bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early-onset stage II/III colorectal adenocarcinoma in the IDEA database: Treatment adherence, toxicities, and outcomes from adjuvant fluoropyrimidine and oxaliplatin.
Authors: Fontana Elisa , Meyers Jeffrey P. , Sobrero Alberto F. , Iveson Timothy , Shields Anthony Frank , Taieb Julien , Yoshino Takayuki , Souglakos Ioannis , Smyth Elizabeth Catherine , Lordick Florian , Moehler Markus H. , Harkin Andrea , Labianca Roberto , Meyerhardt Jeffrey A. , Andre Thierry , Yamanaka Takeharu , Boukovinas Ioannis , Grothey Axel , Ben-Aharon Irit , Shi Qian ,   Adolescent and Young Adult Gastrointestinal Cancer Task Force EORTC
Published: June 2021

3517 Background: Incidence of early-onset colorectal cancer (eoCRC, age < 50) is steadily increasing. Decisions on adjuvant treatment (adjTx) regimen and duration should consider tx adherence, toxicity (tox) and expected outcomes in a population with life-expectancy longer than late onset CRC (loCRC, age ≥ 50). Methods: Individual patient data from stage II/III patients (pts) from 6 randomised trials in the IDEA database were used to compare characteristics, tx adherence, and adverse events of eoCRC to loCRC. To reduce the confounder of non-cancer-related deaths due to age/co-morbidities, time-to-recurrence (TTR) and cancer-specific survival (CSS) were compared by stratified Gay k-sample test. 5-year cancer-specific mortality (CSM) rate were estimated by adjusted cumulative incidence function. 3-year relapse-free survival (RFS) rate were compared by stratified and adjusted COX models. Results: Out of 16,349 pts included, 1564 (9.6%) were eoCRC. Compared to loCRC, eoCRC had lower percent of male pts (51% vs 57%, p < 0.01) better performance status (PS0 86% vs 80%, p < 0.01), similar T stage distribution (% T1-3/T4: 76/24 vs 77/23, p = 0.97), higher rate of N2 disease (24% vs 22%, p < 0.01), more likely to complete pre-planned duration of adjTx (83.2% vs 78.2%, p < 0.01) and received a higher tx intensity especially with 6 month tx (mean oxaliplatin dose intensity 75% vs 72%, p < 0.01; capecitabine 85% vs 78%, p < 0.01; 5FU 85% vs 82% p < 0.01). Gastrointestinal tox was more common in eoCRC (any grade nausea 58% vs 45%, p < 0.01; any grade vomiting 22% vs 16%, p < 0.01); haematological tox was more frequent in loCRC (62% vs, 69%, p = < 0.01); any grade neuropathy rate was similar (75%). Significant interaction was found between age and T stage for TTR (p = 0.04). Clinical outcome estimates and comparisons are shown in Table. Notably, high risk stage III (T4/N2) eoCRC had significantly lower 3-y RFS rate (54% vs 64%, HRadj 0.74, p < 0.01). Conclusions: eoCRC have better tx adherence than loCRC, as expected. While in high risk stage II and low risk stage III, cancer-specific outcomes are not different, in high risk stage III young age is negatively prognostic and associated with significantly higher relapse rate and risk of CRC death; this is despite a higher administered adjTx-intensity, suggesting a more aggressive disease biology. Clinical trial information: NCT00749450 (SCOT); NCT00646607 (TOSCA); NCT01150045 (CALGB/SWOG 80702); NCT00958737 (IDEA France) [Table: see text]
Association between cancer stem cell marker ALDH1 and clinical and morphological factors of colorectal cancer prognosis.
Authors: Dzhenkova Elena A. , Novikova Inna A. , Kit Oleg I. , Zlatnik Elena Yu. , Ulianova Elena P. , Sitkovskaya Anastasia O. , Shulgina Oksana G. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Vereshchak Maksim A. , Katelnitskaya Oksana V. , Savchenko Dmitriy A. , Tolmakh Roman E. 
