bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil-to-lymphocyte ratio and clinical outcomes in liver resection for metastatic colorectal cancer.
Authors: Reddy Sarah , El Hajj Joanna , Karagkounis Georgios , Polanco Patricio M. , Porembka Matthew R. , Sanjeevaiah Aravind , Jones Amy Little , Al Mutar Salwan , Kainthla Radhika , Huang Emina , Kazmi Syed Mohammad Ali 
Published: January 2023

233 Background: The neutrophil-to-lymphocyte ratio (NLR) has been shown to correlate with overall and disease-free survival in patients with colorectal cancer. The data about prognostic value of the NLR in patients undergoing liver resection for colorectal liver metastases (CRLM) is limited. We aimed to describe the relationship between the NLR, overall survival and disease progression in patients who underwent liver resection for CRLM in a safety-net hospital. Methods: We identified patients who underwent liver resection with curative intent for metastatic colorectal cancer at a large safety net hospital between 2008 and 2020. All patients had a complete blood count with differential available within three months prior to resection. We compared patients who had a pre-operative NLR ≤3 with those who had a NLR > 3, a cut-off based on ROC analysis. We used the Chi-squared statistic and t-test to compare the frequencies of categorical variables and the means of continuous variables, respectively. Multivariate survival analyses were performed using the Cox-regression model after adjusting for sex, age at liver resection, race/ethnicity, body mass index, insurance status, initial presentation of colorectal cancer (emergency room vs outpatient), primary malignancy (colon vs. rectal), temporality of CRLM (synchronous vs metachronous presentation with primary), staged vs simultaneous removal of primary mass and CRLM, number and size of liver CRLM, other metastatic sites at the time of liver resection, carcinoembryonic antigen (at initial diagnosis, before and after resection), and receipt of at least six months of peri-liver resection chemotherapy. Results: We identified 76 patients who underwent liver resection with curative intent for CRLM with a median follow up of 40.7 months. The population had a mean age of 56.2 (SD 9.9), was 50% female, and predominantly non-White (73.7%). Compared with patients who had a NLR ≤3 (N = 50), patients with a NLR > 3 (N = 26) were more likely to be white (46.2% vs 16.0%) and have rectal cancer (61.5% vs 28.0%). In unadjusted analysis, patients with NLR > 3 had 1.87 times (95% CI 1.01-3.47) increased risk of mortality, compared with patients who had an NLR ≤3. In adjusted analysis, patients with NLR > 3 had 6.88 times (95% CI 1.61-29.42), increased risk of mortality, compared with patients who had an NLR ≤ 3. There was no significant difference in risk of CRLM recurrence or overall disease progression among patients with NLR ≤3 vs patients with NLR > 3. Conclusions: An elevated pre-operative NLR > 3 is a potential predictor of overall survival among patients undergoing liver resection for metastatic colorectal cancer. This widely available test may aid clinicians in pre-operative risk stratification.
Effect of CXCL1 on the NF-κB/P300 signaling pathway and colon cancer progression.
Authors: Zhuo Changhua , Ruan Qiang , Zhao Xiangqian , Shen Yangkun , Lin Ruirong 
Published: January 2023

236 Background: The upregulated expression of CXCL1 has been validated in colorectal cancer patients. As a potential biotherapeutic target for colorectal cancer, the mechanism by which CXCL1 affects the development of colorectal cancer is not clear. Methods: Expression data of CXCL1 in colorectal cancer were obtained from the GEO database and verified using the GEPIA database and the TIMER 2.0 database. Knockout and overexpression of CXCL1 in colorectal cancer cells by CRISPR/Cas and "Sleeping Beauty" transposon-mediated gene editing techniques. Cell biological function was demonstrated by CCK-8, transwell chamber and Colony formation assay. RT-qPCR and Western Blot assays measured RNA and protein expression. Protein localization and expression were measured by immunohistochemistry and immunofluorescence. Results: Bioinformatics analysis showed significant overexpression of CXCL1 in the colorectal cancer tissues compared to normal human tissues, and identified CXCL1 as a potential therapeutic target for colorectal cancer. We demonstrate that CXCL1 promotes the proliferation and migration of colon cancer cells and has a facilitative effect on tumor angiogenesis. Furthermore, CXCL1 elevation promoted the migration of M2-tumor associated macrophages (TAMs) while disrupting the aggregation of CD4+ and CD8+ T cells at tumor sites. Mechanistic studies suggested that CXCL1 activates the NF-κB pathway. In the in vivo colon cancer transplantation tumor model, treatment with the P300 inhibitor C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer. Conclusions: CXCL1 promotes colon cancer development through activation of NF-κB/P300, and that CXCL1-based therapy is a potential novel strategy to prevent colon cancer development.
Novel blood-based biomarker candidates in screening for colorectal cancer.
Authors: Liggett Jason Lee , Petersen Mathias M , Kleif Jakob , Rasmussen Morten , Jørgensen Lars Nannestad , Seidelin Jakob Benedict , Madsen Mogens R. , Vilandt Jesper , Gotschalck Kåre Andersson , Andersen Lars M. , Khalid Ali , Andersen Berit , Christensen Ib Jarle , Fritsche Herbert A. , Mayer Eric S. , Therkildsen Christina 
Published: January 2023

