bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti PD-1 monoclonal antibody in patients with MSI-high and/or high tumor mutational burden for solid malignancies.
Authors: Guerra Veronica , Alwash Yasmin , Ocampo Marisol Lilian , Cusnir Mike 
Published: June 2022

e15539 Background: High microsatellite instability (MSI-H) tumors have been associated with good responses to check-point inhibitors (CPI). With overall response rates (ORR) ranging between 36-46% among colorectal cancer (CRC) and other solid malignancies. Data regarding predictors of response and responses in non-CRC malignancies remains limited. We sought to evaluate the response to PD-1/PDL-1 CPI in patients with MSI-H and/or high TMB solid malignancies. Methods: Retrospective analysis of 16 patients (pts) who received 18 CPI-based therapies between October 2017 and February 2022. MSI-H and TMB status was assessed by CARIS, Guardant360 or INVITAE genetic testing. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included progression-free survival(PFS); overall survival (OS), and duration of overall response (DOR). Results: A total of 16 pts were included. The median age of 72 years (range 53-83), 44% were male and 75% Hispanic. 44% of pts had RCR and 50% were previously treated, and 50% were stage IV at diagnosis. The most common mutations were BRCA2 31%, PIK3cA 31%, KRAS 25%, and GNAS 25%. The majority of pts received single-agent CPI therapy (72%). After a median follow-up of 52 months, 11 pts continued to receive therapy, 2 pts completed treatment. 3 pts died from progression of the disease. 1 pts switched from single-agent pembrolizumab to nivolumab-ipilimumab combination followed by nivolumab maintenance due to disease progression. 15 pts were evaluable for response with an ORR of 33%, including 33% among pts with CRC and 27% for non-CRC malignancies. (Table - Response rates) The OS was not reached (NR), with a PFS of 53 months (PFS of 64% at 1 year and 56% at 4 years). The median DOR was not reached (NR). The treatment was well tolerated and pts received a median of cycles was 19 (range 3-51) with no discontinuations due to toxicities. The molecular mutations, clinical characteristics, type of malignancy, MSI-H, or H-TMB status were not significantly associated with response to CPI after logistical regression analysis. Conclusions: CPIs are an effective treatment option for patients with MSI-H and/or High TMB, with an ORR of 33%. However, pts achieved durable responses, with a median DOR not reached. We identify a higher incidence of SD rates among CRC pts (67% vs. 18% non-CRC). We did not identify any predictors associated with response to CPI, likely due to the small number of pts. However, there was a tendency to highest response rates among pts with MSI-H and high TMB.[Table: see text]
A multiple centers real-world study of regorafenib treatment modalities in Chinese metastatic colorectal cancer patients.
Authors: Li Xia Fen , Luo Huiyan , Wang Zhiqiang , Xiao Jian , Peng Jianjun , Wang Zi-xian , Zhai Xiaohui , Xu Rui-hua 
Published: June 2022

e15543 Background: To evaluate the efficacy and safety of different treatment modalities of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) in the real-world setting. Methods: Individual patient data were retrieved from three leading oncology centers in China from January 2016 to March 2021. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The characteristics of patients who received treatment are shown in the table. Twenty-one patients received regorafenib combined with capecitabine as the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. The median PFS and median OS were 8 (95% CI 4.36 - 11.00) months and 26.9 (95%CI 20.54 -NR) months. 101 patients received regorafenib and 69 patients received regorafenib plus immune checkpoint inhibitor (ICIs) as third or higher line treatment, the overall response was 4.1%(7/170), including one complete response. Patients combined with ICIs have longer PFS than those with regorafenib monotherapy (median PFS = 3.3 versus 2.1 months; p = 0.01). Starting dose was 80、120 and 160 mg in 64、40 and 39 patients, respectively. Dose reduction was observed in 43.3% (39/79) of patients receiving 120 and 160 mg as the initial dose. Conclusions: Different treatment modalities of regorafenib all showed promising efficacy and safety in the treatment of mCRC. Regorafenib combination is better than regorafenib monotherapy. Regorafenib combined with capecitabine provided a new treatment strategy during the epidemic but requires further investigation. Key words:Colorectal cancer; Regorafenib; Immune check point inhibitors; Real world[Table: see text]
The efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer.
Authors: Li Rongrong , Liu Zhenyang , Yin Xianli , Zeng Deyu , Jiang Shaofeng , Liu Wu 
Published: June 2022

