bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of the presence of polymorphisms in the DPYD gene in patients with colorectal and non-colorectal digestive tumors.
Authors: Gallego Jimenez Inmaculada , Garcia De Veas Jose Luis , Garcia Grove Clara , Tallafigo Fernando Leopoldo , Limon M. Luisa
Published: June 2022

e15530

Background: Recently the European Medicines Agency (EMA) and the Spanish Medicines Agency (AEMPS) recommend performing a phenotypic and/or genotypic test before starting treatment with fluoropyrimidines The objective of this work has been to analyze the detection of polymorphisms in the DPYD gene in order to predict toxicity to fluoropyrimidines in our study population. Methods: Prospective study of 6 months duration in which patients diagnosed with CRC and non-CRC digestive tumors with an age range of 18-99 years have been included. The technique is performed on a sample of DNA extracted from lymphocytes in peripheral blood in an EDTA tube, performing a specific fluorescent allele amplification study (AMRS), which detects point mutations, insertions or deletions of DNA. Results: During the study period, 260 patients have been included, of whom 16 mutations have been detected, all in heterozygosity. Conclusions: Various variants of DPYD have been reported to cause the absence or reduction of dihydropyrimidine dehydrogenase (DPP) activity. Through this technique we avoid the risk of serious toxicity with the administration of these drugs.[Table: see text]
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.
Neoadjuvant versus adjuvant chemotherapy for resectable metastatic colon cancer in non-academic and academic programs.
Authors: Hao Zhonglin , Parasramka Saurabh , Chen Quan , Jacob Aasems , Huang Bin
Published: June 2022

e15607

Background: Approximately 21% of colon cancer patients have synchronous metastatic disease at presentation. Liver is by far the most common site of metastasis. For resectable and borderline resectable metastatic lesions after conversion to surgical resection, five-year survival ranges between 40-70%. Overall survival advantage of chemotherapy before and after metastasectomy of liver or lung lesion is not clear. We here compare the differential effect of neoadjuvant versus adjuvant chemotherapy on overall survival of patients who received resection of both primary and metastatic lesions in non-academic and academic settings from the National Cancer Database (NCDB). Methods: Adults 20 years or older with primary colon cancer and single organ metastatic disease either in the liver or lung at diagnosis between 2010-2015 were identified. All patients had received surgery to the primary site, resection of the distant site and chemotherapy within 1 year of diagnosis. Patients were categorized into 2 cohorts based on whether they received chemotherapy in the pre-operative/peri-operative setting (neoadjuvant chemotherapy –NAC) or post-operative setting (adjuvant chemotherapy AC). Descriptive analysis, Kaplan-Meier plots, Log-Rank tests, and Cox-regression models for multivariate survival analyses were performed. To assess uncertainty of estimates, a sensitivity analysis was also performed based on the intention to treat principle by including additional surgery only and chemotherapy only cases. Results: A total of 3,038 colon cancer patients with liver or lung metastases were identified between 2010-2015. A larger majority of patients (n = 2387, 78.6%) received AC. The percentage of patients receiving NAC had steadily increased from 2010-2015 from 12.29% to 28.31%. The supermajority of metastases was in the liver. On multivariate analysis, patients who received NAC had an overall survival advantage (HR 0.661; 95% CI 0.534-0.879; P = 0.0001) in the non-academic setting whereas no advantage is seen in the patients treated in the academic settings (HR 0.994; 95% CI 0.831-1.189; P < 0.9484). The median overall survival for patients receiving NAC and AC was 47.24 months and 38.08 months respectively. Clinical factors associated with overall survival advantages in NAC patients treated in non-academic programs included age 20-49 years; low-income (< $38,000/year) status; CEA value of > 30; right sided colon primary; low T status and liver metastasis among others. The survival advantage of NAC over AC is associated with more clean resection margin and fewer regional lymph node involvement after surgery. Conclusions: Metastatic colon cancer with single organ liver or lung lesions benefits from neoadjuvant chemotherapy especially in non-academic settings based on our analysis of the NCDB database. The overall survival advantage in this setting has not been shown before.
Prognosis of patients with resected stage II colon cancer -T4 versus T3 with two or more high-risk factors: A retrospective single-center cohort study.
Authors: Fedyanin Mikhail , Rice Anastasia , Polyanskaya Elizaveta , Gordeev Sergey , Mammadli Zaman , Tjulandin Sergei , Tryakin Alexey
Published: June 2022