244 Background: Colorectal cancer (CRC) is the third most common cancer worldwide motivating national screening strategies utilizing fecal immunochemical tests (FIT). Blood-based biomarkers could be an alternative method to increase compliance in population-based screening programs for early detection of CRC. We aimed to identify new blood-based biomarkers that could be potential candidates for use in colorectal cancer screening. Methods: In a nested cohort study of 1967 FIT positive participants of the Danish CRC screening program serum levels of GDF-15, hepsin, IL-8, keratin1-10, L1CAM, MIA, monocyte MCP-1, NSE and OPG were measured using the Luminex xMAP immunoassay platform. Main outcomes were CRC vs non-CRC and CRC, high-risk adenomas (HRA) or medium-risk adenomas (MRA) vs low-risk adenomas (LRA) or clean colorectum. Odds ratios for associations between biomarker expressions and outcomes were calculated using logistic regression models and visualized by area under the receiver operating characteristic (ROC) curve (AUC). Analyses were made on the Luminex biomarkers alone and with addition of clinical and demographic information. Results: FIT-induced colonoscopies detected 240 CRCs and 625 HRA or MRA. Multivariate analyses using all biomarkers and age found hepsin, IL-8 and OPG significantly (p<0.001) associated in relation to the main outcome (CRC vs non-CRC) with odds ratios of 0.74 [0.59-0.92], 2.59 [2.12-3.15] and 0.90 [0.82-0.99], respectively. The full model using all biomarkers and age presented an AUC of 0.73 [0.70-0.77]. Conclusions: Changed serum levels of nine novel biomarkers seem to be potential predictors for early detection of CRC, especially hepsin, IL-8 and OPG. [Table: see text]
Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.
Authors: Viñal David , Rueda-Lara Antonio , Martinez-Perez Daniel , Zwisler Patricia , Garcia-Leal Andrea , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Peña-Lopez Jesus , Alameda-Guijarro Maria , Martin-Montalvo Gema , Perez-Wert Pablo , Martínez-Recio Sergio , Palacios Maria Elena , Ghanem Ismael , Custodio Ana B. , Gutiérrez-Sainz Laura , Feliu Jaime , Rodriguez Salas Nuria 
Published: January 2023

247 Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P <0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P < 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.
Predictive biomarkers for response to immunotherapy in patients with deficient DNA mismatch repair metastatic colorectal cancer.
Authors: Stemmer Amos , Strauss Gal , Halpern Naama , Beller Tamar , Golan Talya , Margalit Ofer , Shacham-Shmueli Einat , Boursi Ben 
Published: January 2023

254 Background: Deficient DNA mismatch repair (MMRD) accounts for approximately 3% of metastatic colorectal cancers (mCRC). Treatment with Immune checkpoint inhibitors (ICI) in this patient population achieve an overall response rate (ORR) of up to 55%. However, to date there are no predictive biomarkers for response. Methods: A retrospective analysis of all MMRD mCRC patients that were treated with either Pembrolizumab, or Ipilimumab and Nivolumab in a large tertiary medical center between 2015-2022. The primary outcome was response to treatment and was assessed at first imaging following treatment initiation. Exposure variables included age, sex, ECOG performance status, metastatic sites (liver, peritoneum, lung, bone and brain) and CEA levels at treatment initiation. CEA below 5 mcg/l was treated as low and above as high CEA levels. Predictive biomarkers were assessed using cox hazard regression and Kaplan Meier analysis. Results: A total of 33 prospective MMRD mCRC patients were included in the study. Of them, 24 (72.7%) responded and 9 (27.3%) did not respond to immunotherapy. Median age was 70 (IQR 66-77) and 64 (IQR 51-75) for responders and non-responders respectively. Site of metastasis was an important predictor for response. Thirteen patients had liver metastasis, of them 6 (46%) responded (HR = 7.16; 95% CI = 1.47-35; p = 0.015). Five patients had single site metastasis in the liver, of them one (20%) responded (HR = 12.7; 95% CI = 2.99-53.8; p < 0.001). Fifteen patients had peritoneal metastasis, of them 13 (87%) responded to treatment (HR = 0.24; 95% CI = 0.05-1.19; p = 0.081). Median CEA at treatment initiation was 2 (IQR 1-4) in responders compared to 32 (IQR 1-70) for non-responders (HR = 5.27; 95% CI = 1.31-21.2; p = 0.019). There was no statistically significant difference between the groups in age, sex and ECOG performance status. Conclusions: Liver metastasis predict poor response to immunotherapy in MMRD mCRC patients while peritoneal metastasis and low CEA level predict response to immunotherapy.
Lack of hierarchical survival prognosis in AJCC staging for colon cancer: Implications for future summary stage classification.
Authors: Bhutiani Neal , Hu Chung-Yuan , Palis Bryan E. , Cotler Joseph , Shi Qian , Goldberg Richard M. , Washington Mary Kay , Nelson Heidi , Steele Scott , Chang George J. 
Published: January 2023

