bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of an individualized immune prognostic signature in colorectal cancer.
Authors: Liu Yang , Zhang Liwen , You Dong 
Published: June 2022

e15531 Background: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850,000 deaths annually. Although the outcome of CRC patients has improved significantly with the recent implementation of annual screening programs, reliable prognostic biomarkers are still needed due to the disease heterogeneity. Accumulating evidence revealed an association between immune signature and CRC prognosis. Therefore, we aim to build a robust immune-related gene pairs (IRGPs) signature that can evaluate the prognosis for CRC patients. Methods: Gene expression profiles and complete clinical information of CRC patients were collected from seven public cohorts, divided into the training cohort (TCGA cohort, N = 460) and six independent validation cohorts (GSE17536, GSE39582, GSE30378, GSE41258, GSE71187 and GSE87211, N = 1,151). Gene expression level in a specific sample or profile underwent pairwise comparison to generate a score for each IRGP. An IRGP score of 1 was assigned if IRG 1 was less than IRG 2; otherwise, the IRGP score was 0. Prognostic IRGPs were selected using log-rank test and LASSO Cox proportional hazards regression model. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were used to examine model predictive performance in the validation cohort. Results: Within 942 immune-related genes that were expressed in all the cohorts, a prognostic immune signature of 80 gene pairs consisting of 101 unique genes was constructed which was significantly associated with patients overall survival in the training dataset (HR, 4.53 [2.89-7.09]; P < 0.0001). In the validation cohorts, the IRGPs signature significantly stratified patients into high-risk and low-risk groups in terms of prognosis and was prognostic in multivariate analyses (HR, 3.08 [2.03-4.65]; P < 0.0001). Biological processes that were dramatically involved in cancer immunology, such as cell chemotaxis and leukocyte migration, were enriched among genes in the IRGPs signature. To further improve accuracy, we combined tumor stage and IRGPs score to fit a Cox proportional hazards regression model using the training dataset and derived an immune-clinical prognostic index (ICPI) as (0.53633 × stage) + (1.31369 × IRGPs score). Significantly improved estimation of survival was achieved by ICPI relative to IRGPs score (mean C-index, 0.81 vs 0.79; P = 0 .014). Conclusions: We developed a robust IRGPs signature for estimating prognosis in CRC patients, providing new insights into the identification of CRC patients with a high risk of mortality. Prospective studies are needed to further validate its analytical accuracy and to test its clinical utility in individualized management of CRC patients.
Cytokine profile in peripheral blood of patients with metastatic colorectal cancer with different responses to chemotherapy in combination with anti-VEGF agents.
Authors: Vladimirova Liubov Yu , Sagakyants Aleksandr B. , Tishina Anna V. , Shulgina Oksana G. , Storozhakova Anna E. , Zolotareva Ekaterina I. , Novikova Inna A. , Kalabanova Elena A. , Kabanov Sergey N. , Samaneva Natalia Yu. , Teplyakova Maria A. , Tikhanovskaya Natalia M. , Abramova Natalia A. , Udalenkova Irina A. , Ryadinskaya Ludmila A. , Popova Irina L. , Sergeeva Marina M. , Kit Oleg I. , Dzhenkova Elena A. , Kolesnikov Evgeniy N. 
Published: June 2022

