Survival analysis in pT1-3 and paracolic lymph-node invasion colorectal cancer: the prognostic role of positive paracolic lymph-node ratio for adjuvant chemotherapy.

PURPOSE: Several studies have observed that some stage III colorectal cancer (CRC) patients cannot benefit from standard adjuvant chemotherapy. However, there is no unified screening standard to date. METHODS: Consecutive patients with pathologically confirmed colon adenocarcinoma treated in 3 centers between January 2016 and December 2018 were included. Patients were divided into four groups according to different stages and positive paracolic lymph-node ratio (P-LNR) [Cohort 1: pT1-3N0M0, Cohort 2: pT1-3N + (P-LNR ≤ 0.15)M0, Cohort 3: pT4N0M0, Cohort 4: stage III patients except for pT1-3N + (P-LNR ≤ 0.15)M0], and further overall survival was compared by Kaplan-Meier method. The univariate and multivariate analyses were employed for cox proportional hazards model. RESULTS: We retrospectively reviewed 5581 consecutive CRC patients with, and 2861 eligible patients were enrolled for further analysis. The optimal cut-off value of P-LNR in our study was 0.15. There was no significant difference in OS (91.36 vs. 93.74%) and DFS (87.65 vs. 90.96%) between stage III patients with pT1-3N + (P-LNR ≤ 0.15)M0 and those with pT1-3N0M0. Further analysis demonstrated that CRC patients with pT1-3N + (P-LNR ≤ 0.15)M0 were less likely to benefit from 8 cycles of CAPOX or FOLFOX chemotherapy and suffered fewer adverse events from declining chemotherapy. Comparing with 0-4 cycles versus 8 cycles, the overall survival rates were 91.35 versus 90.19% (P = 0.79), and with a DFS of 87.50 versus 88.24% (P = 0.49), the duration of adjuvant chemotherapy was not an independent risk factor for patients with pT1-3N + (P-LNR ≤ 0.15)M0 (HR: 0.70, 95% CI 0.90-1.30, P = 0.42). CONCLUSION: The concept of P-LNR we proposed might have a high clinical application value and accurately enable clinicians to screen out specific CRC patients who decline or prefer limited chemotherapy. TRIAL REGISTRY: The clinical trial registration number: ChiCTR2300076883.

The value of ICG-guided left colon vascular variation and anatomical rules for the radical resection of proctosigmoid colon cancer.

Objective: During laparoscopic radical resection for proctosigmoid colon cancer (PCC), surgeons could inadvertently damage the arteries when following the operation path.This study investigated the variations in left colon blood vessels in order to guide the scientific protection of the marginal artery (MA) during laparoscopic surgery for PCC. Methods: Data from seven patients who underwent inferior mesenteric artery (IMA) angiography were included as imaging references to preliminarily explore the vascular structure and variation in the left colon. The clinical video data of 183 PCC patients were retrospectively analyzed to observe intraoperative MA injury. Meanwhile, a prospective cohort of 96 patients with the same disease underwent intraoperative indocyanine green (ICG) fluorescence imaging of the peripheral sigmoid artery network, the variation of marginal arteries was summarized, and the distance between vessels and the bowel was measured at different levels. Patients were divided into 'ICG group' and 'non-ICG group' according to whether ICG guidance was performed, and perioperative conditions were compared between the two groups. Taking the integrity of lymph node dissection into consideration, 18 patients underwent carbon nanonode tracing. This study was conducted under the standard consent and ethical approval of the Ethics Committee of our center. Results: 7 patients with IMA angiography shared some vascular structures, defined as 'Dangerous Triangle' and 'Secure Window'. Through intraoperative observation, the primary arch was typically located 4.2 (2.3-6.0) cm away from the intestinal canal, and 5.21% (5/96) patients had poor anastomosis at the primary arch. Moreover, secondary vascular arches (6.4 (4.6-10.0) cm from the intestinal wall) were observed in 38.54% of patients. MA injury was identified in 2 of 183 cases, and the ischemic bowel was timely dissected, whereas no such injury occurred during ICG fluorescenceguided surgery. Guided by carbon nanoparticles, the integrity of lymph node dissection can be maintained while preserving the secondary arch in all patients. Conclusions: This study demonstrated the benefits of ICG guidance in protecting the intestinal blood supply in laparoscopic PCC surgery. By enhancing the understanding of primary and secondary vascular arches, secure windows, and dangerous triangles, surgeons can safely optimize the surgical path during surgery.

Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro.

Background: Ferroptosis is involved in many malignant tumors and has been implicated in important mechanisms of colorectal cancer (CRC) suppression. However, the prognostic and predictive values of the ferroptosis activation pattern in CRC patients have not been noted. Here, we aimed to construct and validate a prediction model based on ferroptosis-related genes (FRGs) for CRC patients and investigated the expression pattern and biological function of the most significantly altered gene. Methods: A total of 112 FRGs were obtained from the FerrDb website, and the clinical characteristics of 545 CRC patients and their global gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Survival-related FRGs were identified by Cox proportional hazards regression analysis. Finally, the expression pattern and biological function of NOS2, the most implicated gene was explored in vitro and in vivo. Results: The prediction model was established based on 8 FRGs. Patients in the high- or low-risk group were stratified based on the median risk value calculated by our model, and patients in the high-risk group experienced poor overall survival (p<0.01). Further validation demonstrated that the FRG model acted as an independent prognostic indicator for CRC patients (HR=1.428, 95% CI, 1.341-1.627; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival was 0.741. NOS2 was one of the most significantly affected FRGs and was highly expressed in malignant tissue, but it inhibited tumor growth and induced tumor cell death in vitro and in vivo, possibly by repressing the NF-κB pathway. Conclusion: Our study revealed that FRGs have potential prognostic value in CRC patients and that NOS2 suppresses tumor progression, providing a novel therapeutic target for CRC treatment based on ferroptosis.

"Caudal to cranial" versus "medial to lateral" approach in laparoscopic right hemicolectomy with complete mesocolic excision for the treatment of stage II and III colon cancer: perioperative outcomes and 5-year prognosis.

The purpose of this study was to compare the "caudal to cranial" (CC) versus "medial to lateral" (ML) approach for laparoscopic right hemicolectomy. Pertinent data from all patients with stage II and III between January 2015 and August 2017 were entered into a retrospective database. A total of 175 patients underwent the ML (N = 109) or CC approach (N = 66). Patient characteristics were equivalent between groups. The CC group showed a shorter surgical time 170.00 (145.00, 210.00) vs. (206.50 (178.75, 226.25) min) than the ML group (p < 0.001). The time to oral intake was shorter in the CC group than in the ML group ((3.00 (1.00, 4.00) vs. 3.00 (2.00, 5.00) days; p = 0.007). For the total harvested lymph nodes, there was no statistical significance between the CC group 16.50 (14.00, 21.25) and the ML group 18.00 (15.00, 22.00) (p = 0.327), and no difference was found in the positive harvested lymph nodes (0 (0, 2.00) vs. 0 (0, 1.50); p = 0.753). Meanwhile, no differences were found in other perioperative or pathological outcomes, including blood loss and complications. For 5-year prognosis, overall survival rates were 75.76% in the CC group and 82.57% in the ML group (HR 0.654, 95% CI 0.336-1.273, p = 0.207); disease-free survival rates were 80.30% in the CC group and 85.32% in the ML group (HR 0.683, 95% CI 0.328-1.422, p = 0.305). Both approaches were safe and feasible and resulted in excellent survival. The CC approach was beneficial in terms of the surgical time and time to oral intake.

Primary extra-gastrointestinal stromal tumor of retroperitoneum: Clinicopathologic characteristics and prognosis of six cases.

Aim: This study investigates the clinicopathological features and prognostic genic biomarker factors of primary retroperitoneal extra-gastrointestinal stromal tumors (EGISTs). Methods: The clinicopathological data of six patients with primary retroperitoneal EGIST were analyzed, including cell type (epithelioid or spindle), mitoses, and the presence of intratumoral necrosis and hemorrhage. Mitoses were counted and summed from 50 high power fields (HPFs). Mutations of exons 9, 10, 11, 13, 14, and 17 of the C-kit genes and those of exons 12 and 18 of the PDGFRA gene were examined. Follow-up was performed via telephone, and all outpatient records were reviewed. The last follow-up date was February 2022, the median follow-up was 27.5m and the postoperative status, medication, and survival of the patients were recorded. Result: The patients were treated with radical intent. Four cases (patients 3, 4, 5, and 6) underwent multivisceral resection for encroachment on the adjacent viscera. The postoperative pathological results demonstrated that all biopsy specimens were negative for S-100 and desmin, and positive for DOG1 and CD117. Additionally, four patients (case 1, 2, 4, and 5) were positive for CD34, four (case 1, 3, 5, and 6) were positive for SMA, four (case 1, 4, 5, and 6) had >5/50 HPFs, and three (case 1, 4, and 5) had Ki67 >5%. According to the modified National Institutes of Health (NIH) guidelines, all patients were graded as high-risk cases. By exome sequencing, exon11 mutations were detected in the six patients, while exon10 mutations were detected in two cases (patients 4 and 5). The median follow-up time was 30.5 (11-109) months, with only one fatality at 11 months. Conclusion: Retroperitoneal EGIST is a rare mesenchymal tumor that is difficult to distinguish from other retroperitoneal tumors. To diagnose this highly malignant tumor, low-threshold suspicion is necessary, and Kit and PDGFRA gene mutations should be routinely tested to confirm the diagnosis and guide subsequent treatment.