e15608

Background: in 2021 ASCO has updated guidelines on adjuvant therapy for stage II colon cancer with the statement: “Patients with T4 tumors are at higher risk of recurrence and should be offered adjuvant chemotherapy, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT”. We performed a single-center retrospective study to assess the prognostic role of postoperative tumor stage T4 and T3 with ≥2 negative prognostic factors in patients with resected stage II colon cancer. Methods: We retrospectively analyzed 1457 pts with stage I-III colon cancer treated in Russian Cancer Research Center n.a. N.N. Blokhin from 2001 to 2015. We included pts with resected stage II colon cancer with following negative prognostic factors: T4; sampling of fewer than 12 lymph nodes in the surgical specimen; perineural or lymphatic invasion; poorly or undifferentiated tumor grade; intestinal obstruction; and tumor perforation. Three cohorts were studied: pts with pT4N0M0 with no other high-risk factors (group A), pts with pT4N0M0 with additional high-risk factors (group B), and pts with pT3N0M0 with ≥2 high-risk factors (group C). The primary study endpoint was 3-year disease-free survival (DFS). The secondary endpoint was 5-year overall survival (OS). Statistical analysis was done with SPSS v.20. Results: 164 pts met the inclusion criteria with 17 (10%) pts in group A, 90 (55%) pts in group B, and 57 (35%) pts in group C. Adjuvant chemotherapy was performed in 8 (47%), 25 (28%), and 9 (16%) pts, respectively (p = 0.035). At a median follow-up of 62 months (range, 2-135 months), the 3-year DFS was 82%, 68%, and 78% for groups A, B, and C, respectively (HR, 1.55; 95% CI, 0.99-2.4; p = 0.053). No difference in 3-year DFS was found between group A and C (HR, 1.0; 95% CI, 0.34-3.2; p = 0.9). The 5-year OS was 75%, 65%, and 78% for groups A, B, and C, respectively (HR, 1.38; 95% CI, 0.84-2.3; p = 0.2). Conclusions: Patients with pT4 with additional high-risk features had worse overall survival compared to other subgroups with resected stage II colon cancer. There was no difference in survival rates between patients with pT4 with no additional negative prognostic factors and pT3 with ≥2 negative prognostic factors. Therefore, we propose that patients with pT4 as well as with pT3 with ≥2 negative prognostic factors are at a higher risk of recurrence and should be offered adjuvant chemotherapy.
Thromboprophylaxis in surgically treated colorectal cancer patients with tinzaparin: Intermediate results from the Onco-CAST trial.
Authors: Papadopoulos V.N. , Timotheadou E.I. , Aggelopoulos St. , Arkadopoulos N. , Manganas D. , Papavasileiou Ch. , Papaziogas V. , Tzovaras G. , Alexandrou D. , Baloyiannis I. , Flamourakis M. , Galanis I. , Perivoliotis K. , Pramateftakis Manousos-Georgios , Bachlitzanakis Em. , Koffas S. , Menni A. , Papadoliopoulou M. , Tzitzis P. , Michalopoulos Antonios ,   Hellenic Society of Coloproctology
Published: June 2022

e15611

Background: The incidence of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) after colorectal surgery is approximately 29% and 1.6% respectively. The incidence of asymptomatic postoperative DVT in colorectal cancer (CRC) patients has been reported as high as 20%, even under thromboprophylaxis. Thus, thromboprophylaxis after surgical treatment for CRC is crucial. Latest guidelines from International Initiative on Thrombosis and Cancer (ITAC 2019) recommend use of highest prophylactic dose of Low Molecular Weight Heparin (LMWH). Methods: Onco-CAST is a prospective, phase IV, observational, non-interventional cohort study evaluating a) current management approach for CRC surgical prophylaxis and b) efficacy and safety of tinzaparin at 8.000 Anti-Xa IU, once daily (OD), for at least one month post hospital discharge. Patients enrolled after signing informed consent. Onco-CAST was conducted by the Hellenic Society of Coloproctology. Results: Results from 175 CRC patients from 9 Onco Surgical Clinics are reported. Participation completed 79% of patients at report time: 66% males, 67±12 years, BMI: 27.4±5.5. Histology: adenocarcinomas NOS 81%, mucinous adenocarcinomas 9%, small cell neuroendocrine carcinomas 2%, and others. High grade differentiation indicated: 26% and 5% metastatic. 32% treated with right hemicolectomy, 20% with low anterior resection, 12% with sigmoid colectomy, 9% with abdominal-perineal resection, 9% with left hemicolectomy and other methods. 67% treated open and 33% laparoscopic while the median number of lymph nodes dissected for left and right hemicolectomy was 32.5 (Q1-Q3:26-38) and 24 (Q1-Q3: 14.5-32), p = 0.0253. Factors related to thrombosis risk are presented in table, notably, 95% of patients accumulated ≥3 risk factors. Median thromboprophylaxis duration with tinzaparin 8.000 Anti-Xa IU, OD, was: 37 days (1st-3rd quartile: 33-45 days). Three thrombotic events occurred (efficacy 98.3%, 95% CI: 95.1-99.4%), one DVT+PE, one DVT and one due to Central Venous Catheter (CVC). Eight patients experienced bleeding events (4.6%, 95%CI: 2.3-8.8%), 3 minor, 3 major and 2 CNMB, 2 had a possible relation to thromboprophylaxis (1.1%, 95%CI: 0.3-4.1%). Conclusions: Thromboprophylaxis in Surgically Treated Colorectal Cancer Patients with Tinzaparin intermediate dose seems safe and efficient approach.[Table: see text]
Patient-derived xenografts of colorectal cancer for testing new pharmacological substances.
Authors: Egorov Georgiy Yu. , Goncharova Anna S. , Khodakova D. V. , Kurbanova L. Z. , Mindar Maria V. , Zaikina Ekaterina V. , Komarova Ekaterina Fedorovna , Kolesnikov Evgeniy N. , Maksimov Aleksey Yu. , Katsieva Tanzila B. , Myagkov Roman E. , Averkin Mikhail A. , Snezhko Aleksandr V. , Gaziev Umar M. , Nikolaeva Nadezhda V.
Published: June 2022