e15545 Background: For many years, colorectal cancer has been among the most frequently diagnosed cancers and one of the leading causes of cancer death. The effect of monoclonal antibodies on the immunological status remains relevant, since chemotherapy in combination with monoclonal antibodies (anti-EGFR, anti-VEGF) plays a key role in the treatment of patients with metastatic colorectal cancer. The purpose of this study was to reveal specific features of the cytokine profile of patients with metastatic colorectal cancer (mCRC) receiving bevacizumab in combination with chemotherapy before and after the treatment. Methods: The study included 15 patients with newly diagnosed mCRC receiving mFOLFOX6 chemotherapy combined with bevacizumab as the first-line treatment. Cytokine levels were determined in the blood serum (BS) by multiplex assay with the Bio-Plex Pro Human Immunotherapy 20-Plex Panel (GM-CSF, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL-15, IL-17A, IL-18, IP-10, MCP-1, MIG, MIP-1α, MIP-1β, RANTES, TNF-α) (Bio-Rad, USA) before and after 4 cycles of the therapy. Results were evaluated using the Luminex 200 Analyzer (Bio-Rad, USA) with the Bio-Plex Manager Software. Results: Complete response to the therapy was registered in 5 (33.3%) patients, partial remission in 8 (53.3%) patients, progression in 13.3%. IL-6, IP-10, MIG, RANTES, and TNF-a were statistically significantly (p < 0.05) elevated in patients with complete response. IL-8 showed a tendency to decreasing after the therapy. Levels of IL-6, IL-8, IL-15, IL-17, and MIP-1a in patients with partial remission after the therapy reduced to zero values. An analysis of the cytokine profiles in patients with progression demonstrated a decrease of all the studied indices, except for elevated IL-15 and IL-17. Conclusions: Anti-VEGF agents together with chemotherapy changed the cytokine profiles in patients with mCRC. Probable mechanism may include the implementation of the antitumor response through the activation of some pro-inflammatory cytokines, since the complete response was accompanied by an increase in IL-6, IP-10, MIG, RANTES, TNF-a and a decrease in IL8.
Metastasis model of tumor deposit in colorectal cancer based on phylogenetic tree.
Authors: Zhang Qi , Yu Tao , Zhang Shiyao , Zhao Zhicheng , Liu Jian , Liu Tong , Liu Gang 
Published: June 2022

e15549 Background: Colorectal cancer(CRC) is often accompanied by tumor deposit(TD) metastasis, and TD status was only adressed in N1c staging in the TNM staging for CRC. However, TD states are very complex and diverse, including quantity, morphology, and biological behavior. The correlation between TD and clinical prognosis is far more complicated and needs to be discussed in more dimensions. At present, there are no reports of TD research from the genetic perspective. In this study, the phylogenetic tree approach was used to explore the metastasis pattern of TD, which might lay a foundation for better understanding its clinical significance. Methods: Poly-G was used to sequence multiple sections (n = 427) of normal tissue, primary tumor, TD, positive lymph node, and distant metastasis from 25 patients. Then, using the poly-G genotype to calculated the genetic distance between tumor and normal tissue and built the phylogenetic tree. We use root diversity score (RDS) index to reflect the intratumor heterogeneity of TDs. The evolutionary connection and clone origin between TD and paired samples was evaluated using a phylogenetic tree and RDS index. Results: A total of 427 samples from 25 patients were included, including 171 primary tumor (40.0%), 94 positive lymph nodes (22.0%), 110 tumor deposits (25.8%), 28 liver metastases (6.6%), 4 lung metastases (0.9%), and 20 peritoneal metastases (4.7%). There were 43 (39.1%) TDs with envelope and 67 (60.9%) TDs with irregular morphology, according to pathological morphology. A phylogenetic tree based on migration patterns and clonal origins was used to highlight the differences between envelope-TDs and irregular-TDs. The genetic distance between envelope-TDs and positive lymph nodes appeared to be less, and they were more likely to derive from the same source, but the genetic distance between irregular-TDs and positive lymph nodes was larger (P < 0.05). Envelope-TDs had a sequential metastatic model that was consistent with positive lymph nodes. Unlike envelope-TDs, irregular-TDs tend to show more complex biological characteristics, such as nerve and vascular invasion, resulting in a more convoluted evolutionary relationship in the phylogenetic tree. Conclusions: Our findings provide genetic evidence for TD metastatic model, which has to be supported in future studies to ameliorate CRC TNM staging.
Chromosome 20q and 13q gain in metastatic colorectal cancer: Prognostic significance and genomic correlates.
Authors: Maharaj Satish , Sharaf Radwa , Redman Rebecca A. , Rojan Adam 
Published: June 2022

