CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. METHODS: The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). RESULTS: Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CONCLUSIONS: CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.

Cancer-associated fibroblast-derived exosome miR-181b-3p promotes the occurrence and development of colorectal cancer by regulating SNX2 expression.

Tumor microenvironment (TME) (e.g., stromal cells) has been closely related to the pathological process of colorectal cancer (CRC). In TME, tumor-associated fibroblasts (CAFs) are the main stromal cells. The studies have showed that CAFs promoted tumor growth and metastasis in CRC and led to poor prognosis. Mounting evidence indicates that CAFs-mediated exosomes regulate the pathological process of neighboring tumor cells through the transmission of miRNAs. In our study, we aimed to explore the function of CAFs-derived exosome miR-181b-3p in CRC. First, the expression of miR-181b-3p in CRC was found to be up-regulated and its expression was dramatically up-regulated in CRC cells after co-incubation of CAFs-mediated exosomes with CRC cells. Then, it was found that the CAFs-derived exosomes were markedly enhanced the proliferation and migration of the CRC cells, and substantially reduced apoptosis. To elucidate the influence of CAFs-derived exosome miR-181b-3p on CRC, we overexpressed and knocked down the miR-181b-3p expression in CAFs, respectively. It was found that miR-181b-3p significantly increased the proliferation and migration of CRC cells. Furthermore, we conducted in vivo experiments. Finally, we demonstrated that CAF-derived exosome miR-181b-3p regulated sorting nexin 2 (SNX2) expression in CRC cells by bioinformatics prediction combined with luciferase reporter assay. Further cellular and animal experiments jointly elucidated that miR-181b-3p promoted the pathological process of CRC by SNX2 expression. In brief, our results demonstrated that CAFs-derived exosome miR-181b-3p promoted the pathogenesis of CRC by regulating SNX2 expression, which provides a novel idea for CRC treatment.

Excessive HSP70/TLR2 activation leads to remodeling of the tumor immune microenvironment to resist chemotherapy sensitivity of mFOLFOX in colorectal cancer.

For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC.

Oncologic outcomes of single-incision laparoscopic surgery versus conventional laparoscopic surgery for colorectal cancer (CSILS): study protocol for a multicentre, prospective, open-label, noninferiority, randomized controlled trial.

BACKGROUND: In most previous studies, single-incision laparoscopic surgery (SILS) for colorectal cancer (CRC) was feasible and safe in the short term. However, long-term oncologic outcomes remain uncertain, as only a few studies contained long-term survival data. SILS for CRC is still in the early stages of research. Further studies, particularly large-scale, prospective randomized controlled trials, are necessary to assess the value of SILS for CRC. METHODS: This study is a prospective, multicentre, open-label, noninferiority, parallel-group randomized controlled trial that investigates the long-term oncologic outcomes of SILS compared to conventional laparoscopic surgery (CLS) for CRC. A total of 710 eligible patients will be randomly assigned to the SILS group or the CLS group at a 1:1 ratio using a central, dynamic, and stratified block randomization method. Patients with ages ranging from 18 to 85 years old, of both sexes, with CRC above the peritoneal reflection diagnosed as cT1-4aN0-2M0 and a tumour size no larger than 5 cm will be considered for the study. The primary endpoint is 3-year disease-free survival (DFS). The secondary endpoints include: intraoperative outcomes, postoperative recovery, postoperative pain assessment, pathological outcomes, early morbidity and mortality rate, cosmetic effects, quality of life, 3-year overall survival (OS), incidence of incisional hernia, 5-year DFS and 5-year OS. The first two follow-up visits will be scheduled at one month and three months postoperatively, then every three months for the first two years and every six months for the next three years. DISCUSSION: Currently, no randomized controlled trials (RCTs) have been designed to investigate the long-term oncologic outcomes of SILS for CRC. This study is expected to provide clinical evidence of the oncologic outcomes of SILS compared to CLS for CRC to promote its widespread use. TRIAL REGISTRATION: ClinicalTrials.gov:  NCT04527861 (registered on August 27, 2020).