e15612

Background: The purpose of this study was to create a patient-derived xenograft model of human colorectal cancer and to determine its histological and molecular characteristics, including the status of the KRAS, NRAS, BRAF genes and the presence of microsatellite instability factors. Methods: Biological materials obtained from tumors of 4 patients with colorectal cancer were used to create the first-generation in vivo model. The study was performed on immunodeficient Balb/c Nude mice (20 females aged 5-6 weeks). Subcutaneous xenografts were obtained by the implantation of a 3×3×3 mm donor tumor fragment to recipient animals under the skin of the right thigh, 5 samples from each patient. For the second, third and fourth PDX generations, mice of the same strain were used (n = 3 for each generation). All manipulations were performed in accordance with the rules for using laboratory animals. Genomic DNA was extracted from PDX samples, and mutations in exons 2, 3 and 4 of the KRAS and NRAS genes and BRAF V600 mutations were identified by direct sequencing. Microsatellite instability was determined by fragment analysis for five loci Bat-25, Bat-26, NR21, NR24, NR27. Results: Stable transplantable xenografts of colorectal cancer were obtained from two out of four patients. The average waiting time between implantation and growth of the first-generation xenograft was 28 days. The model was confirmed to reproduce the histotype, differentiation and mutational status of the KRAS, NRAS, BRAF genes and microsatellite instability similar to those of donor tumors. Conclusions: The results confirm the possibility of the model use for testing both new pharmacological substances with a cytotoxic effect and drugs based on monoclonal antibodies.
Oxaliplatin and capecitabine (XELOX) plus toripalimab as perioperative treatment for locally advanced gastric or gastro-esophageal junction adenocarcinoma (Neo-Capture): A single-arm, phase 2 study.
Authors: Jiang Zhichao , Xie Yibin , Wang Bingzhi , Zhu Yongjian , Ke Yan , Zhang Wen , Sun Yongkun , Li Yin , Wang Chengfeng , Zhao Dongbing , Tian Yantao , Zhou Ai-Ping
Published: June 2022