e15553 Background: Chromosome 13q and 20q gain are major molecular events in adenoma-carcinoma progression and metastasis. The prognostic significance and correlates of 13q and 20q gain in metastatic colorectal cancer (CRC) have not been established. Methods: A total of 108 cases were selected at the University of Louisville. We ran a custom research-use only algorithm to assess whole arm chr13q and chr20q gain from next generation sequencing data of CRC samples. The algorithm utilized the coverage data of baited regions of the genome to model the copy number of each segment. A gain call was made if > 50% of the chromosome arm was gained. Tumors were noted as left-sided colon, right-sided colon, or rectal cancers. Data on demographics, treatment and Kaplan-Meier survival were analyzed. Results: The prevalence of 13q gain was 58% and 20q gain was detected in 61% of cases. Concurrent 13q and 20q gains were frequent, with 49% prevalence. The only 2 MSI-High samples were negative for 13q or 20q gain. Tumors with 13q and 20q gain were significantly more likely to have mutations in TP53 and APC (Table). Rectal tumors were significantly enriched for 13q gain ( p= 0.020) and 20q gain ( p= 0.007). Examining survival by tumor location, 13q gain conferred significantly worse outcome for rectal cancers ( p= 0.007), as did 20q gain ( p= 0.037). Conclusions: With median follow up of over 3 years, 13q and 20q gains were significantly associated with worse prognosis in rectal cancers. The data indicate that 13q/20q gain and associated molecular signature are important prognostic markers in CRC.[Table: see text]
The response of PD-1 inhibitor combined with Radiotherapy and GM-CSF(PRaG) with or without IL-2 in microsatellite stable metastatic colorectal cancer: Analysis of pooled data from two phase II trials.
Authors: Yang Jiabao , Zhou Wei , Ma Yifu , Su Di , Kong Yuehong , Xu Meiling , Xing Pengfei , Zhang Liyuan 
Published: June 2022

e15561 Background: Immunotherapy has improved outcomes for metastatic colorectal cancer(mCRC) patients with MSI-H/dMMR but has not been effective in MSS/pMMR tumors, which comprise 95% of mCRC. In metastatic cancers, radiotherapy can be used as a local therapy and a sensitizer to PD-1/PD-L1 inhibitors. The synergistic effects of radiotherapy and PD-1/PD-L1 inhibitors can be reinforced by adding cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2(IL-2). Our previous PRaG trial demonstrated that PD-1 inhibitors in combination with radiotherapy and GM-CSF could improve clinical response in patients with advanced refractory solid tumors. We found that mCRC patients with MSS/pMMR could also benefit from the PRaG regimen. Methods: Patients of mCRC with MSS/pMMR were collected from the PRaG trial and PRaG 2.0 trial. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 14 days(d1-14), or GM-CSF 200μg (d1-7), and then sequentially followed by IL-2 200 million IU SC once daily for 7 days(d8-14). PRaG regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose. Pooled analysis of response rate (ORR), median progression-free survival (PFS), and treatment-related adverse eventswere calculated. Results: With the cutoff date of 31 December 2021, a total of 9 mCRC patients with MSS/pMMR were enrolled. All of the patients completed at least 2 cycles of PRaG therapy and one evaluation. The median follow-up was 7.6 months (95%CI, 3.8, 11.4). The ORR was 22.2%, and the disease control rate(DCR) was 66.7%. The median PFS was 5.6 months (95%CI, 1.5 to 9.7). One patient got complete remission, with PFS over 17months. Treatment-related adverse events (TRAE) occurred in 7 of 9 (77.8%) patients. One patient (11.1%) occurred Grade3 TRAE of renal insufficiency. Conclusions: Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity.
Patterns of care and survival of first line anti-EGFR therapy; results from South Australian (SA) metastatic colorectal (mCRC) registry.
Authors: Price Timothy Jay , Piantadosi Cynthia , Karapetis Christos Stelios , Roy Amitesh Chandra , Padbury Robert , Roder David , Geerinckx Barbara , Townsend Amanda Rose 
Published: June 2022

