechallenging patients with the same chemotherapy that did not work earlier. Although this strategy is reasonable, it should not necessarily take precedence over use of agents with proven efficacy in later lines of therapy in randomized clinical trials, such as regorafenib and trifluridine/tipiracil. Clinicians now commonly adjust the dose of regorafenib. A delay in the initiation of these third-line agents can allow the patient's performance status to decrease, thus diminishing the opportunity for a successful outcome.

Rationale: Currently, the 5-year survival rate remains poor for patients with metastatic colorectal cancer (mCRC), and the purpose of therapy is to prolong survival while maintaining the quality of life. Trifluridine/tipiracil, an oral drug combining trifluorothymidine and a thymidine phosphorylase inhibitor, is indicated as salvage therapy for mCRC patients who have progressed after all available regimens. Combination of local treatments with systemic therapy such as trifluridine/tipiracil represents an apt management strategy for mCRC patients., Patient Concerns: A 72-year-old man diagnosed with stage IV rectal adenocarcinoma (KRAS mutation) with peritoneal carcinomatosis and liver metastases developed resistance to 2 lines of treatment (bevacizumab/irinotecan/S-1 and bevacizumab/oxaliplatin/HDFL [high-dose 24-hour infusion of 5-fluorouracil and leucovorin regimen]) within 5 months., Diagnosis: Refractory stage IV rectal adenocarcinoma., Interventions: Systemic treatment of trifluridine/tipiracil has been given for approximately 15 months in addition to radiotherapy, Yttrium-90 radioembolization, and trans-arterial chemoembolization for peritoneal and liver metastases., Outcomes: After 15 months, the patient was still taking trifluridine/tipiracil for disease control with a good quality of life., Lessons: Trifluridine/tipiracil plus other appropriate local therapy may significantly prolong patients survival with a satisfactory quality of life for patients with refractory mCRC. The favorable safety profile of trifluridine/tipiracil renders it a suitable option to be combined with other local therapies for metastatic lesions.

Management of metastatic colorectal cancer reflects a continuum of care. The primary treatment goals are to prolong survival while maintaining the best quality of life. The recommended standard-of-care treatments in the first-line setting consist of combination chemotherapy regimens, given with or without biologic agents. Most patients will receive different lines of therapy for the rest of their life. In the context of lifelong therapy, incorporating chemo-free intervals is one strategy to help achieve these treatment goals. A principle of management is to ensure that all potentially active agents are available to patients. Third-line options for patients with an inadequate response to first-line and second-line therapy include regorafenib and trifluridine/tipiracil. These treatments should be initiated before the patient's performance status deteriorates. Patient characteristics should guide selection. The management plan now incorporates new lessons learned during the current global COVID-19 pandemic. One of the primary guiding principles underlying these recommendations is to avoid unnecessary clinic and hospital exposure. Telemedicine permits the remote management of patients who are receiving oral therapies. Many of these strategies will likely remain in place after the pandemic ends.

Background: Quality of life (qol) is important for oncology patients, especially for those with late-stage disease. The present study was initiated to address the lack of published prospective data about the qol benefits of trifluridine/tipiracil (ftd/tpi) compared with best supportive care (bsc) in patients with refractory metastatic colorectal cancer (mcrc)., Methods: This prospective, cross-sectional, non-interventional study used multidimensional validated scales to evaluate patient-reported qol in two study cohorts of patients and also to measure differences in mcrc-related symptoms and pain in a real-world clinical setting., Results: Our findings demonstrate that patients with refractory mcrc report better overall qol when treated with ftd/tpi than with bsc alone. In that population, statistically significant differences in mean qol measures favoured ftd/tpi over bsc for physical symptom distress, psychological distress, activity impairment, overall valuation of life, and symptomatology. The overall better qol for patients receiving ftd/tpi implies that treatment was well tolerated and was associated with a lower symptom burden. No significant differences for pain were observed between the groups., Conclusions: This study suggests that ftd/tpi is a well-tolerated option for the treatment of patients with refractory mcrc, showcasing the value of capturing real-world qol data in routine clinical practice., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: WYC serves as an advisor to tcan and has received research grants and honoraria from the company; PK has received educational and research grants from tcan and participated on company- organized advisory boards; AD is Director, Medical, at tcan. This real-world treatment study was supported by tcan, who also contributed to study design, data collection, and data interpretation. The authors had full access to all data in the study, and all authors had responsibility for the final decision to submit the work for publication., (2020 Multimed Inc.)