Clinical and oncological outcomes of single-incision vs. conventional laparoscopic surgery for rectal cancer.

BACKGROUND: To evaluate the clinical and oncological outcomes of single-incision laparoscopic surgery (SILS) vs. conventional laparoscopic surgery (CLS) for patients with rectal cancer (RC) who underwent total mesorectal excision (TME) surgery. METHODS: This was a retrospective case-control study of patients with RC operated between 12/2013 and 12/2017 in Ruijin Hospital North, Shanghai Jiaotong University School of Medicine. In total, 177 patients who underwent CLS and 51 who underwent SILS met the inclusion and exclusion criteria and were matched 1:1 using propensity score matching method (PSM). RESULTS: Compared with the CLS group, the SILS group showed shorter operation time [105 (40) vs. 125 (55) min, P = 0.045], shorter total incision length [4 (1) vs. 6.5 (1.5) cm, P < 0.001], lower VAS score on POD2 [1 (1) vs. 2 (1), P < 0.001], shorter time to soft diet [7 (1) vs. 8 (2) days, P = 0.048], and shorter length of hospital stay [9 (2) vs. 11 (3) days, P < 0.001]. The postoperative complications were similar between two groups [1(2%) vs. 5 (9.8%), P = 0.205]. No readmissions or mortality in either group occurred within 30 days of surgery. All 102 specimens met the requirements of TME. No significant differences were observed in the pathologic outcomes between the two groups. The median follow-up period was 32.6 months in the SILS group and 36.8 months in the CLS group (P = 0.053). The 3-year disease-free survival rates and overall survival rates of the SILS and CLS groups were 89.8% vs. 96.0% (P = 0.224) and 90.9% vs. 96.9% (P = 0.146), respectively. CONCLUSIONS: Compared with CLS, TME surgery for rectal cancer can be performed safely and effectively using the SILS technique with better cosmetic results, less postoperative pain, faster postoperative recovery, and acceptable clinical and oncological outcomes.

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB.

ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-ß/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.

Clinical and oncologic outcomes of single-incision laparoscopic surgery for right colon cancer: a propensity score matching analysis.

BACKGROUND: Single-incision laparoscopic surgery (SILS) for right colon cancer is going to be considered as a new option. The potential benefits, clinical, and oncologic outcomes are still controversial. The aim of this study was to investigate clinical and oncologic outcomes of single-incision laparoscopic surgery (SILS) compared to conventional laparoscopic surgery (CLS) for right colon cancer using propensity score matching analysis. METHODS: From December 2013 to June 2017, 174 patients underwent laparoscopic radical right hemicolectomy through a single-incision (n = 32) or a conventional (n = 142) approach. The data were prospectively collected and the patients were matched at a radio of 1:1 according to age, sex, body mass index (BMI), previous abdominal surgeries, comorbidities, ASA score (≤ 2/> 2), and pathologic stage. RESULTS: No significant differences were observed in estimated blood loss, time to diet, postoperative pain score, length of hospital stay between the SILS and CLS groups. However, the SILS group showed longer operation time (175 (40) vs 145 (52.5), p = 0.011) and shorter incision length (4 (1.4) vs 7 (1.9), p < 0.001). There were 2 (6.3%) postoperative complications in the SILS group and 5 (15.6%) in the CLS group (p = 0.426). The pathologic outcomes were similar between two groups. The median follow-up period was 26.5 months in the SILS group and 34.9 months in the CLS group (p = 0.002). There were 3 recurrences (9.4%) in the SILS group and 3 (9.4%) in the CLS group. The 3-year disease-free survival rates were 92.4 and 93.8% (p = 0.984), and overall survival rates were 92.3 and 93.0% (p = 0.884) in the SILS and the CLS groups, respectively. No incisional hernia was observed during the follow-up period. CONCLUSIONS: Though single-incision laparoscopic surgery for right colon cancer showed longer operation time in this study, it appears to be a safe and feasible option with comparable clinical and oncologic outcomes to conventional laparoscopic surgery.

LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer.

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.

MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF.

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-378-5p is dysregulated in numerous human cancers including colorectal cancer (CRC) which hypothesizes that miR-378-5p may play an important role in tumorigenesis. However, its role in CRC carcinogenesis remains poorly defined because of lacking target genes information. In the present study, it was demonstrated that the expression of miR-378-5p was down-regulated in CRC tissues and cell lines as determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Furthermore, overexpression of miR-378-5p suppressed cell proliferation, as indicated by CCK-8 assay. Flow cytometric analysis demonstrated that overexpression of miR-378-5p induced cell cycle arrest and promoted apoptosis in CRC cells. A luciferase reporter assay indicated that BRAF was a direct target of miR-378-5p. Western blot and qRT-PCR analysis indicated that BRAF was significantly down-regulated by miR-378-5p in CRC cells. Moreover, miR-378-5p was negatively associated with BRAF in CRC tissues compared to adjacent non-tumor tissues. These results demonstrate that down-regulation of miR-378-5p promotes CRC cells growth by targeting BRAF and restoration of their levels is a potentially promising therapeutic in CRC.

CHD1L promotes tumor progression and predicts survival in colorectal carcinoma.

BACKGROUND: To evaluate the expression of chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like gene (CHD1L) in colorectal carcinoma (CRC) and its clinical significance. Its oncogenic ability was also investigated. MATERIALS AND METHODS: CHD1L amplification and overexpression were detected by fluorescence in situ hybridization, real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry in 86 patients with CRC. The correlation between the clinical characteristics and prognosis was also determined. To evaluate the tumorigenic ability of CHD1L, it was cloned into expression vector pcDNA3.1(+) and transfected into CRC cell line SW1116. Next, the changes in the biologic behavior of the CRC cells, including cell proliferation, adhesion, migration, and invasion, were examined. Apoptosis and the cell cycle of the CRC cells were detected using flow cytometry. RESULTS: We have demonstrated that CHD1L is frequently amplified and overexpressed in CRC. Overexpression of CHD1L correlated with a large tumor size, deep tumor invasion, and a high histologic grade. It also conferred worse disease-free survival. CHD1L-transfected cells possessed a strong oncogenic ability, increasing the tumorigenicity in nude mice, which could be effectively suppressed by small interfering RNA against CHD1L. Functional studies showed that overexpression of CHD1L could promote G1/S-phase cells and inhibit apoptosis. CONCLUSIONS: Our results suggest that CHD1L is the target oncogene within the 1q21 amplicon and plays a pivotal role in CRC pathogenesis.

Single-incision robotic assisted surgery: a nonrandomized cohort pilot study on a novel surgical platform in colorectal surgery.

BACKGROUND: The technological barriers and steep learning curve of single-incision laparoscopic surgery had kept it from further applications. A literature review had reported that robotic technology could preserve its advantages while simplifying its difficulties. This nonrandomized cohort pilot study aims to evaluate the feasibility and safety of single-incision robotic assisted colorectal surgery based on a novel robotic surgical platform, the SHURUI Endoscopic Surgical Robotic System (SR-ENS-600). METHOD: This study enrolled 7 patients with colorectal malignancy who underwent single-incision robotic assisted surgery (SIRAS) at a tertiary general surgery center, and retrospectively included 23 patients who underwent robotic assisted surgery from September 2015 to June 2016 and 35 patients who underwent single-incision laparoscopic surgery from June 2017 to March 2018, which were labeled as the initial in-learning-curve attempts from the same surgical team. The technological feasibility and safety of SIRAS were evaluated. Perioperative outcomes, short-term postoperative outcomes, clinicopathologic outcomes, and follow-up were reported. RESULTS: Six SIRAS operations were completed successfully without eventful intraoperative complications, except for one operation that encountered a large-volume of intraoperative hemorrhage. Two SIRAS cases were converted to multiport laparoscopic surgery because of intraoperative hemorrhage and difficulty in retraction. Postoperative pathology reported satisfactory specimen qualities. There were no short-term postoperative complications, no short-term mortality, no tumor recurrence, or metastasis reported. There was one incisional hernia reported half a year after operation. Patients with advanced staging were sent to standard evaluation and chemotherapy, and follow-up is still on-going. CONCLUSIONS: SIRAS can be feasibly performed by a skilled surgical team via the SR-ENS-600 platform for strictly-selected patients, which provides preferable instrument maneuverability and stability in confined surgical fields and overcomes the technical difficulty of multisite dissection through a single-incision. Large-volume investigations and high-level evidences are required to further validate its safety and superiority.