e16001

Background: PD-1 inhibitor combined with chemotherapy showed remarkable objective response rate in the first line treatment of metastatic gastric cancer. While, the benefit of perioperative PD-1 inhibitor plus chemotherapy in locally advanced gastric or gastro-esophageal junction (G/GEJ) cancer was not clear. Therefore, we aimed to assess the efficacy and safety of perioperative XELOX plus toripalimab in the patients with locally advanced G/GEJ cancer in this study. Methods: This was a prospective single arm phase 2 study. Eligible patients were with histologically confirmed locally advanced G/GEJ (Siewert II/II type) adenocarcinoma (cT3-4 Nany M0 or T1-2 N2-3 M0). Patients received 4 preoperative and 2 postoperative cycles of XELOX plus toripalimab (oxaliplatin 130mg/m2 D1, capecitabine 1000mg/m2 bid D1-14, toripalimab 240mg D1, Q3W) followed by subsequent 2 cycles of toripalimab monotherapy. Patients underwent D2 gastrectomy after preoperative treatment. The primary endpoint was major pathological response (MPR) according to Becker TRG criteria. Secondary endpoints included safety, R0 resection rate, pathological complete response (pCR), 3-year disease free survival (DFS) and 3-year overall survival (OS). Results: From Jul, 2019, to Dec, 2021, 35 pts were recruited. The median age was 61 (34-72) years old. 80% of the pts were men. Acutally, all the pts had cT4 (cT4a [48.6%] & cT4b [51.4%]) and 88.6% had cN+ by CT, MRI and ultrasound gastroscopy. 2 pts suffered disease progression during neoadjuvant treatment. 4 pts have not yet completed preoperative therapy. 29 pts had received gastrectomy and 2 pts were pathologically diagnosed with large cell neuroendocrine carcinoma. Therefore, 27 adenocarcinoma pts were included in this analysis. 3 (11.1%) pts achieved pCR (TRG1a) and 4 (14.8%) pts achieved MPR (TRG1a/b). R0 resection was achieved in 96.3% (26/27) of the pts. No patient had pT4b. The most common (≥10%) grade 1-2 treatment related adverse events (TRAEs) included leucopenia (45.7%), neutropenia (42.9%), thrombocytopenia (20%), nausea (34.1%), vomiting (14.3%), anorexia (14.3%), ALT increased (40%) and AST increased (34.3%). Only 4 (11.4%) pts experienced grade 3 neutropenia. No other ≥ grade 3 TRAEs occurred. Most of the potential immune-related adverse events were grade 1-2 including hypothyroidism (8.6%), adrenal insufficiency (2.9%) and hyperglycemia (11.4%). Only one (2.9%) patient had grade 3 hyperglycemia. No serious perioperative complication and death occurred. Conclusions: Perioperative XELOX plus toripalimab preliminarily showed a favorable R0 resection rate and acceptable MPR in cT4a/T4b locally advanced G/GEJ cancer patients with a manageable safety profile. Clinical trial information: NCT04119622.
Neoadjuvant sintilimab combined with chemotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC): Preliminary results from a phase II study.
Authors: Guo Jincheng , Qiao Chengrui , Lu Jiabin , Yang Shiqing , Zhang Boyi
Published: June 2022

e16008

Background: Although preoperative chemoradiotherapy is the standard of care for patients with resectable locally advanced esophageal cancer, prognosis still remains poor. Combining PD-1 blockade to chemotherapy has demonstrated significant clinical benefits in first line treatment of metastatic ESCC. Sintilimab, a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in metastatic ESCC. We aimed to assess the activity and safety profile of the combination of sintilimab with paclitaxel and cisplatin for neoadjuvant treatment of ESCC. Methods: In this ongoing, single-arm, phase II study, we recruited patients from the First Affiliated Hospital of Henan University of Technology in China with histopathologically diagnosed resectable ESCC who had clinical cT2-4/N1-3M0 (stage II-IVA). Patients were given 2 cycles of chemotherapy (nab-paclitaxel 260 mg/m2, d1 and cisplatin 75 mg/m2, d1-3) in combination with 2 cycles of sintilimab (200mg, iv, d1, q3w), followed by esophagectomy. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and objective response rate (ORR). Results: Between Nov 2020 and Dec 2021, 15 patients were enrolled and commenced treatment. A total of 11 patients (75%) completed neoadjuvant and radical resection, 4 patients refused surgery. Six patients (54.5%) achieved major pathologic response (MPR), including five (45.5%) with a pathologic complete response (pCR) in primary tumor. According to RECIST v1.1, 1 of 8 patients (12.5%) achieved partial response (CR), 4 of 8 patients (50%) achieved partial response, and 3 of 8 patients (37.5%) achieved stable disease (SD). The objective response rate (ORR) and disease control rate (DCR) for 8 patients were 62.5% and 100%, respectively. The most frequent treatment-related adverse events (TRAE) included leukopenia (60%), nausea (40%) and diarrhea (20%). The grade 3 or 4 TRAE were leukopenia (26.7%), neutropenia (20%) and pneumonia (6.7%). There was no surgical delays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of sintilimab and chemotherapy is a safe and efficacious treatment option for patients with resectable ESCC, and 45.5% pCR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: ChiCTR2000040345.
Sintilimab combined with chemotherapy in conversion therapy of advanced gastric cancer: A retrospective study.
Authors: Fang Jingquan , Huang Xingmao , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian , Pengfei Yu
Published: June 2022