Published: June 2021

3522 Background: Cancer stem cells (CSCs) capable of self-sustaining and multipotent differentiation are considered among the most important factors limiting treatment effectiveness. ALDH1 is a marker of colorectal cancer (CRC) CSCs; it is involved in cell differentiation and proliferation, determines resistance to alkylating chemotherapeutic agents, and also induces epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potential of tumors. The purpose of the study was to assess the association between the expression of the ALDH1 CSC marker in tissues of CRC of different stages and clinical and morphological factors of the disease prognosis. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. Tissues of surgically removed tumors were studied with IHC analysis using mouse monoclonal anti-ALDH1 antibodies (clone B-5, Santa Cruz Biotechnology) diluted 1:1800 and the Reveal Polyvalent HRP-DAB Detection System. The percentage of cells positively stained for ALDH1 among all tumor cells was assessed. Statistical analysis was performed using the STATISTICA 13.0 program (StatSoftInc., USA). Results: Positive ALDH1+ expression was registered in 52.5% of all patients, negative expression – in 47.5%. Statistically significant association was observed between the ALDH1 expression and the CRC stage, since the ALDH1+ expression increased from stage II to stage IV (p = 0.003). The ALDH1 expression was statistically significantly associated with the depth of tumor invasion (p = 0.018) and the presence of distant metastases (p < 0.001). No significant relationship was observed between the ALDH1 expression and regional lymph node metastasis (p = 0.788). Statistically significant association was registered between the ALDH1 expression and the tumor grade (p < 0.001), perineural invasion (p = 0.010) and lymphocytic infiltration (p < 0.001). No significant relationship was observed between the tumor histological structure (p = 0.979), lymphovascular invasion (p = 0.772) and ALDH1 expression. Tumor site was not statistically significantly associated with ALDH1 expression (p = 0.349). Conclusions: The study demonstrated statistically significant association between the ALDH1 expression and clinical and morphological characteristics of CRC, determining invasive and metastatic potential of the tumor, and ALDH1 may be an independent prognostic factor and a new therapeutic target for the regulation of the progression process.
Profiling plasma angiogenesis factors after use of biologics in metastatic colorectal cancer (mCRC): Update results from GI-SCREEN CRC Ukit study.
Authors: Sunakawa Yu , Yuki Satoshi , Shiozawa Manabu , Masuishi Toshiki , Nishina Tomohiro , Yasui Hisateru , Ohta Takashi , Takahashi Naoki , Satake Hironaga , Kanazawa Akiyoshi , Goto Masahiro , Bando Hideaki , Taniguchi Hiroya , Okugawa Yoshinaga , Yamazaki Kentaro , Ebi Hiromichi , Abe Yukiko , Nomura Shogo , Asano Chiharu , Yoshino Takayuki 
Published: June 2021

3529 Background: No predictive biomarkers have been validated to determine which patients (pts) with metastatic colorectal cancer (mCRC) benefit the most from angiogenesis inhibitors. Recent studies suggest that plasma angiogenesis factors and their dynamics may have some prognostic or predictive value. Methods: In this prospective longitudinal study, serial plasma sample collections were done at the time points of pre- and post-treatments in mCRC pts receiving biologics in either first- or second-line chemotherapy (chemo). Comprehensive measurements of 17 factors were performed by the multiplex assay with Luminex technology. Statistical analyses were conducted by using the Brunner-Munzel and Jonckheere-Terpstra test. Results: From Sep 2017 to Dec 2020, 789 plasma samples were collected from 498 enrolled pts [first-line chemo plus bevacizumab (BEV, n=102), first-line chemo plus anti-EGFR antibody (aEGFR, n=100), second-line chemo plus BEV (n=100), second-line FOLFIRI plus ramucirumab (RAM, n=99), second-line FOLFIRI plus aflibercept (AFL, n=85) and other treatment (n=7)]. 789 samples were evaluable for this analysis. In the analysis of first-line, level of VEGF-D was significantly higher in both post-BEV and post-aEGFR comparing with pre-first-line [pre-first-line; 264 pg/ml, post-first-line BEV; 354 pg/ml (p<0.001), post-first-line aEGFR; 380.5 pg/ml (p<0.001)], while PlGF was significantly higher only in post-BEV [pre-first-line; 6.7 pg/ml, post-first-line BEV; 23.4 pg/ml (p<0.001), post-first-line EGFR; 7.4 pg/ml (p=0.650)]. These dynamics were also observed in pts with paired samples (Table). In pts with paired samples who received second-line treatment, level of VEGF-A was significantly decreased in post-BEV, while it significantly increased in post-RAM and AFL. A significant elevation of VEGF-D level was observed in only post-RAM. PlGF level significantly increased in post all second-line angiogenesis inhibitors. In the distribution analysis of angiogenesis factors, there were no or weak correlations between VEGF-D and PlGF at the time points of all post-treatments (r = 0.09-0.26). Conclusions: Plasma levels of VEGF-D, VEGF-A and PlGF were independently changed by angiogenesis inhibitors as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting better biologics by measuring baseline angiogenesis-related factors in first- and second-line chemo. Clinical trial information: UMIN000028616. [Table: see text]
Resectability, conversion and resections rates, and outcomes in RAS&BRAF wildtype (wt), RAS mutant (mt) and BRAFmt metastatic colorectal cancer (mCRC) subgroups in the prospective Finnish RAXO-study.