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD-L1 expression.

BACKGROUND: Anti-PD1/PD-L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first-line therapy for HER2 overexpression-positive advanced gastric cancers (GC), suggesting that HER2 and PD-L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD-L1 expression. PATIENTS AND METHODS: Next-generation targeted sequencing and PD-L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD-L1 expression were analyzed. RESULTS: The most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy-six (10%) patients were HER2 amplification, and 291 (40%) had positive PD-L1 expression. Classifying the total population based on HER2 amplification and PD-L1 expression level, 735 patients were divided into four subgroups: HER2+/PD-L1+ (4.5%), HER2+/PD-L1- (5.9%), HER2-/PD-L1+ (35.1%), and HER2-/PD-L1- (54.5%). The HER2+/PD-L1- and HER2+/PD-L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD-L1- subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2-/PD-L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD-L1- subgroup had the highest TMB level and HER2-/PD-L1+ subgroup had the highest proportion of patients with microsatellite instability-high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD-L1 expression and therapeutic genomic alterations, but no impact on the prognosis. CONCLUSION: The combination of HER2 amplification and PD-L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

Clinical status and future prospects of single-incision robotic-assisted surgery: a review.

Since the advent of conventional multiport laparoscopic surgery, the prosperity of minimally invasive surgery has been thriving on the advancement of endoscopic techniques. Cosmetic superiority, recovery benefits, and noninferior surgical outcomes weigh single-incision laparoscopic surgery as a promising modality. Although there are surgical challenges posed by steep learning curve and technological difficulties, such as instruments collision, triangulation loss and limited retraction, the establishment of robotic surgical platform as a solution to all is inspiring. Furthermore, with enhanced instrument maneuverability and stability, robotic ergonomic innovations adopt the advantages of single-incision laparoscopic surgery and surmount its recognized barriers by introducing a novel combination, single-incision robotic-assisted surgery. As was gradually diffused in general surgery and other specialties, single-incision robotic-assisted surgery manifests privileges in noninferior clinical outcomes an satisfactory cosmetic effect among strictly selected patients, and has the potential of a preferable surgical option for minimally invasive surgery.

Colorectal cancer vaccines: The current scenario and future prospects.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.

Short- and long-term outcomes of robotic- versus laparoscopic-assisted right hemicolectomy: A propensity score-matched retrospective cohort study.

BACKGROUND: This study aimed to retrospectively compare the short- and long-term outcomes of robotic- and laparoscopic-assisted right hemicolectomies. MATERIALS AND METHODS: Patients who underwent right hemicolectomy with either robotic (46 patients) or laparoscopic (186 patients) surgery between January 2016 and December 2018 were analyzed retrospectively using propensity score matching (PSM). RESULTS: After matching, the robotic group included 45 patients (out of 46) and the laparoscopic group included 100 patients (out of 186). Compared to the laparoscopic group, the robotic group had shorter median times to first flatus (2 vs. 4 days; p < 0.01) and a liquid diet (4 vs. 5 days; p < 0.01) and shorter median postoperative hospital stays (7 vs. 8 days; p < 0.01). There were no significant differences in other short-term or oncological outcomes between the two groups. The 3-year overall survival and disease-free survival rates were equivalent. CONCLUSIONS: Robotic-assisted right hemicolectomy had the advantages of a quick recovery of bowel functions and an earlier postoperative discharge and was non-inferior to laparoscopic-assisted right hemicolectomy in all other outcomes.