e15546 Background: To explore the efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer (mCRC). Methods: We retrospectively evaluated the outcomes of the patients with mCRC who received at least one cycle of sintilimab plus regorafenib in the Hunan Cancer Hospital between July 2019 and June 2021. These patients had previously received at least two lines of standard chemotherapy including fluorouracil, oxaliplatin, and irinotecan with or without targeted drugs such as bevacizumab and cetuximab.The primary end point was overall survival (OS). Results: With a median follow-up of 6.00 months (range 0.70-22.47), the median overall survival (mOS) and progression-free survival (mPFS) were 9.00 months (95%CI: 5.00-NA) and 3.30 months (95%CI: 2.50-4.70).There was no significant difference in OS and PFS between patients with and without liver metastases,the mOS was 9.00 months 95%CI:[8.00-NA] vs 8.00months 95%CI:[5.00-NA]; P= 0.38, the mPFS was 3.87 months 95%CI:[3.10-13.70] vs 2.79 months 95%CI:[2.37-5.03]; P= 0.12.Cox multivariate regression analysis demonstrated that cycles of regorafenib plus PD-1 was a significant independent risk factor for the OS ( P0.001),and it was a positive factor that there was just one metastatic site ( P= 0.0038).Patients who had previously undergone surgery were better than those who had not ( P= 0.0470).Seven patients got partial response and another 9 patients got stable disease in the 35 patients who were evaluated, but no complete response. Thus the objective response rate(ORR) was 20.0% and the disease control rate(DCR) was 45.7%.The incidence of grade 3/4 adverse evevts was 10.6%. Conclusions: The combination of sintilimab plus regorafenib had a manageable safety profile and promising efficacy in refractory mCRC patients. This combined therapy needs further prospective studies to verify the outcomes.[Table: see text]
Intratumor heterogeneity of positive lymph nodes provide a promising prognostic stratification factor for stage III colorectal cancer.
Authors: Gao Xin , Zhang Qi , Yu Tao , Zhang Shiyao , Liu Jian , Liu Tong , Liu Gang 
Published: June 2022

e15554 Background: Stage III colorectal cancer (CRC) is defined as patients with regional positive lymph nodes (pLN) but without distant metastasis, including stage IIIA, IIIB, IIIC. The prognosis of patients with stage III CRC varies dramatically, with 5-year survival rates ranging from 80 percent to 30 percent form stage IIIA to IIIC CRC, that does not exactly to be fully explained by the difference in the number of pLN. Therefore, other prognostic indicators need to be identified to improve and personalize prognosis prediction for patients with stage III CRC. Intratumor heterogeneity (ITH) widely exists between primary and metastatic lesions of CRC, however, there have been few studies focused on ITH of pLN. Therefore, this study aims to explore whether ITH of pLN could serve as a novel prognostic stratification factor for stage III CRC. Methods: We retrospectively analyzed the Poly-G genotype to reconstruct high-confidence phylogenetic trees for 20 CRC patients using 317 accurately scraped biopsy (134 primary tumors, 66 lymph node metastases and 37 normal samples). Root diversity score (RDS) index was used to reflect ITH of pLN. The association among Poly-G mutation rates, RDS index and clinical pathological data was analyzed. The area under the receiver operating characteristic (ROC) curves were calculated and the cut-off valve was confirmed. Results: Poly-G mutations accumulate in the occurrence and development of CRC. Poly-G mutation rate was correlated with tumor grade, N stage and microsatellite state (all P < 0.05), and had a certain correlation trend with age (P = 0.066). The results of multivariate Cox regression analysis showed that ITH of pLN was an independent risk factor for recurrence and metastasis which lead to a poor progression free survival (PFS). The area under the curve (AUC) was 76%, and the cut-off valve of RDS index was 0.25. We also found ITH of pLN was not associated with substages of stage III CRC, which indicated that ITH of pLN and the number of metastases are two different dimensions. Conclusions: ITH of pLN may provide a promising prognostic stratification factor for the patients with stage III CRC. A higher ITH of pLN indicates that subclones with distant metastasis potential might more likely to exist in the primary tumors, which lead to a poor PFS including recurrence and distant metastasis. In addition, ITH of pLN is not related to the number of lymph node metastases in stage III CRC, suggesting that ITH of pLN is promising to serve as a supplementary strategy of TNM staging for patients with Stage III CRC.
The effect of tumor purity on next generation sequencing of colorectal cancer.
Authors: Yu Tao , Zhao Xinyu , Guo Xianchao , Zhang Qi , Zhang Shiyao , Zhao Zhicheng , Liu Tong , Liu Gang 
Published: June 2022