An innovative and convenient technique to reduce anastomotic leakage after double stapling anastomosis: laparoscopic demucositized suture the overlapping point of the "dog ear" area.

Anastomotic leakage (AL) is a major cause of postoperative morbidity and mortality in the treatment of colorectal cancer. The aim of this study was to investigate an innovative and convenient technique of laparoscopic demucositized suture the overlapping point of the "dog ear" area after the double stapling anastomosis (lds-DSA), as an improved alternative for conventional DSA, and whether it could reduce the AL rate in laparoscopic anterior resection (Lapa-AR). Between January 2018 and December 2020, a total of 245 patients who underwent Lapa-AR for the treatment of adenocarcinoma of the sigmoid colon or rectal cancer were divided into the lsd-DSA group (n = 99) and the DSA group (n = 146). Data were analyzed retrospectively. Morbidity, AL rate and other perioperative outcomes were compared between the two groups. Patient demographics, preoperative comorbidity, preoperative chemoradiotherapy, tumor size, stage, and other operative details were comparable between the two groups. There was no difference in surgical time between the two groups (196.41 ± 76.71 vs. 182.39 ± 49.10 min, p = 0.088). The overall complication rate was also without a difference (11/99, 11.11% vs. 21/146, 14.38%, p = 0.456), but AL rate significantly lower in the lsd-DSA group than in the DSA group (2/99, 2.02% vs. 12/146, 8.22%, p = 0.040). For other perioperative outcomes, the lsd-DSA group shortened the total and postoperative hospital stay, and the time to pull out drainage tube than in the DSA group. Our comparative study demonstrates lds-DSA to have a better short-term outcome in reducing AL compared with DSA. This technique could be an alternative approach to maximize the patients' benefit in Lapa-AR.

GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Abundant metabolic fuels have been implicated as potential drivers of CRC. However, it remains unclear whether fructose, an ample sugar in daily diets, is essential for CRC growth. In the present study, we found that glucose levels were always insufficient in human CRC tissues. Compensating for this, fructose was flexibly utilized by tumor cells as an alternative energy source to maintain proliferation and exert chemotherapy resistance in vitro by upregulating GLUT5, a major fructose transporter encoded by SLC2A5. Mechanistically, in glucose-deprived but fructose-rich environments, GLUT5 could interact with ketohexokinase and inhibit its autophagy-dependent degradation, thus trapping fructose into glycolysis and tricarboxylic acid cycle for the malignant growth of CRC cells. In addition, reducing dietary fructose or pharmacological blockade of fructose utilization significantly reduced CRC growth and sensitized CRC cells to chemotherapy in vivo. Taken together, our findings highlight the role of elevated fructose utilization mediated by the GLUT5-KHK axis in governing CRC growth and imply that efforts to refine fructose intake or inhibit fructose-mediated actions may serve as potential therapeutic strategies.

Improving the overall survival prognosis prediction accuracy: A 9-gene signature in CRC patients.