256 Background: Current staging for colon cancer utilizing the American Joint Committee on Cancer TNM framework stratifies disease into groups according to how advanced the disease is and provides important standardized, individual prognostic information. Ideally, staging systems should exhibit hierarchical logic, with increasing stage reflecting worse prognosis. We sought to evaluate hierarchy within the 8th edition AJCC staging system for colon cancer. Methods: All patients with primary colon (including rectosigmoid) cancer diagnosed 2010-2017 were identified from the National Cancer Database (NCDB). Patients were only included if they carried a histologic diagnosis of invasive primary (non-recurrent) cancer, underwent radical surgery, and had complete pathologic staging data (T, N, M category data). Patients with missing follow-up data were excluded. Kaplan-Meier curves were used to assess overall survival by AJCC 8th edition pathologic summary stage group to determine whether staging was hierarchical for colon cancer. Multivariable modeling and log likelihood ratio test was then used to identify relative contributions of T and N variables to overall survival. Results: Among 270,584 colon cancer patients, pathologic staging was noted to be hierarchical by T category alone and by N category alone. However, summary staging was non-hierarchical in both instances. Multivariable modeling confirmed the AJCC non-hierarchy issue (colon HRs: 1, 1.54, 2.62, 2.60, 1.02, 2.15, and 4.38 for stage 1 as reference, 2a, 2b, 2c, 3a, 3b, 3c respectively). Multivariable modeling demonstrated that high T category (T4a, T4b) conferred the greatest risk of mortality based on hazard ratio (T4a HR 2.76, T4b HR 3.04), while high T category as well as high N category (N2a, N2b) contributed substantially to the survival model based on z-score. Further modeling assessing the predictive power of T and N category with respect to overall survival demonstrated that T category more strongly predicted overall survival than N category in colon cancer (likelihood chi-square test statistic pT:7009 vs pN:3586). Conclusions: Hierarchy in survival based on AJCC summary stage was not observed for patients with stage II-III colon cancer resulting in a paradoxical better observed survival with some stage III cancer subgroups compared to stage II cancer subgroups. High T category appears to more significantly impact survival than N category for patients with N0-N1 disease, while high N category appears more important for patients with T1-3 disease. Future revisions of the AJCC staging system should account for the differential impact of T and N category identified herein to more accurately confer prognostic information.
HERIZON: A phase 2 study of HER-Vaxx (IMU-131), a HER2-targeting peptide vaccine, plus standard of care chemotherapy in patients with HER2-overexpressing metastatic or advanced gastric/GEJ adenocarcinoma— Overall survival analysis.
Authors: Maglakelidze Marina , Ryspayeva Dinara E. , Andric Zoran , Petrovic Zoran , Bulat Iurie , Nikolic Ivan , Nagarkar Rajnish , Wiedermann Ursula , Blumenstein Brent A. , Chong Leslie Mi Ok , Ede Nicholas , Nixon Bonnie , Yavrom Sharon , Selvaggi Giovanni , Good Anthony J. , Chawla Tanuj 
Published: January 2023

