bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fruquintinib versus fruquintinib combined with PD-1 inhibitors for metastatic colorectal cancer: Real-world data.
Authors: He Lina , Cheng Xiaojiao , Tu Shuiping 
Published: June 2023

e15592 Background: The treatment in patients with metastatic colorectal cancer (mCRC) have limited effectiveness and options. And research findings have revealed that combining anti-angiogenesis inhibitors with programmed death-1(PD-1) inhibitors can reverse the immunosuppressive tumor microenvironment and synergistically enhance the antitumor immune response. The goal of the study was to add more real-world data to prove the clinical efficacy and safety of this regimen. Methods: We conducted a Real-World observation study by comparison of the efficacy and safety of fruquintinib versus fruquintinib combined with PD-1 inhibitor in patients with mCRC who received treatment between June 2019 and October 2022 in our center. Results: A total of 106 patients with mCRC were observed to receive fruquintinib(F group) (n = 26, mean age = 63 years, female = 46.2%) or fruquintinib combined with PD-1 inhibitor (FP group)(n = 80, mean age = 62 years, female = 46.3%). 3.8% of patients achieved partial response (PR) in FP group and 47.5% had stable disease (SD). Of the F group, no patient had PR and SD was 50%. No difference was found for median progression-free survival(PFS) (F group 6.7 months vs. FP group 4.5 months, p = 0.271). Median overall survival(OS) was significantly prolonged with F group compared with FP group (18.7 months vs. 13.6 months, p = 0.008), which was mainly attributed to the disease course before the treatment of fruquintinib or fruquintinib combined with PD-1 inhibitor in the two groups (42.9 months vs. 31.8 months, p = 0.031). And univariate Cox regression analysis showed that clinical factors (Stage at first diagnosis, PD-L1 gene, number of organs with metastases, and operative treatment) were associated with OS in the FP group (p < 0.05), while only PD-L1 gene positive had significant difference in multivariate analysis (p = 0.024). In the F group, no factors had a significant impact on OS in Cox analysis. Further analysis on immune indices in the FP group indicated that total-MDSCs and PMN-MDSCs significantly decreased after treatment (p = 0.039), mainly resulting from the PR/SD subgroup (p = 0.019) rather than the PD subgroup (p = 1.000). Most adverse events occurred between these two groups were very similar, while any grade of myelosuppression, hepatic injury, abdominal pain, palmar-plantar erythrodysesthesia and hypothyroidism were more frequently observed in the FP group and≥grade 3 myelosuppression was more common. Conclusions: Among patients with metastatic CRC, fruquintinib combined with PD-1 inhibitor couldn't significantly prolong PFS and OS compared with only fruquintinib therapy, but could made a few patients partial response. Total/PMN-MDSCs may be an important indicator of the efficacy of the combined therapy. The combined treatment increased more side effects, yet showed an acceptable safety profile.
Influence of levothyroxine concomitant treatment on treatment responses and outcomes in patients with metastatic colorectal adenocarcinoma.
Authors: Pretta Andrea , Ziranu Pina , Donisi Clelia , Pinna Giovanna , Loi Francesco , Deias Giulia , Palmas Enrico , Cimbro Erika , Cadoni Andrea , Murgia Sara , Mariani Stefano , Rizzo Daiana , Dell'Utri Veronica , D'Agata Alessandra Pia , Bardanzellu Fabio , Maccioni Antonio , Lai Eleonora , Puzzoni Marco , Pusceddu Valeria , Scartozzi Mario 
Published: June 2023