Colorectal cancer (CRC) is a malignant tumor and morbidity rates are among the highest in the world. The variation in CRC patients' prognosis prompts an urgent need for new molecular biomarkers to improve the accuracy for predicting the CRC patients' prognosis or as a complement to the traditional TNM staging for clinical practice. CRC patients' gene expression data of HTSeq-FPKM and matching clinical information were downloaded from The Cancer Genome Atlas (TCGA) datasets. Patients were randomly divided into a training dataset and a test dataset. By univariate and multivariate Cox regression survival analyses and Lasso regression analysis, a prediction model which divided each patient into high-or low-risk group was constructed. The differences in survival time between the two groups were compared by the Kaplan-Meier method and the log-rank test. The weighted gene co-expression network analysis (WGCNA) was used to explore the relationship between all the survival-related genes. The survival outcomes of patients whose overall survival (OS) time were significantly lower in the high-risk group than that in the low-risk group both in the training and test datasets. Areas under the ROC curves which termed AUC values of our 9-gene signature achieved 0.823 in the training dataset and 0.806 in the test dataset. A nomogram was constructed for clinical practice when we combined the 9-gene signature with TNM stage and age to evaluate the survival time of patients with CRC, and the C-index increased from 0.739 to 0.794. In conclusion, we identified nine novel biomarkers that not only are independent prognostic indexes for CRC patients but also can serve as a good supplement to traditional clinicopathological factors to more accurately evaluate the survival of CRC patients.

S100P contributes to promoter demethylation and transcriptional activation of SLC2A5 to promote metastasis in colorectal cancer.

BACKGROUND: SLC2A5 is a high-affinity fructose transporter, which is frequently upregulated in multiple human malignant tumours. However, the function and molecular mechanism of SLC2A5 in colorectal cancer (CRC) remain unknown. METHODS: We detected the expression levels of SLC2A5 in CRC tissues and CRC cell lines by western blotting, qRT-PCR and immunohistochemistry. CRC cell lines with stable overexpression or knockdown of SLC2A5 were constructed to evaluate the functional roles of SLC2A5 in vitro through conventional assays. An intrasplenic inoculation model was established in mice to investigate the effect of SLC2A5 in promoting metastasis in vivo. Methylation mass spectrometry sequencing, methylation specific PCR, bisulphite sequencing PCR, ChIP-qPCR and luciferase reporter assay were performed to investigate the molecular mechanism underlying transcriptional activation of SLC2A5. RESULTS: We found that SLC2A5 was upregulated in colorectal tumour tissues. Functionally, a high level of SLC2A5 expression was associated with increased invasion and metastasis capacities of CRC cells both in vitro and in vivo. Mechanistically, we unveiled that S100P could integrate to a specific region of SLC2A5 promoter, thereby reducing its methylation levels and activating SLC2A5 transcription. CONCLUSIONS: Our results reveal a novel mechanism that S100P mediates the promoter demethylation and transcription activation of SLC2A5, thereby promoting the metastasis of CRC.

Regional lymph nodes distribution pattern in central area of right-sided colon cancer: in-vivo detection and the update on the clinical exploration.

Distribution of regional lymph nodes (LNs) is decisive for the lymphadenectomy boundary in radical resection of right-sided colon cancer (RCC). Currently, the data of LNs in central area remains ambiguous and scarce. Herein we aim to provide a more detailed anatomical research on LNs surrounding the superior mesenteric vessels for RCC and investigated the metastasis rate. In this study, Carbon Nanoparticles (CNs) and Indocyanine Green (ICG) were used for regional LNs mapping by preoperative colonoscopic tattooing (PCT) and we laparoscopically observed the stained LNs distribution pattern. Lastly, 143 RCC patients who received a "superior mesenteric artery (SMA)-oriented" hemicolectomy were included to calculate the probability of LNs metastasis in our target area. 27 patients diagnosed as RCC (mean age 58.04 years, 17 male) were included. 14 patients underwent CNs injection and 13 patients consented to the ICG, while 4 cases suffered from imaging failure. The unequal number of the regional LNs located between SMV and SMA was detected in 22 cases (81.48%), posterior to SMV area in 6 cases (22.22%), and anterior to SMA in 16 cases (59.26%), respectively. The presence of LNs posterior to SMV was associated with the crossing pattern of ileocolic artery (χ2 = 4.24, P = 0.039). The probability of LNs metastasis in the above areas (target areas) was 2.10% (3/143). In conclusion, right-hemi colon-draining lymphatic vessels anteriorly/posteriorly traversed the SMV and arrived at the surface of SMA near the middle colonic artery (MCA) level, which highlights the potential need of removing mesenteric tissue in our target area on lymphatic resection.

Transcriptional information underlying the generation of CSCs and the construction of a nine-mRNA signature to improve prognosis prediction in colorectal cancer.