289 Background: Active immunization with the B-lymphocyte stimulating HER2 vaccine, HER-Vaxx (IMU-131), has shown clinical response correlated with HER2-specific antibodies (Wiedermann et. al., Clinical Cancer Research, 2021). The HER-Vaxx HERIZON study is based on the landmark ToGA study (Bang et. al., The Lancet, 2010) and included patients with HER2/neu over-expressing metastatic or advanced gastric/GEJ adenocarcinoma who were naïve to HER2 therapy. Methods: Thirty-six patients were randomized to either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint was overall survival (OS). HER-Vaxx plus chemotherapy treated patients received 50 µg dose of HER-Vaxx by intra-muscular injection at Days 0, 14, 35, 77 and every 63 days until disease progression. Both groups received chemotherapy starting at Day 0 and then every 21 days for a maximum of 6 cycles or until disease progression. Standard chemotherapy consisted of cisplatin + 5FU or capecitabine, or oxaliplatin + capecitabine. Statistical analysis pre-specified a 1-sided false positive probability of 0.10. Results: Of 36 patients randomized (19 treated with HER-Vaxx plus chemotherapy and 17 with chemotherapy alone), 32 patients had a survival event (15 and 17 respectively) at the time of final analysis. All patients received oxaliplatin + capecitabine chemotherapy. Analysis showed a 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy compared to chemotherapy alone. This translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927) with a statistically significant p-value of 0.066. The median OS for patients receiving HER-Vaxx plus chemotherapy was 13.9 (7.5, 14.3) months, compared to 8.3 (6.0, 9.6) months in patients treated with chemotherapy alone. Median duration of response was 30 vs 19 weeks in favor of the HER-Vaxx arm. There was no difference in safety between the two treatment arms, indicating HER-Vaxx does not add toxicity to standard chemotherapy. HER-Vaxx induced persistent HER2 specific antibodies which correlated with clinical response. Additional response parameters including DOR and biomarker data will be presented at the meeting. Conclusions: These data demonstrate that in patients with HER2 over-expressing gastric/GEJ cancer active HER2 immunization with HER-Vaxx is safe and provides relevant clinical benefit over standard of care chemotherapy. Clinical trial information: NCT02795988 .
Survival and clinical characteristics of patients with colorectal cancer and brain metastases.
Authors: Gordon Caroline , Cecchini Michael , Lacy Jill 
Published: January 2023

29 Background: Brain metastases (BM) are rare in colorectal cancer (CRC) with 1-3% of patients developing BM over their lifetime. There are no screening recommendations for BM in patients with CRC and most are diagnosed after a patient develops symptoms. Identifying the clinical characteristics for patients with CRC and BM may aid clinicians to consider BM early in symptom onset and potentially screen appropriate patients. Methods: We performed a retrospective chart review of patients >18 years diagnosed with CRC and BM at Yale New Haven Hospital from 1/2012-9/2021. Clinical characteristics were analyzed by descriptive statistics, time intervals were compared using the Mann-Whitney test, and survival analysis was done using the Kaplan-Meier method. Results: We identified 93 patients with CRC and BM. Median age at diagnosis was 56 years, 55% were male, 75% of patients had a left sided primary tumor and 47% were rectal primary. At initial diagnosis, 38% and 39% were stage III and IV respectively. RAS/RAF mutations were present in 45% of patients and all were mismatch repair proficient. The median time from CRC diagnosis to BM was 3.81 years (95% CI 3.09, 4.41) and median time from metastatic CRC to BM was 2.21 years (95% CI 1.48, 2.75). Median overall survival after developing BM was 0.49 years (95% CI 0.24, 0.70). Patients with RAS/RAF mutations had a decreased median time from CRC diagnosis to BM of 3.33 years (95% CI 2.69, 4.37) compared to RAS/RAF wildtype at 5.09 years (95% CI 4.44, 7.97) (p 0.0028). Median time to BM from CRC diagnosis was also decreased in females (p 0.01). The location of primary tumor did not significantly decrease time to BM. Prior to BM diagnosis, 76% of patients had lung metastasis. 84% of patients received treatment for BM while 14% had no BM treatment and 2% were unknown. For treatment 50% had Gamma Knife Radiosurgery, 22% underwent surgical excision +/- adjuvant radiation, and 12% underwent whole brain radiotherapy. After BM treatment, 43% of patients received additional chemotherapy. Conclusions: Although BM in CRC is uncommon, early diagnosis in those at risk is critical given the urgent nature of BM. Patients with CRC that develop BM frequently have tumors that originate in the left side of the colon and preexisting lung metastasis. In patients with CRC and BM, the majority develop BM > 3 years after initial CRC diagnosis, and BM onset is significantly shorter in females and patients with tumors harboring a RAS/RAF mutation. After BM diagnosis and treatment, less than half of patients are able to receive subsequent therapy, and median survival is < 6 months. [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648.
Authors: Kato Ken , Ajani Jaffer A. , Doki Yuichiro , Xu Jianming , Wyrwicz Lucjan , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez Freitas Melro , Holtved Eva , Blum Murphy Mariela A. , Patel Apurva , Hu Nan , Matsumura Yasuhiro , Chau Ian , Kitagawa Yuko 
Published: January 2023

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]