Authors: Osterlund Pia J. , Osterlund Emerik , Uutela Aki , Halonen Päivi , Kallio Raija S. , Ålgars Annika , Salminen Tapio , Lamminmäki Annamarja , Soveri Leena-Maija , Ristamäki Raija , Lehtomäki Kaisa I , Stedt Hanna , Heervä Eetu , Nordin Arno , Ovissi Ali , Sundström Jari , Nieminen Lasse , Mäkinen Markus J , Ristimäki Ari , Isoniemi Helena ,   The RAXO study group
Published: June 2021

3532 Background: Outcomes of metastasectomy varies with RAS and BRAF-status, but the effect on resectability, conversion and resection rates has not been extensively studied. Methods: The prospective Finnish RAXO study (NCT01531621) included 1086 patients 2011-2018 (Osterlund et al TLRHE 2021, Isoniemi et al BJS 2021) of which 906 were included in this secondary endpoint analysis. Excluded had missing KRAS/ NRAS/ BRAF-V600E test, were untreatable or had an atypical BRAF mutation. We studied repeated centralized resectability assessment, conversion and resectability rates in mCRC, and overall survival (OS) after resection and/or local ablative therapy (LAT) and systemic therapy. Results: Included were 289 RAS& BRAFwt, 529 RASmt (overrepresented) and 88 BRAFmt, with median age 65.8/66.1/66.9 years. Demographics per RAS& BRAFwt, RASmt and BRAFmt showed significant differences in male proportion (68/61/39%), ECOG PS 2-3 groups (16/14/25%), primary tumour location (right colon 16/30/69%, left colon 47/34/17%, rectum 38/36/14%), but not for Charlson comorbidity index, BMI, resection of primary, synchronous presentation or adjuvant therapy (Bonferroni corrected Chi-square). Metastatic profile was different for liver (78/74/61% per RAS& BRAFwt, RASmt and BRAFmt), lung (24/35/28%) and peritoneal (15/15/32%) metastases, but not for lymph nodes or other sites, nor for number of metastatic sites (1 in 53/54/52%). Upfront resectability rates were different with 32/29/15% for RAS& BRAFwt, RASmt and BRAFmt, respectively, as were conversion rates with 16/13/7%, and resection/LAT rates with 45/37/17%, respectively. Kaplan-Meier median OS estimate in R0/1/2-resected and/or LAT group (n = 342) was 83/69/30 months for RAS& BRAFwt, RASmt and BRAFmt groups, respectively and 5-year OS-rates 67/60/24%, with Cox HR ref/1.53 (95% CI 1.04-2.25)/3.11 (1.49-6.49). In the “systemic therapy only” (n = 564) OS was 29/21/15 months and 5-year OS-rates 11/6/2% respectively, with HR ref/1.43 (1.15-1.76)/2.34 (1.73-3.17). Resection/LAT patients had improved OS over “systemic therapy only” patients in all subgroups, HR 5.74 (3.90-8.44)/5.06 (3.92-6.55)/2.89 (1.43-5.86). Conclusions: There were significant differences in resectability, conversion and resection/LAT rates according to RAS& BRAFwt, RASmt and BRAFmt status. OS was also significantly longer for RAS& BRAFwt versus either mutant. Resected/LAT had better OS than “systemic therapy alone” patients in all subgroups. Clinical trial information: NCT01531621.
Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild type colorectal cancer: OGSG 1602, survival update data.