Purpose: This study evaluated the cost utility of regorafenib and trifluridine/tipiracil (T/T) compared with that of best supportive care (BSC) in the treatment of patients with metastatic colorectal cancer previously treated with, or not considered candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti-vascular endothelial growth factor agents; and anti-epidermal growth factor receptor agents, in Japan., Methods: Efficacy data, utility values, and costs were extracted from published studies. The cost and effectiveness of regorafenib and of T/T were compared with those of BSC and examined between the 2 agents over a 5-year time horizon using a partitioned survival analysis. The health outcomes were life-years (LYs) and quality-adjusted life-years (QALYs) gained. The costs were year-2018 revisions to the drug prices and medical fees. The uncertainty and robustness of the model were verified by 1-way sensitivity analysis, probability sensitivity analysis, and scenario analysis compared with different clinical studies. A 2% per-annum discount was applied to expenses and QALYs. The willingness-to-pay threshold used was 5 million Japanese yen (JPY)., Findings: Regorafenib and T/T had incremental costs of 11,898,982 JPY (107,781 US dollars [USD]) and 5,000,141 JPY (45,291 USD), incremental effects of 0.249 QALYs (0.280 LYs) and 0.344 QALYs (0.421 LYs), and incremental cost-effectiveness ratios of 47,773,791 JPY (432,734 USD) and 14,550,577 JPY (131,799 USD) per QALY, respectively. Results of sensitivity analyses all exceeded the willingness-to-pay threshold of 15 million JPY. In the comparison of the 2 agents, T/T was a dominant alternative over regorafenib., Implications: As a third-line or later treatment of metastatic colorectal cancer in Japan, T/T is cost-effective compared with BSC, whereas regorafenib is not. It is necessary to adjust the price of regorafenib based on the results of this analysis, with the improvement of clinical parameters such as survival time and adverse events., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer., Materials and Methods: The search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS)., Results: No difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS., Conclusions: No differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC., Patients and Methods: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m 2 , twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis., Results: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups., Conclusion: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies., Implications for Practice: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Trifluridine and tipiracil (FTD + TPI) and regorafenib (REG) are approved treatments for the treatment of refractory metastatic colorectal cancer (mCRC). This study assesses adherence and duration of therapy with FTD + TPI versus REG and explores the effect of sequencing on adherence., Materials and Methods: Adults diagnosed with mCRC were identified in the IQVIA Real-World Data Adjudicated Claims: U.S. database (October 2014-July 2017). The observation period spanned from the index date (first dispensing of FTD + TPI or REG) to the earliest of a switch to another mCRC agent, the end of continuous enrollment, or the end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC), and persistence and time to discontinuation (gap ≥45 days) were compared between FTD + TPI and REG users and among switchers (FTD + TPI-to-REG vs. REG-to-FTD + TPI)., Results: A total of 469 FTD + TPI and 311 REG users were identified. FTD + TPI users had higher compliance with an MPR ≥80% (odds ratio [OR], 2.47; p < .001) and PDC ≥80% (OR, 2.77; p < .001). FTD + TPI users had better persistence (82.8% vs. 68.0%; p < .001) and lower risk of discontinuation (hazard ratio [HR], 0.76; p = .006). Among switchers (96 FTD + TPI-to-REG; 83 REG-to-FTD + TPI), those switching from FTD + TPI to REG were more likely to have an MPR ≥80% (OR, 2.91; p < .001) and PDC ≥80% (OR, 4.60; p < .001) compared with REG-to-FTD + TPI switchers while treated with these drugs. Additionally, FTD + TPI-to-REG switchers had a lower risk of first treatment discontinuation (HR, 0.66; p = .009)., Conclusion: FTD + TPI users had significantly higher adherence and persistence, and patients who were treated with FTD + TPI before switching to REG also had higher adherence and persistence outcomes., Implications for Practice: Trifluridine plus tipiracil (FTD + TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) but have different tolerability profiles. This study assessed real-world adherence to treatment with FTD + TPI versus REG and compared outcomes among patients who switched from FTD + TPI to REG and vice versa. FTD + TPI was associated with significantly higher medication adherence and longer time to discontinuation than REG. Patients treated with FTD + TPI prior to switching to REG also showed higher adherence outcomes. Findings could help inform decision making regarding the choice and sequencing of treatment with FTD + TPI versus REG in patients with mCRC., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