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies.

Digestive system malignancies are one of the primary causes of cancer-related death. Meanwhile, angiogenesis has been proved to play an important role in the process of cancer neovascularization. Apatinib, a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis. Furthermore, completed clinical trials demonstrated that apatinib could prolong the progression-free survival and overall survival in advanced gastric cancer and primary liver cancer. Recent studies revealed that apatinib had a synergistic effect with immunotherapy as a second-line and third-line treatment regimen for some other cancers. In this review, we summarize the pharmacological properties of apatinib and the latest clinical application in chemotherapy-refractory patients with advanced digestive system cancer. Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway. Treatment of apatinib monotherapy or combination immunotherapy remains the optimal option for patients with digestive system malignancies in the future.

AFF4 Predicts the Prognosis of Colorectal Cancer Patients and Suppresses Colorectal Cancer Metastasis via Promoting CDH1 Expression.

INTRODUCTION: AF4/FMR2 family member 4 (AFF4) is a core component of super elongation complex (SEC) and regulates the transcription elongation of many genes. AFF4 depletion or amplification is associated with multiple cancers, but its role in colorectal cancer (CRC) has not been investigated so far. METHODS: qRT-PCR and Western blot analyzed AFF4 expression in the paired clinical CRC tissues. The patients' overall survival curve was determined using the Kaplan-Meier plotter. In vitro experiments, such as cell proliferation, migration, and invasion, were used to preliminarily ascertain the role of AFF4 in CRC. A CRC cell liver metastasis animal model was well established. Livers were harvested and examined histologically by a series of indicators, such as tumor nodules, liver weight, ALT/AST activity, and tumor cell identification by hematoxylin-eosin (HE) staining. RESULTS: We firstly examined the expression of AFF4 in colorectal cancer and normal tissues by collecting paired CRC tissues and adjacent normal tissues, revealing that AFF4 was significantly downregulated in CRC patients and lower expression of AFF4 was correlated with poor prognosis. Next, we observed that presence or absence of AFF4 in CRC cells had no effect on cancer cell proliferation, while AFF4 depletion significantly promoted the migration or invasion of CRC cells in vitro. Furthermore, we confirmed that AFF4 deficiency enhanced the metastatic capacity of CRC cells in vivo. Mechanistically, we found that AFF4 upregulated the transcription of CDH1 gene, which encodes E-cadherin and suppresses the epithelial-mesenchymal transition (EMT). Knockdown of AFF4 interfered with CDH1 transcription, resulting in downregulation of E-cadherin expression and the progression of CRC. Moreover, restored CDH1 expression could rescue the phenotype of CRC cells without AFF4. CONCLUSIONS: Collectively, our data demonstrated that AFF4 served as a significant novel regulator of CRC via CDH1 transcriptional regulation and a potential effective therapy target for patients with CRC.

Single-docking robotic-assisted artery-guided segmental splenic flexure colectomy for splenic flexure cancer-a propensity score-matching analysis.