e15577 Background: Treatment of mCRC has changed dramatically over the last decade with therapy guided by clinical and molecular features which include side of primary, RAS, BRAF and MMR status. For left sided RAS WT mCRC survival is optimized by using first line anti-EGFR anti-bodies combined with chemotherapy. This is reflected in modern guidelines. Methods: We aim to assess the uptake of first line anti-EGFR/chemotherapy combinations in patients with mCRC and assess for difference between cetuximab (C) and panitumumab (P) use from the SAmCRCR. The real word registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2/2006. We compared RAS WT patients treated with chemo/bevacizumab (CB). Survival was analysed using the Kaplan Meier method. Results: Of the 5537 patients currently entered onto the registry, only 97 had RAS status recorded and had received first line anti-EGFR/chemotherapy (FaEC). 102 patients were RAS WT and received CB. Table summarises patient characteristics and median OS for FaEC (C or P) and CB. There was no statistical difference in survival for C v P (p = 0.055). Conclusions: When comparing C & P choice in first line therapy, C was more often combined with irinotecan/chemo. C patients had higher rate of left sided primary. There were lower rates of liver resection in patients treated with C which may explain the numerically lower median overall survival. An updated cohort analysis will be included to assess changes in practice over time.[Table: see text]
Clinical characteristics, outcomes and survival of patients with metastatic colorectal cancer on phase I trials: A single center experience from 1999 to 2022.
Authors: Hammami M Bakri , Ghalib Mohammad Haroon , Maitra Radhashree , Acuna-Villaorduna Ana , Goel Sanjay 
Published: June 2022

e15593 Background: Metastatic colorectal cancer (mCRC) is a leading cause of cancer mortality. Few treatment options exist for patients who fail to respond to standard therapeutic agents. For patients with good performance status, phase I studies offer a valuable treatment option with a chance of clinical benefit. In this study, we report clinical characteristics, outcomes and survival of patients enrolled in phase I clinical trials at our institution. Methods: Medical records of patients with mCRC enrolled in phase I clinical trials between January 1999 to January 2022 at our institution were reviewed. Patient demographics, clinical characteristics, laboratory values, toxicities and survival time were analyzed. Overall survival (OS) was calculated as date of diagnosis of metastatic disease to death or last follow up. Phase 1 specific OS was analyzed from date of entry to first phase I trial to death. Results: 212 enrollments corresponding to 174 unique patients enrolled in 50 phase 1 clinical trials were reviewed. 53% (n = 112) were females with a median age of 60 years old [range 29-83]. 95% (n = 201) had an ECOG score of 0-1. The clinical benefit rate (stable disease plus partial response) was 35% and ORR was 4.3%. The median OS was 149 weeks, and the phase I OS was 23 weeks. Majority of the patients (53%, n = 110) received 3 or more lines of chemotherapy prior to phase I trial. In a univariable (UVA) model, the factors associated with better clinical outcome were WBC < 10.8 (P < 0.001), Hb > 12 (p = 0.011), ECOG score 0 or 1 (p = 0.005), baseline AST < 50 (p = 0.006), baseline albumin > 3.5 (p < 0.001), baseline LDH < 305 (p < 0.001). Conclusions: Phase I trials offer a reasonable option for patients with metastatic CRC. Our experience sheds light on the potential for improved outcomes in terms of survival. The survival of patients is at par with those used in late-stage disease including regorafenib and trifluridine/tipiracil. As expected, normal baseline lab parameters and better PS affect survival. Further modeling will be continued.
Short-course radiotherapy combined with CAPOX and toripalimab for the total neoadjuvant therapy of locally advanced rectal cancer: Preliminary findings from a randomized, prospective, multicenter, double-arm, phase II trial (TORCH).
Authors: Wang Yaqi , Xia Fan , Shen Lijun , Wan Juefeng , Zhang Hui , Wu Ruiyan , Wang Jingwen , Wang Yan , Xu Ye , Cai Sanjun , Zhang Zhen 
Published: June 2022