In clinical trials of metastatic colorectal cancer, progressive disease after second-line therapy is often defined according to Response Evaluation Criteria in Solid Tumors criteria. In the clinic, however, disease progression can be identified through a composite of factors, including new lesions, carcinoembryonic antigen level, and symptoms such as pain and fatigue. It is optimal to switch to third-line treatment before the patient's performance status deteriorates. In the third-line setting, regorafenib and trifluridine tipiracil are approved for the treatment of patients with metastatic colorectal cancer who are refractory to standard chemotherapy. Both of these treatments are associated with prolonged overall survival and progression-free survival in heavily pretreated patients. Data suggest that a chemotherapy break may be beneficial in patients with metastatic colorectal cancer. Some data suggest that treatments beyond the third-line setting might also improve outcome.

Aim: To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents in Greece., Methods: A partitioned survival model was locally adapted from a third-party payer perspective over a 10 year time horizon. Efficacy data and utility values were extracted from published studies. Resource consumption data were obtained from local experts using a questionnaire developed for the purpose of the study and was combined with unit costs obtained from official sources. All costs reflect the year 2017 in euros. Primary outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs) per QALY and LYs gained., Results: Total life time cost per patient for FTD/TPI, BSC and regorafenib was estimated to be €10,087, €1,879 and €10,850, respectively. In terms of health outcomes, FTD/TPI was associated with 0.25 and 0.11 increment in LYs compared with BSC and regorafenib, respectively. Furthermore, FTD/TPI was associated with 0.17, and 0.07 increment in QALYs compared with BSC and regorafenib, resulting in ICERs of €32,759 per LY gained and €49,326 per QALY gained versus BSC. Moreover, FTD/TPI was a dominant alternative over regorafenib., Conclusion: The results indicate that FTD/TPI may represent a cost-effective treatment option compared with other alternative therapies as a third-line treatment of metastatic colorectal cancer in Greece.

Medication for nonalcoholic fatty liver disease (NAFLD) is an unmet need. Glucocorticoid (GC) stress hormones drive fat metabolism in the liver, but both full blockade and full stimulation of GC signaling aggravate NAFLD pathology. We investigated the efficacy of selective glucocorticoid receptor (GR) modulator CORT118335, which recapitulates only a subset of GC actions, in reducing liver lipid accumulation in mice. Male C57BL/6J mice received a low-fat diet or high-fat diet mixed with vehicle or CORT118335. Livers were analyzed histologically and for genome-wide mRNA expression. Functionally, hepatic long-chain fatty acid (LCFA) composition was determined by gas chromatography. We determined very-low-density lipoprotein (VLDL) production by treatment with a lipoprotein lipase inhibitor after which blood was collected to isolate radiolabeled VLDL particles and apoB proteins. CORT118335 strongly prevented and reversed hepatic lipid accumulation. Liver transcriptome analysis showed increased expression of GR target genes involved in VLDL production. Accordingly, CORT118335 led to increased lipidation of VLDL particles, mimicking physiological GC action. Independent pathway analysis revealed that CORT118335 lacked induction of GC-responsive genes involved in cholesterol synthesis and LCFA uptake, which was indeed reflected in unaltered hepatic LCFA uptake in vivo. Our data thus reveal that the robust hepatic lipid-lowering effect of CORT118335 is due to a unique combination of GR-dependent stimulation of lipid (VLDL) efflux from the liver, with a lack of stimulation of GR-dependent hepatic fatty acid uptake. Our findings firmly demonstrate the potential use of CORT118335 in the treatment of NAFLD and underscore the potential of selective GR modulation in metabolic disease.

Background: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016., Methods: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting., Results: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population., Conclusion: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.