e15557 Background: Considerable advancements have been made in tumorigenesis, therapeutic target and diagnostic markers of colorectal cancer by next generation sequencing (NGS). However, almost tumor tissues contain the non-cancerous components, such as inflammatory cells and stromal cells. The DNA from these cells may cause the fraction of reads containing somatic mutations from tumor cell decreases. Therefore, it’s necessary to systematically clarify the relationship between tumor purity and NGS in colorectal cancer. Methods: Formalin fixed and paraffin embedded (FFPE) blocks were collected and cut into 20-40 8 um-thick sections used for genomic DNA extraction. Sections were evenly divided into two groups, purity group and non-purity group. In purity group, the sections were stained with Histogene (Life Technologies), a PCR-compatible tissue stain. And the tumor samples were accurately collected on the section under the microscope. No special treatment before sequencing in non-purity group. Next-generation sequencing (NGS) based on a 425-gene panel was performed in tumor samples and matched plasma samples. Results: 30 samples were included in this study. 687 non-synonymous mutations were found in purity group, 271 mutations were found in non-purity group, including 247 common mutations in both group, 440 purity-specific mutations (false negative mutations), and 24 non-purity-specific mutations (false positive mutations). The Variant allele fraction (VAF) of common mutations in purity group was significantly higher than that in non-purity group (Wilcoxon test: P< 0.05). The number of mutations in purity group was higher than that in non-purity group, but no significant difference between them (10.5[3, 154] vs 9[3-90], Wilcoxon test: P> 0.05). The false positive ratio (the number of false negative mutations/the number of common mutations) was negatively correlated with tumor purity (Spearman rank correlation test: r = 0.4280, P = 0.02596). When the tumor purity below 30%, 86% false negative mutations belong to high-frequency mutation (VAF > 10%) in purity group. Only 8% false negative mutations belong to high-frequency mutation when purity above 30%. The false positive ratio (the number of false positive mutations/the number of common mutations) wasn’t correlated with tumor purity (Spearman rank correlation test: r = 0.1387, P= 0.4648). Conclusions: Tumor purity is an importance role in precise NGS of colorectal cancer. Higher tumor purity can ensure the integrity of NGS.
Neutropenia as a predictor of efficacy in the treatment of metastatic colorectal cancer with TAS-102 (trifluridine - tipiracil).
Authors: Rodriguez Garcés Maria Yeray , Domínguez Senín Loreto , Amor Urbano María , Aviñó Tarazona Victoria 
Published: June 2022