e15602 Background: For patients with locally advanced rectal cancer (LARC), the standard treatment is neoadjuvant chemoradiotherapy combined with curative surgery. Total neoadjuvant therapy (TNT) has been used to increase rates of complete response and organ preservation, and achieve early control of distant metastasis. Recently, hypofractionated radiotherapy shows better synergistic effects in combination with PD-1/PD-L1 antibodies than conventional fractionated radiotherapy, as well as less impact on peripheral lymphocytes and more abscopal effects. Thus, the combination of immunotherapy and short-course radiotherapy (SCRT) based TNT is likely to further improve both tumor response and prognosis for LARC patients. Methods: TORCH is a randomized, prospective, multicentre, double-arm, phase II trial. 130 LARC (T3-4/N+M0, distance from anus ≤10cm) patients will be treated with TNT approach and assigned to the consolidation arm (A) and induction arm (B). Arm A will receive SCRT (25Gy/5Fx), followed by 6 cycles of Toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Arm B will first receive 2 cycles of ToriCAPOX, then receive SCRT, followed by 4 cycles of ToriCAPOX. Both groups will receive curative surgery or W&W strategy. The primary endpoint is the rate of complete response (CR, pCR plus cCR). The secondary endpoints include the grade 3-4 acute adverse effects (AE) rate, 3-year DFS rate, 3-year OS rate, etc. The “pick the winner” method is used to investigate the better regimen. Results: Up to Jan 20th 2022, 67 patients have been recruited in the trial (arm A: 35; arm B: 32). A total of 11 patients (all MSS) have completed all neoadjuvant therapy. Most of them showed high risk factors of recurrence, including lower location (≤5cm, 10/11), deeper primary lesion invasion (cT4/MRF+, 6/11) and more positive lymph nodes (cN2, 6/11). Finally, 2 patients (both arm B) achieved cCR and received W&W strategy. 9 patients received surgery and the pathological results showed 7 cases of pCR (arm A:3; arm B: 4), one near-pCR (arm A) and one non-pCR (arm A). Thus, the CR rate was amazingly high (CR rate: 81.8%, 9/11; pCR rate: 77.8%, 7/9). Even 5 patients who were evaluated as ycT3/N+/MRF+/EMVI+ before surgery was still demonstrated to be pCR after strict pathological examination. The only grade 3 AE was thrombocytopenia (4/11). And no grade 4 AE was observed. Conclusions: SCRT base TNT approach combined with Toripalimab have achieved surprisingly excellent CR rate and good tolerance in LARC patients (in our cohort), which has great clinical value in improving organ preservation. In the future, this ongoing trial will demonstrate this efficacy and compare the two arms by larger sample size. Clinical trial information: NCT04518280.
PD-1 blockade boosted chemo-target therapy in cT4NxM0 pMMR/MSS colorectal cancer.
Authors: Huang Jun , Pei Fengyun , He Wan , Duan Yinghua , Shi Tianhao , Zhao Yandong , Hu Huabin , Liu Shuai , Chen Haiyang , He Fang , Liu Tingzhi , Chen Jiaoting , Zheng Yijia , Meng Xiaochun , Li Heping , Guo Xiaofang , Chen Yaoxu , Huang Mengli , Wang Jianping , Huang Meijin 
Published: June 2022

e15606 Background: Immune checkpoint inhibitors (anti-PD-1 antibodies) have been testified good response in DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancers (CRC), while DNA mismatch repair-proficient/microsatellite stable(pMMR/MSS) CRCs, accounting for 85% of all CRCs, display poor response. Effective combined therapies for pMMR/MSS are needed for patients with local advanced colorectal cancers. Methods: In this pilot study, we administered 6 preoperative doses of anti-PD-1 antibody Sintilimab and Oxaliplatin and 5-FU/CF (mFOLFOX6) combined with Bevacizumab (only 5 doses in order not to delay surgery) in patients with cT4NxM0 colon or upper rectal cancers. Sintilimab (at a fixed dose of 200mg) was administered intravenously every 2 weeks, with surgery planned approximately 12 weeks after the first dose. The primary end point was pathological complete response(pCR). We also evaluated the major pathological response, radiological and pathological regression, safety, tumor mutation burden and tumor microenvironment (TME) molecules. Results: As of data cutoff (Dec 31,2021), median follow-up was 4.5 months (IQR 1.5-9.4). All patients underwent R0 surgical resection without treatment-related surgical delays. Of the 18 tumors that were removed, 18 were completely resected. A pCR occurred in 10 of 18 resected tumors (56%) and a major pathological response (MPR, ≤10% residual viable tumor) in 14/18(78%). At data cutoff, 18 were alive and 17 were free of recurrence. Treatment-related adverse events of grade 3 or higher occurred in 10% of the patients. Among the pCR tumors, two were found to harbored POLE mutation. The degree of pathological regression was deeper than radiological tumor shrinkage. The expression of CD3+ or/and CD3+/CD4+ stroma around tumor in pretreated tissue was significantly lower when comparing pCR and non-pCR (both p= 0.024). Conclusions: Neoadjuvant Sintilimab combined with Bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery and lead to a striking 56% and 78% complete and major pathological response. Stroma down-regulation of CD3 or CD3/CD4 expression was related to pCR.