BACKGROUND: Splenic flexure cancer (SFC) is a rare condition in colorectal cancer (CRC). The appropriate surgical treatment for SFC remains controversial. In recent years, we have used artery-guided segmental splenic flexure colectomy (ASFC) to treat SFC in which robotic access is gradually applied. The study sought to assess the clinical and oncologic outcomes of robotic-assisted ASFC compared to laparoscopic-assisted ASFC for SFC by undertaking a propensity score-matching analysis. METHODS: Seventy patients underwent a robotic-assisted ASFC (n=19) or laparoscopic-assisted ASFC (n=51) to treat SFC from Dec 2015 to Dec 2019. Their data were prospectively collected. The patients were matched at a ratio of 1:1 according to sex, age, body mass index (BMI), comorbidities, the American Society of Anesthesiologists (ASA) score (≤2 or >2), previous abdominal surgeries, and pathologic stage. RESULTS: No statistically significant differences were found between the robotic- and laparoscopic-assisted ASFC groups in relation to operation time, estimated blood loss, length of postoperative hospital stay, time to liquid diet, postoperative complications, tumor size, distal resection margins, histology, lymph node harvest, metastatic lymph nodes, and neuro-vascular invasion. Additionally, no case was converted to a laparotomy. There were no cases readmission or mortality within 30 days of surgery. The distal resection margins were longer in the robotic-assisted ASFC group than the laparoscopic-assisted ASFC group. The robotic-assisted ASFC group had significantly higher operation expenses than the laparoscopic-assisted ASFC group. However, there was no significant difference in the surgical material expenses between the two groups. There were 2 cases of complications in each group; both cases were classified as grade I or II under Dindo's classification of surgical complications. CONCLUSIONS: With the exception of operation expenses, robotic-assisted ASFC rivals laparoscopic-assisted ASFC in many respects. ASFC meets the recommended oncological criteria in terms of resection margins and lymph node harvest. We await the results for the long-term oncologic outcomes.

Single-docking robotic assisted proctectomy for rectal cancer below peritoneal reflection: a propensity score matching analysis.

BACKGROUND: The aim of this study was to compare the short and long-term outcomes of robotic assisted proctectomy (RP) and laparoscopic assisted proctectomy (LP) for rectal cancer below the peritoneal reflection using propensity score matching (PSM) analysis. METHODS: We evaluated the medical records of 200 patients who underwent proctectomy for rectal cancer below the peritoneal reflection through a robotic (n=81) or laparoscopic (n=119) approach between Jan 2015 and Dec 2017. The data were prospectively collected, and the patients were matched at a ratio of 1:1 according to age, sex, body mass index (BMI), previous abdominal surgeries, comorbidities, American Society of Anesthesiologist score (≤2/>2), and pathologic stage. RESULTS: After matching, each group included 74 patients. Compared to the LP group, the RP group showed shorter postoperative hospital stays (PHS) [7 (±2) vs. 9 (±2.3) d, P=0.003], shorter time to liquid diet [3 (±2) vs. 5 (±3) d, P<0.001], and shorter time to removal of catheter [6 (±2) vs. 7 (±2.3) d, p=0.014]. The operative expense was higher in the RP group [8,365 (±1,600) vs. 6,922 (±1,220) RMB, P<0.001]. The operation time, estimated blood loss, postoperative complications, and pathologic outcomes were similar between the two groups. No conversion to laparotomy, readmission, or mortality was observed in either group within 30 days after surgery. The 3-year disease-free survival (DFS) were 75.2% and 88.3% (P=0.070), and overall survival (OS) were 92.9% and 93.7% (P=0.810) in the RP and the LP groups, respectively and the risk of low anterior resection syndrome (LARS) was lower in the RP group (OR =0.304, 95% CI: 0.124-0.745, P=0.009). CONCLUSIONS: Compared to LP, RP is worth recommending as it has long-term survival, faster postoperative recovery, and a lower risk of LARS in patients with rectal cancer below the peritoneal reflection.

Clinical Status and Future Prospects of Transanal Total Mesorectal Excision.

Low rectal cancer has always posed surgical challenges to gastrointestinal surgeons. Transanal total mesorectal excision (taTME) is a novel approach to radical resection for low rectal cancer. Compared with conventional laparoscopic TME (laTME), taTME is relevant to the benefits of better vision of the mesorectal plane, feasibility of operating in a narrow pelvis, and exact definition of distal resection margin, which may lead to a higher possibility of free circumferential resection margin, better quality of TME specimen, and lower conversion rate. Although there are concerns about its long-term oncological outcomes and complex learning curve, taTME is a promising alternative for rectal cancer. In this review, we discuss the application status and prospects of taTME.