Authors: Noura Shingo , Kato Takeshi , Terazawa Tetsuji , Goto Masahiro , Ohta Katsuya , Satake Hironaga , Kagawa Yoshinori , Kawakami Hisato , Hasegawa Hiroko , Yanagihara Kazuhiro , Shingai Tatsushi , Nakata Ken , Kotaka Masahito , Hiraki Masayuki , Konishi Ken , Nakae Shiro , Sakai Daisuke , Kurokawa Yukinori , Shimokawa Toshio , Satoh Taroh ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: June 2021

3558 Background: We previously reported the result of the phase II OGSG1602 study in which single agent of panitumumab (Pmab) demonstrated 76.5% and 50% of disease control rate (DCR), primary endpoint, and response rate (RR), respectively, in chemotherapy-naïve frail or elderly patietns (pts) with wild-type (wt) RAS unresectable colorectal cancer (CRC). Here, we reports the survival analysis including overall survival (OS) and progression free survival (PFS) in terms of sidedness and early tumor shrinkage (ETS). Methods: Thirty-six pts aged ≥76 years, or ≥65 considered unsuitable for intensive chemotherapy were enrolled and received Pmab 6 mg/kg intravenously every 2 weeks. Primary tumors located in the cecum to transverse colon were coded as right-sided tumors (RST), while tumors located from the splenic flexure to rectum were considered left-sided tumors (LST). Early tumor shrinkage (ETS) was determined as tumor reduction of 20% at week 8 compared to baseline. Results: Of total of 36 enrolled pts, 34 pts were included in the efficacy analysis, with pts with LST vs. RST being 26 vs. 8 cases, while pts who achieved ETS (ETS+) vs. those who did not achieve ETS (ETS-) being 15 vs. 19 cases. Among the evaluable 34 pts, the median PFS (mPFS) and median OS (mOS) were 6.0 months (95% Confidence Interval [CI]: 5.4-10.0) and 17.5 months (95%CI, 13.8-24.3), respectively, with the median follow-up of 17.0 months. For PFS, there were no significant differences between pts with LST vs. RST [6.6 months (95%CI, 5.4-11.5) vs. 4.9 months (95%CI, 1.9-NA), p = 0.120] but between pts with ETS+ vs. ETS- [10.4 months (95%CI, 7.4-NA) vs. months (95%CI, 2.1-7.9), p = 0.001]. Furthermore, OS was significantly different either in pts with LST vs. RST [19.3 months (95%CI, 14.2-NA) vs. 12.3 (95%CI, 9.9-NA), p = 0.043] or in pts with ETS+ vs. ETS- [ months (n = 15, 95%CI, 19.6-NA) vs. 10.1 months (n = 19, 95%CI, 6.8-21.8), p < 0.001]. Conclusions: Pmab monotherapy showed the favolable OS in the frail or elderly pts with RAS wt, unresectable CRC. Our data also confirmed the prognostic value of sidedness as well as predictive value of ETS in this setting. Clinical trial information: UMIN000024528. [Table: see text]
Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer.
Authors: Kim Tae Won , Lee Keun Wook , Ahn Joong Bae , Lee Jin , Ryu Jiyeon , Oh Bitna , Ock Chan-Young , Hwang Sunjin , Hahm Ki Baik , Kim Seong-Jin , Park Young Suk 
Published: June 2021

3573 Background: Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC. Methods: In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1). Results: Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%). Conclusions: The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851.
The prognostic impact of RAS and TP53 mutation according to primary tumor location in colorectal liver metastases.