e15593 Background: Hypothyroidism is the most common thyroid disorder and levothyroxine is the mainstay treatment. Levothyroxine is mainly used to restore the euthyroid clinical and biochemical status in the gland. Recent literature has correlated chronic hormonal treatment with adverse effects on bone and heart function, as well as correlated with an increased risk of tumor onset. Data available in the literature are controversial, therefore the aim of our study was to evaluate the correlation between chronic levothyroxine intake and outcomes and response to first line treatments in patients affected by metastatic colorectal cancer. Methods: We retrospectively collected the data from 139 patients with metastatic colorectal adenocarcinoma, belonging to the Medical Oncology Department of the University Hospital of Cagliari from 2016 to 2019. All patients enrolled in the study had received metastatic first-line treatment with doublet or triplet chemotherapy associated with anti-VEGF or anti-EGR monoclonal antibody. Patients with ECOG PS ≤1 with no more than two relevant comorbidities were included in the study. The primary objective of the study was median overall survival (mOS) and secondary objectives were: median progression free progression (PFS), median overall survival (mOS) differences between RAS wild type and mutant tumour. BRAF mutant tumors were excluded from the evaluation. Results: Median age was 65 years (±10), 51% were male and 49% were female. 63% patients had an ECOG-PS 0, while 37% had an ECOG-PS 1. 67% developed from the left colon; 33% from the right colon and the transverse colon. All patients had synchronous metastases. 18% patients took levothyroxine and 82% patients did not take it. Among the patients receiving levothyroxine therapy, 64% had a RAS wild type and 36% a RAS mutated. Levothyroxine treated patients showed a significantly lower median OS than not treated patients (15 months versus not reached, p = 0,0001). Levothyroxine treated patients also showed a significantly lower median PFS than non treated patients (6 versus 8 months, p = 0,035). Within levothyroxine treated pts, no statistically significant differences were found in mOS and mPFS between RAS wt and RAS mut (mOS 15 versus 14 months, respectively, p = 0.9; mPFS 8 versus 7 months, respectively, p = 0,7). Conclusions: The results show a possible correlation between levothyroxine therapy and outcomes in mCRC. This would deserve further study to understand further biological-molecular aspects, to date partially explained by preclinical studies, in order to clarify some of the possible underlying mechanisms.
Efficacy of immunotherapy in MSI metastatic colorectal cancer patients: A Real-World Italian multicentric retrospective study (Colon-MSI Study).
Authors: Iachetta Francesco , Cremolini Chiara , Caputo Francesco , Ciardiello Giamaica , Iacono Donatella , Gelsomino Fabio , Bernardini Ilaria , Maria Germani Marco , Romagnani Alessandra , Damato Angela , Brugia Marco , Ratti Margherita , Santucci Sara , Rapisardi Stefania , Di Fabio Francesca , Garajová Ingrid , Frisinghelli Michela , Aschele Carlo , Palazzo Michele , Pinto Carmine 
Published: June 2023

e15595 Background: The treatment with Immune checkpoint inhibitors (ICIs) is the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The aim of the study was to describe a cohort of MSI mCRC pts treated with ICIs, before pembrolizumab approval, to evaluate efficacy and toxicity in a real-world setting and to identify possible predictive factors of response. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs (anti-PD1 or anti-CTLA-4 antibodies, or in combination) before June 30, 2021, in 14 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. Survival analyses were stratified between treatment naïve and pre-treated pts. We explored the correlation between clinicopathological factors and refractory pts who underwent progression disease (PD) within 3 months from the start of ICI. Results: In this preliminary analysis, we reported 60 consecutive pts with data available. Among all, 30 (50%) were male, 37 (62%) with ECOG PS 0-1; 21 (35%) were at stage IV, and 37 (62%) had right colon tumor site. The most common metastatic sites were lymph nodes, liver, and peritoneum, and 34 (57%) pts had a single metastatic site. 23 (38%) pts had a mucinous adenocarcinoma, and 20 (33%) were BRAF mutated. Nivolumab, Pembrolizumab, and Ipilimumab plus Nivolumab were administered in 24 (40%), 34 (57%), and 2 (3%) pts, respectively, and as first-line therapy in 13 (22%) pts. The median duration of treatment was 22 months (0-43), with 21 pts still ongoing. 13 (22%) pts were refractory to ICIs, and only 4 (7%) pts discontinued treatment for G3-G4 adverse events. The OS, PFS and DCR were different between treatment naïve and pre-treated pts with a positive trend (not statistically significant) toward untreated pts (Table 1). Male gender (p = 0.03), stage IV (p = 0.04), and ≥ 2 metastatic sites (p = 0.01) were significantly associated with refractory ICIs pts, but none of these factors was correlated with poor outcomes in multivariate analysis. Conclusions: Our preliminary data confirm that immunotherapy is an effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest better outcomes when ICIs are administered in the first-line setting. Further analysis will be provided after the completion of the accrual. [Table: see text]
Adjuvant chemotherapy after surgical resection of colorectal metachronous metastases: A phase II nonrandomized trial.
Authors: Evdokimova Sevindzh , Kornietskaya Anna , Bolotina Larisa , Sidorov Dmitriy , Kaprin Andrey 
Published: June 2023