e16012

Background: Gastric cancer is the fifth most common cancer in the world and the third leading cause of cancer death. At present, traditional chemotherapy is still the main treatment method of advanced gastric cancer, but the efficacy is limited. Immunotherapy has been identified as a treatment for chemotherapy-refractory gastric cancer, and sintilimab is a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1). This study aims to investigate the efficacy of sintilimab combined with chemotherapy in patients with inoperable metastatic gastric cancer and analyze the prognostic factors of these patients. Methods: Patients with advanced gastric cancer which were initially treated unresectable and with distant metastasis in Zhejiang Cancer Hospital from August 2018 to December 2021 were retrospectively analyzed in this research. Patients received sintilimab combined with chemotherapy (PS regimen) ：sintilimab 200mg, day 1, paclitaxel was administered intravenously (150 mg/m2 ) on day 1, and S-1 was administered orally (80 mg/m2/day) on days 1–14 of a 3-week cycle. The primary endpoints were treatment efficiency; and the secondary endpoint was safety and overall survival (OS) time. Results: A total of 66 patients were enrolled, including 43 males and 23 females, with an average age of 62.2 years (29-77 years). All of these patients had one or more distant metastases (liver 28 cases, peritoneum 20 cases, retroperitoneal lymph node 21 cases and ovary 5 cases). 33 patients (50%) underwent surgery, including conversion surgery (26 cases), palliative surgery (7 cases). The mean OS of patients with conversion surgery was 19.2 months (95%CI 16.5̃21.9 months), and the 2-year survival rate was 50.0%. The mean OS of non-conversion surgery was 16.9 months (95%CI 12.9̃20.1 months), and the 2-year survival rate was 29.1% (P=0.028). 24 (92.3%) cases had R0 resection. Multivariate analysis showed that postoperative CA125 level was an independent risk factor for prognosis of these gastric cancer patients. Conclusions: Sintilimab combined with chemotherapy is safe and effective, and combined with conversion surgery can improve the prognosis of patients with partially unresectable advanced gastric cancer.
Anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.
Authors: Zhang Yan-Feng , Hao An-Lin , Hong Yong-Gui , Li Xiao-Ming , Liang Wei-Min , Zheng Zhi-Xin , Yang Guang-Yi , Guo Xiao-Feng , Wen Yan-Yan , Cao Heng , Le Cheng , Song Hua-Jie , Su Wen-Zhong
Published: June 2022

e16015

Background: Neoadjuvant therapy could significantly improve survival for patients with locally advanced esophageal cancer. However, postoperative complications and recurrence are still urgent problems to be solved. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Nab-paclitaxel plus cisplatin as first-line therapy exhibited moderate efficacy in ESCC patients. This study was to investigate the efficacy and safety of nab-paclitaxel and cisplatin combined with anlotinib as neoadjuvant treatment for ESCC. Methods: ESCC patients with preoperative clinical stage II-III and all patients who can receive radical surgery were recruited in this study. Eligible patients received anlotinib (12mg, po, d1̃14, q3w) combined with nab-paclitaxel (175mg/m2, iv, q3w) and cisplatin (20mg/m2, iv, d1̃3, q3w) for 2 cycles during neoadjuvant therapy. 4 weeks after the end of neoadjuvant therapy, the patients underwent radical surgery after exclusion of contraindications to surgery. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans at baseline and within 2 weeks before surgery. The calculated sample size was 62. The primary endpoint was ORR, secondary endpoints were R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Dec 2021, a total of 26 eligible patients were enrolled. Among them, 17 patients underwent surgery after completing 2 cycles of neoadjuvant therapy, 3 patients chose other treatment options, and 6 patients are still receiving neoadjuvant therapy. patients who had received surgery (n = 17) were included in this analysis. In best overall response assessment, there were 4 CR (23.5%), 11 PR (64.7%) and 2 SD (11.8%). Consequently, ORR was 88.2% (95%CI: 63.6̃98.5%) and DCR was 100.0% (95%CI: 80.5̃100.0%). At the data cut-off date, 17 patients (100.0%) had underwent R0 resection. Among them, 4 patients (23.5%) were confirmed to be pCR. And the median DFS was not yet available. The safety profile suggested that the most common treatment-emergent adverse events with the incidence > 10% were gastrointestinal reactions (65.4%), hypokalemia (19.2%), nausea (15.4%), liver damage (15.4%), myelosuppression (11.5%) and vomit (11.5%). No grade ≥3 adverse events were noted. Conclusions: Preliminary results suggested that anlotinib combined with nab-paclitaxel and cisplatin in neoadjuvant treatment of ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients included subsequently.