e15564 Background: TAS-102 (trifluridine - tipiracil) increases the survival of patients with metastatic colorectal cancer (mCRC) in 3rd or successive lines based on the results in overall survival (OS) of the phase 2 trial by Yoshino T et al and of the subsequent phase 3 RESOURCE and TERRA. It has a good toxicity profile, mainly at the gastrointestinal and hematological levels. Different publications relate neutropenia secondary to this drug with greater clinical benefit. Methods: Retrospective and multicenter observational study with patients diagnosed with mCRC treated with TAS-102 in the Juan Ramón Jiménez and General de Río Tinto hospitals (Huelva) between January 2016 and September 2021. We describe demographic data and other variables; subsequent Cox regression and multivariate analysis between OS and the different variables. We represent the OS median using Kaplan-Meier curves. Results: 47 patients were included. Median age 66 years; 66% men. No patient with ECOG > 2. Primary colon tumor in 55.4%; 72.3% with various metastatic locations. KRAS mutation in 63.8%. 78.8% in third line and the rest in fourth or successive. 80.9% have died. 82.9% abandoned due to progression and 8.5% due to toxicity: anemia 76.6% (grade ≥3 4.3%), neutropenia 74.5% (grade ≥3 44.7%), thrombocytopenia 10, 6% (grade ≥3 2.1%) and gastrointestinal 44.7% (grade ≥3 6.4%). The Kapplan Meier shows significant differences between the neutropenia curves 0 and grade 3-4 (median: 8 (95% CI 5.91-10.08) vs. 19 (95% CI 16.55-21.44) months; p = 0.043) and between the curves for grade 1-2 and grade 3-4 neutropenia (median: 8 (95% CI 2.9-13.09) vs. 19 (95% CI 16.55-21.44) months; p = 0.019). Cox regression identified grade 3-4 neutropenia and grade 1-2 anemia as positive predictors of OS. Multivariate analysis describes similar results (Table). Conclusions: Japanese series (Yohei Nose, et al; Katsuya Makihara, et al and T. Yoshino, et al) suggest a benefit in OS directly proportional to the degree of neutropenia found. In our study we obtain similar results, with better OS results for patients with grade 3-4 neutropenia. Therefore, we consider severe neutropenia as a possible predictor of the efficacy of TAS-102. Although our series is one of the largest published to date, we need more studies with a larger sample to obtain robust and enlightening results.[Table: see text]
Plasma methylated DNA markers detect recurrence and response to therapy in colorectal cancer.
Authors: Zhu Mojun , Taylor William R. , Mahoney Douglas W. , Then Sara S. , Berger Calise K. , Burger Kelli , Gonser Anna M. , Doering Karen A. , Foote Patrick H. , Kaiser Michael W. , Allawi Hatim T. , Hubbard Joleen M. , Kisiel John B. 
Published: June 2022

e15567 Background: Radiographic surveillance of colorectal cancer (CRC) after therapy is costly and insensitive. We have reported high cross-sectional performance of methylated DNA markers (MDMs) for detection of primary CRC and metastatic recurrence. This study evaluated MDMs to detect recurrence and measure response to anti-cancer therapy in a longitudinal cohort. Methods: This was a nested case-control study drawn from a prospective cohort of adult patients with CRC who completed definitive treatment and followed forward from the start of surveillance by cross-sectional imaging (CT or MRI) and carcinoembryonic antigen (CEA), collected every 3-6 months under routine care. Blood was collected in LBgard® tubes (Biomatrica, San Diego CA). Cases had recurrent CRC (defined by RECIST v1.1 or radiographic findings that justify re-initiation of anti-cancer therapy as determined by treating clinicians). Controls remained NED (no radiographic recurrence and off therapy for ≥4 surveillance visits). From 6mL of plasma, MDMs ( CNNM1, ANKRD13B, FER1L4, ZNF568, CHST2, ZNF671, VAV3, QKI, GRIN2D, DTX1, PDGFD, SFMBT2, JAM3) were measured by target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Previously published random forest models of MDMs +/- CEA, developed on independent patients with intact primary tumors, were used to develop a summary score. Results: With a median follow-up of 276 days (IQR 187-343) and 3 visits per patient (54 visits total), 18 patients had recurrence after start of surveillance. Another 18 patients remained NED after median 555 days (IRQ 469-662) and 4 surveillance visits per patient (76 visits total). Using a 90th %-ile cut-off summary score from 60 NED patients in a prior cross-sectional measurement, the MDM panel was positive in 15 of 18 patients who recurred and only 2 of the 18 NED patients (Table). Of the 76 patient visits for NED patients, 67 (88%) were below the threshold. The MDM panel score crossed the positivity threshold by a median of 127 days (IRQ 0-233) preceding clinical or radiographic documentation of recurrence. A random forest model with CEA was more sensitive but less specific (Table). In patients who resumed therapy, the MDM panel scores correlated closely with subsequent RECIST scores (not shown). Conclusions: Plasma MDMs rise in anticipation of recurrent CRC prior to radiographic detection and remain low in patients without radiographic disease over serial measurements, warranting further development of this tumor-agnostic liquid biopsy approach as a cost-effective tool to assist cancer surveillance.[Table: see text]
Prognostic values of immune landscape in Ras-mutant colorectal cancer peritoneal metastases.
Authors: Yan Dong , Sun Lixin , Yang Jiandong , Zhang Xuyang , You Xia , Sun Tingting , Qi Chuang 
Published: June 2022