e15597 Background: Currently, six months of perioperative or adjuvant chemotherapy (ACT) is a standard treatment option after radical surgical removal of metachronous metastases in patients with metastatic colorectal cancer (CRC). Data show that ACT improves relapse-free survival in such patients, although no difference in overall survival rate was observed. We conducted a non-randomized trial to examine the efficacy of ACT after radical resection of metachronous metastases from CRC. Methods: Patients older 18 years old and more with confirmed CRC and any site of resectable metachronous metastases were assigned to either surgery alone or adjuvant mFOLFOX6 for 6 months. The primary end point was 2-year disease-free survival (DFS). Results: Between June 2008 and September 2022, 123 patients were assigned to surgery alone group (51 patients) or ACT after surgery (72 patients). At a median follow-up of 27.0 months (20.9-33.1), 2-year DFS was 54.2% in surgery alone group versus 45.5% in ACT group. Median DFS (mDFS) was 25.5 months (95% CI 9.8 – 41.2) in surgery alone group versus 20.9 months (95% CI 13.5 – 28.4) in systemic chemotherapy (HR 0.75; 95% CI 0.45-1.25, P = 0.26). Conclusions: ACT didn’t improve DFS among patients after radical surgical resection of metachronous metastases from CRC.
Outcomes of early onset colorectal cancer (EOCRC) with synchronous liver oligometastasis.
Authors: Emiloju Oluwadunni Eunice , Elboraey Mohamed , Montazeri Seyed Ali , Zaazoue Karim , Jones Jeremy Clifton , Wu Christina , Toskich Beau , Hubbard Joleen M. 
Published: June 2023

e15599 Background: Screening and removal of pre-malignant adenomas has reduced CRC incidence in adults older than 50 years (later onset CRC [LOCRC]), but EOCRC incidence has increased by 1-2% annually since the 1990s. The liver is the commonest site of CRC metastasis, and EOCRC presents with more advanced stage compared with LOCRC. Oligometastasis (OM) refers to potentially resectable CRC, and complete resection of CRC primary and OM is associated with improved survival and potential cure. Here, we examined treatment outcomes of EOCRC with synchronous liver oligometastases (sLiOM) at our institution. Methods: We performed a retrospective review of institutional electronic health records and identified 160 EOCRC patients with sLiOM treated with curative intent in the last decade. Demographics, treatment, and follow up data were recorded, and analysis for survival outcomes performed. The study protocol was exempt after review by Mayo Clinic institutional review board. Results: Of 160 patients, median age at diagnosis was 43 years. Primary tumor was in the left colorectum in 73% and right colon in 26% of patients. Metastasis was limited to the liver only in 64%, and liver metastasis was solitary in 14% of patients (table 1). Fluoropyrimidine doublet backbone (81%) was more commonly used compared to triplet (19%), with doublet + bevacizumab (41%) as the most common regimen. Hepatectomy only (59%), combined hepatectomy with ablation (32%), ablation only (5%), transarterial radioembolization (2%), and trans arterial embolization (1%) were the modalities employed for sLiOM. Of the 148 patients who underwent hepatectomy, R0 resection was achieved in 51%. After a median follow-up of 37 months, progression-free survival was 11.6 mos (95% CI 9-14mos) and median overall was 83.6 mos (95% CI 62-105mos). The median time to liver progression was 16 mos (95% CI 12-20 mos). At data cut off, 41 patients (26%) were alive and disease-free, and 60 patients (38%) were alive and disease free in the liver only. Conclusions: This multi-site, retrospective analysis of EOCRC patients demonstrates excellent survival outcomes with localized treatment of sLiOM. Median OS in this cohort compares favorably to previously reported mOS of 36 months in EOCRC patients (Arhin et al, 2021). Cure is not often achieved even after treatment of sLiOM in this cohort, suggesting aggressive disease biology and the need for improved patient selection. [Table: see text]
Safety and efficacy of trifluridine/tipiracil plus bevacizumab in RAS mutated patients with metastatic colorectal cancer.
Authors: Michalaki Vasiliki , Theodosopoulos Thedosios , Vezakis Antonios , Papaconstantinou Ioannis , Kontis Ioannis , Dafnios Nikolaos , Frangoulidis George , Karandrea Despina , Papadimitriou Christos 
Published: June 2023