Authors: Cha Yongjun , Kim Bun , Roh Seung Jae , Choi Moon Ki , Lee Dong Woon , Han Sung-Sik , Kim Seong Hoon , Park Sang-Jae , Baek Ji Yeon , Park Sung Chan , Chang Hee Jin , Oh Jae Hwan 
Published: June 2021

3582 Background: Somatic gene mutations have been suggested to impact survival following resection of colorectal liver metastases (CRLM). However, most studies included a selected population with known mutation data and did not employ homogeneous methods. This study aimed to determine the prognostic impact of somatic gene mutations and microsatellite instability (MSI) in CRLM using a standardized protocol and assess their survival effects according to primary tumor location. Methods: A total of 568 patients who underwent resection of CRLM during 2001-2014 were identified from a prospectively maintained registry of the National Cancer Center. MassARRAY based mutation profiling of cancer-related genes ( KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, PTEN, APC, TP53)/MSI analysis was made in primary tumors from 538 (94.7%)/526 (92.6%) patients. Results: Primary tumor locations were: right colon for 51 (9.0%); transverse colon for 42 (7.4%); left colon for 238 (34.5%); rectum for 279 (49.1%) patients. Right sided tumors were associated shorter overall survival (OS) after liver resection compared to left colon primary tumors (5-year OS, 31.4% vs. 54.0% [ P = 0.011]). Mutation frequencies were: 45.9% for RAS ; 2.4% for BRAF ; 8.4% for PIK3CA ; 0.2% for PTEN ; 0.4% for MET ; 12.1% for APC ; 24.3% for TP53. RAS (5-year OS, 40.8% vs. 55.7% [ P = 0.001], PIK3CA (5-year OS, 31.1% vs. 50.5% [ P = 0.027]), and TP53 mutation (5-year OS, 42.7% vs. 50.8% [ P = 0.035]) were associated with worse OS after liver resection. On multivariable analyses, RAS (hazard rato [HR] 1.27; P = 0.033) and TP53 mutation (HR 1.35; P = 0.014) were significantly associated with poor OS after adjustment for covariates. Co-mutation in RAS/ TP53 (12.4%) was associated with the worst oncologic outcome (HR 1.81; P <.001). Notably, while the negative prognostic impact of RAS mutation did not differ significantly according to primary tumor location, the adverse effect of TP53 mutation was limited to rectal cancer (interaction P = 0.002). In this study, MSI-high (2.3%) was not associated with survival. Conclusions: Both RAS and TP53 mutation are associated with worse survival following CRLM resection. In contrast to RAS mutation, the negative prognostic impact of TP53 mutation appears to be limited to CRLM from the rectal origin.
Young-onset colorectal cancer treatment side effects: Infertility, sexual dysfunction, and quality-of-life outcomes.
Authors: Porter Laura Diane , Yarden Ronit , Newcomer Kim Lynn , Fathi Negeen ,   N2Y Advisory Board
Published: June 2021

3587 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. Young-onset colorectal cancer refers to individuals diagnosed under the age of 50. In recent years, the incidence has increased by 2.2% annually in individuals younger than 50 years and 1% in individuals 50-64, in contrast to a 3.3% decrease in adults 65 years and older. Young-onset (YO) CRC patients and survivors face unique clinical challenges with fertility and sexual dysfunctions, but this risk is not well quantified. There is limited data and public discussion on the long-term effects of colorectal cancer treatments on fertility and sexual dysfunction and the long-term impact on the quality of life. Methods: To explore the unique challenges and unmet needs of the young-adult patient population, a cross-sectional study was conducted. Colorectal cancer patients and survivors (N = 884) diagnosed between the ages of 20 to 50 years old (median age 42 ± 7.0) completed an online questionnaire based on established instruments EORTC-QOL-30, EORTC-CR-29, and EORTC-SHC-22. Results: Thirty-one percent of respondents stated that a medical professional spoke to them about fertility preservation at the time of diagnosis and during treatment. Only 31% were referred to a reproductive endocrinologist, even though 37% of women and 16% of men reported that treatment left them infertile or sterile. Among survey respondents, 12% of women had an egg retrieval procedure, and 36% of men had their sperm preserved prior to the start of treatment. Fifty-three percent of women reported treatment led to premature menopause. Sixty-five percent of respondents suffer from some level of sexual dysfunction due to treatment. In patients who received radiation therapy, women were 12% less likely than men to have discussed sexual side effects with the provider before treatment. Patients who have an ostomy reported more severe sexual dysfunction (17.8%). Rectal cancer patients were 2.5 times more likely than those with colon cancer to report severe dysfunction after their treatment. More than 25% of the respondents said they would have considered alternative treatment if they would have known the risks of sexual dysfunction. Conclusions: Our survey demonstrates inadequate communications between patients and providers about the irreversible fertility and sexual effects of colorectal cancer treatments. Younger patients and survivors face unique long-term challenges and require further information about fertility preservation options and emotional support regarding their sexuality post-treatment. Other studies are needed to assess the physical and psychological side effects endured by young-onset CRC patients and survivors.