e15583 Background: The peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor survival, especially in those with Ras mutations. However, knowledge on the mechanism of molecular biology in CRC peritoneal metastasis (CRCPM) is limited, and the impact of tumor immune microenvironment (TME) on PM pathogenesis and the prognosis of CRCPM remain unclear. Therefore, we characterized the TME of CRCPM and evaluated its potential diagnostic and prognostic values. Methods: This study involved 21 patients with metastatic CRC (mCRC), of whom 11 with CRCPM were classified into the experimental group and 10 with mCRC without PM (noCRCPM) were classified into the control group. Formalin-fixed and paraffin-embedded tissue of primary tumors from all patients was examined using the NanoString RNA sequencing system. The clinicopathological variables and TME biomarkers were compared using the chi-square test and Cox regression analysis. According to the results of multivariate analysis, a prognostic nomogram was generated, and its prediction ability was measured using the concordance index (C-index). Survival curves were generated using the Kaplan–Meier method, and survival comparison between groups was conducted using the log-rank test. Results: The TME in the CRCPM and noCRCPM groups was different, especially the expression of NOS2, TNSF9, KIR3DL2, MAGEA12, MRC1, KIR3DL1, and CD244 and the content of DC cells, macrophages, exhausted CD8+T cells, NK CD56dim cells, and M2 macrophages. Univariate analysis revealed that the expression of PTPN11, TIE1, MAGEA4, PDGFB, and PMS2 was significantly correlated with progression-free survival (PFS) time. These genes were subjected to the least absolute shrinkage and selection operator regression analysis and established a risk score model. Multiple Cox regression analysis showed that the risk score was a significant independent prognostic factor. However, considering the particularity of serum carcinoembryonic antigen (CEA), we built a combined model that included the CEA level and risk score. It could perform well in predicting the PFS time in patients with CRCPM (C-index 0.77). Conclusions: The TME of the primary lesion was significantly different between the CRCPM and noCRCPM groups. The model that combined the risk score and CEA level was a better outcome predictor among patients with CRCPM.
Analysis of demographic and staging characteristics in patients with colorectal cancer using the SEER registry.
Authors: Devanaboyina Monika , Bailey Morgan Marie , Kahlon Navkirat , Hamouda Danae M. 
Published: June 2022

e15589 Background: Screening for colorectal cancer (CRC) has traditionally begun at age 50, with more recent guidelines suggesting beginning at age 45 to enhance earlier detection. Methods: Incidence data of CRC from the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 21 registry was utilized for this study. This study analyzed data from 2014-2018 with 95% confidence intervals for ages 50-64, 64-74, and 75+. Localized, regional and distant metastasis were coded according to the SEER database. Results: The incidence of CRC increased with age as individuals ages 75+ had the highest incidence at 211.8 per 100,000, compared to 70.7 for ages 50-64. In the age group of 75+, the incidence of localized CRC was 70.1 (95% CI: 69.2-71.0) and regional CRC was 69.2 (68.4-70.1) which was not statistically significant. Upon analyzing sex in CRC, female patients have a statistically lower chance of presenting with CRC at 59.5, 107.6, 192.1 for the age groups 50-64, 65-74, and 75+ respectively, whereas male counterparts have rates of 82.7, 152.9, and 240.2. Analysis of Asian females showed no difference in incidence of local and regional disease for ages 50-74. For ages 75+, the incidence of regional disease at 54.6 (51.3-58.1) was much higher than local disease at 45.3 (42.3- 48.5). Of note, Asian females aged 50-64, Hispanic females ages 65 and older, and Black and White females ages 75+ were equally likely to present with local or regional disease. White males had statistically significant higher odds of localized compared to regional cancer in all age groups. Further analysis shows that Asian males have an equal incidence of local and regional disease for ages 65 and above. Black males ages 75+ and Hispanic males ages 50+ had a similar incidence of local and regional CRC. Conclusions: Ensuring equitable access to screening and earlier screening may be beneficial and improve cancer-related mortality in certain demographics. A more modern data set should be analyzed to support these findings. This analysis was limited to incidence of CRC, and future studies assessing presentation at diagnosis could be insightful.[Table: see text]