e15605 Background: Trifluridine-tipiracil (FTD/TPI) plus bevacizumab has shown efficacy inrefractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in Ras mutated population, is limited. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to KRAS status. Methods: Eligible patients were mCRC refractory or intolerant to all standard therapies including fluoropyrimidines, irinotecan and oxaliplatin. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), PFS, and safety data were collected and analyzed. Results: Forty-two patients were enrolled. Median age was 67 years (range 41–79 years), 44% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, 85% were KRAS and 15% NRAS mutant, and 75% underwent primary tumor resection; 68% of patients had liver metastases, 49% had lung metastases, and 18% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range1–3), and 85% of patients received at least one previous anti-angiogenic agent. DCR was 57.1% (90% CI, 44.6 %-69.3%, P = 0.0690), respectively. The median progression-free survival (PFS) was 4.6 months. The most common grade 3 or higher adverse event was neutropenia (54%), and anemia (16%); 32% of patients required either dose delays or dose reductions due to toxicity. No treatment-related deaths occurred. Conclusions: FTD/TPI is an important therapeutic resource in refractory RAS mutated metastatic colorectal cancer that combines manageability and safety.
3D genomics identifies previously unreported yet clinically actionable gene fusions and complex rearrangements in a cohort of driver-negative colorectal carcinoma tumors.
Authors: Sikkink Kristin , Beck Alyssa , Schmitt Anthony , Sigal Darren 
Published: June 2023

e15608 Background: Molecular characterization by next-generation sequencing (NGS) has been unable to detect pathogenic driver mutations in a significant number of tumors. For example, 40% of colorectal carcinomas (CRC) are RAS and BRAF wild-type and do not have therapeutic targets after comprehensive molecular characterization using FISH, IHC and NGS. Analysis of 3D genomics data produced by DNA-based chromosome conformation capture (Hi-C) assay has been shown to detect gene fusions and other rearrangements in tumor biopsies. We applied Hi-C in a cohort of CRC tumors previously characterized using FISH, IHC, whole exome sequencing (WES) and whole transcriptome sequencing (WTS) by a large commercial reference laboratory, where no targets had been reported, to evaluate the potential for Hi-C to identify novel therapeutic targets. Methods: FFPE tissue from 14 CRC tumors were subjected to Hi-C using the Arima HiC+ for FFPE kit. Hi-C libraries were sequencing to ~100M raw read-pairs on an Illumina NovaSeq, and fusions were called using the Arima-SV pipeline. To attribute clinical significance, we characterized fusions based on whether the fusion event involved a Tier 1 therapeutic level biomarker or a Tier 3 diagnostic or prognostic biomarker according to NCCN and OncoKb, or a Tier 2 biomarker if the biomarker was the target of a therapy in an ongoing clinical trial. Results: Hi-C detected fusions implicating a Tier 1 biomarker in 50% (7/14) of tumors, a Tier 2 level biomarker in 14% (2/14), and a Tier 3 level biomarker in 14% (2/14). Homologous recombination repair (HRR) gene rearrangements were detected in 29% (n = 4/14) of CRC tumors, disrupting HRR genes ( BRIP1, BRCA1, BRCA2, RAD51D). NRG1 gene fusions were detected in 14% (2/14), and amplified complex rearrangement carrying KRAS was detected in one CRC case. A complex rearrangement involving extrachromosomal DNA (ecDNA) amplification carrying EGFR was detected in two cases that were both previously found to have EGFR amplifications, but the ecDNA nature was not previously known and was confirmed by FISH. Lastly, Hi-C detected gene rearrangements involving POLE or APC in two CRC cases, alterations in which are known to increase risk for colonic polyposis. Conclusions: Fusion detection by Hi-C in CRC may uncover numerous therapeutic biomarkers not currently detected by molecular profiling. Our data suggests that homologous recombination deficiency (HRD) may frequently result from HRR gene rearrangements readily detectable by Hi-C, and this alternate mechanism for HRD may serve as a therapeutic biomarker for HRD directed therapies. Our data also suggests that therapeutically targetable gene fusions and complex rearrangements involving therapeutic level biomarkers are also readily detectable by Hi-C, detection of which may increase the number of CRC patients treatable with targeted therapies.
Comparative efficacy of later-line therapies for metastatic colorectal cancer (mCRC) using novel methods for patient survival data reconstruction and network meta-analysis (NMA) of survival curves.
Authors: Abraham Ivo , Obeng-Kusi Mavis , Roe Denise , Erstad Brian L 
Published: June 2023

e15611 Background: NMAs of cancer treatments are usually based on the proportional hazard assumption (PHA) which implies a constant hazard ratio as well as treatment effect on only scale parameter and therefore not reflecting clinical dynamics of survival outcomes over time. Multivariate NMA which does not rely on the PHA is often constrained by lack of individual patient-level data (IPD). We applied a novel method of reconstructing pseudo-IPD from published survival curves that enabled application of a dynamic method of NMA of survival curves without PHA constraint to compare the efficacy of 6 later-line therapies for metastatic colorectal cancer (mCRC), compared to placebo. Methods: We identified 8 phase II/III trials reporting the efficacy of 6 later-line therapies for mCRC from PubMed, Embase, Scopus and Cochrane Library. Trial survival curves were reconstructed based on pseudo-IPD generated using the Guyot method, and the estimated survival proportions and hazard ratios (HRs) over 12 months (12m) of follow up were calculated using a random effects lognormal distribution model with placebo as the common comparator. Results: Compared to placebo, 12m PFS HRs varied from 0.29 (95%CrI = 0.19-0.44) for TAS+bevacizumab to 0.72 (95%CrI = 0.62-0.85) for atezolizumab. Similarly, OS HRs ranged from 0.55 (95%CrI = 0.26-0.92) for TAS+bevacizumab to 1.01 (95%CrI = 0.79-1.20) for atezolizumab (Table). Conclusions: In this NMA of survival curves, all therapies except atezolizumab were superior to placebo in PFS and OS over 12m follow up period. TAS+bevacizumab provided the highest survival advantage over placebo, with fruquintinib, regorafenib, and TAS-102 also showing survival benefits. TAS+bevacizumab may be the preferred choice for later-line mCRC treatment. [Table: see text]
Intraarterial chemotherapy of liver metastases of colorectal cancer. Experience of National Cancer Institute of Ukraine.
Authors: Patsko Veronika , Lukashenko Andrii , Ostapenko Yuriy 
Published: June 2023

e15619 Background: Liver - is the most often site of colorectal cancer metastases. Although surgical resection of primary tumor and liver metastases is the most radical type of treatment, only 10-25% of patients are eligible for this approach. Our aim was to evaluate efficacy of intraarterial chemotherapy for patients with primary unresectable metastatic colorectal cancer (mCRC) to improve prognosis and overall response for treatment. Methods: records of 73 patients with primary unresectable mCRC, who undergone catheterization of liver artery and received intraartetial chemotherapy (with 5-FU) in period 2008-2018 years at the Clinic of National Cancer Institute (Ukraine). Results: the figure of overall response: 57.5% (n = 42) - partial response, 8.2% (n = 6) - complete radiological response, 12.3% (n = 9) - stable disease, 21.9% (n = 16) - chemoresistant tumor. 46.6% (n = 34) of patient undergone resection of previously unresectable liver metastases. In 4.1% (n = 3) complete histological response was estimated. Surgical mortality and morbidity rate were 1.3% and 6.8% respectively. Cause of postoperative mortality was lung embolism, complications included bacterial infections and hemorrhage in postoperative period. Main reason for inability to perform operations were post chemotherapeutic toxicity, which did not resolved on optimal terms for operation. The overall 5-year survival rate was 29.4% in group who undergone resection and 17.9% in group, were patients were not radically operated (p < 0.05). Conclusions: catheterization of liver artery with further intraarterial chemotherapy can potentially convert unresectable metastases into resectable, therefore improving treatment results and overall survival.