BACKGROUND: Despite recent progress in screening survival-related genes, there have been few attempts to apply methods based on cancer stem cells (CSCs) for prognosis. We aimed to identify a CSC-based model to predict survival in colorectal cancer (CRC) patients. MATERIAL/METHODS: Differentially expressed genes between CRC and normal tissues and between CD133- and CD133+ cells were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, and intersections were evaluated. Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyzes were performed. STRING was used to investigate interactions between the encoded proteins and the Kaplan-Meier method to verify mRNAs associated with survival. A prognostic model based on CSCs was established via univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was conducted to test the model's sensitivity and specificity. The KS test was applied to provide evidence for relationships between expression levels of nine mRNAs in our model and pathological stage. RESULTS: In total, 155 common differentially expressed mRNAs were identified, and nine (AOC1, UCN, MTUS1, CDC20, SNCB, MAT1A, TUBB2B, GABRA4 and ALPP) were screened after regression analyses to establish a predictive model for classifying patients into high- and low-risk groups with significantly different overall survival times, especially for stage II and IV patients. CONCLUSIONS: We developed a novel model that provides additional and powerful prognostic information beyond conventional clinicopathological factors for CRC survival prediction. It also provides new insight into the molecular mechanisms underlying the transition from normal tissues to CSCs and formation of tumor tissues.

SNX16 activates c-Myc signaling by inhibiting ubiquitin-mediated proteasomal degradation of eEF1A2 in colorectal cancer development.

Sorting nexin 16 (SNX16), a member of the sorting nexin family, has been implicated in tumor development. However, the function of SNX16 has not yet been investigated in colorectal cancer (CRC). Here, we showed that SNX16 expression was significantly upregulated in CRC tissues compared with normal counterparts. Upregulated mRNA levels of SNX16 predicted poor survival of CRC patients. Functional experiments showed that SNX16 could promote CRC cells growth both in vitro and in vivo. Knockdown of SNX16 induced cell cycle arrest and apoptosis, whereas ectopic overexpression of SNX16 had the opposite effects. Mechanistically, SNX16-eukaryotic translation elongation factor 1A2 (eEF1A2) interaction could inhibit the degradation and ubiquitination of eEF1A2, followed by activation of downstream c-Myc signaling. Our study unveiled that the SNX16/eEF1A2/c-Myc signaling axis could promote colorectal tumorigenesis and SNX16 might potentially serve as a novel biomarker for the diagnosis and an intervention of CRC.

POTEE drives colorectal cancer development via regulating SPHK1/p65 signaling.

Aberrant gene expression plays critical roles in the development of colorectal cancer (CRC). Here we show that POTEE, which was identified as a member E of POTE ankyrin domain family, was significantly upregulated in colorectal tumors and predicted poor overall survival of CRC patients. In CRC cells, POTEE could act as an oncogene and could promote cell growth, cell-cycle progression, inhibit apoptosis, and elevates xenograft tumor growth. Mechanically, we used microarray analysis and identified a POTEE/SPHK1/p65 signaling axis, which affected the biological functions of CRC cells. Further evaluation showed that overexpression of POTEE could increase the protein expression of SPHK1, followed by promoting the phosphorylation and activation of p65 protein. Altogether, our findings suggested a POTEE/SPHK1/p65 signaling axis could promote colorectal tumorigenesis and POTEE might potentially serve as a novel biomarker for the diagnosis and an intervention of colorectal cancer.

CD36 inhibits ß-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis.

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of ß-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as ApcMin/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-ß-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.

[Experimental Research on Detection of Breast Carcinoma and Adjacent Tissues Based on Open-ended Coaxial Probe Tumor Sensor with Radio Frequencies].

This study aimed to verify whether the open-ended coaxial line tumor sensor with radio frequency was effective or not in detecting the differences in permittivity and conductivity between the breast malignant tissues and adjacent tissues.Sixteen breast infiltrating ductal carcinoma samples were freshly obtained from the department of general surgery in Zhujiang Hospital.The permittivity and conductivity of cancerous nidus points of breast samples,3cm adjacent tissue points and 5cm adjacent tissue points were detected respectively by the open-ended coaxial line tumor sensor with radio frequency noninvasively in conjunction with vector network analyzer at the frequency ranging from 42.85~500 MHz.All the detected points were marked.After finishing the detection,we conducted postoperative pathological examinations on all the marked points.According to the statistics,there were statistically significant differences between the breast cancerous tissues and the 3cm adjacent tissues for the dielectric properties(P<0.01).There were statistically significant differences between the breast cancerous tissues and the 5cm adjacent tissues for the dielectric properties(P<0.01).There was no statistically significant difference in the dielectric properties between the 3cm adjacent tissues and 5cm adjacent tissues(P>0.05).Both the 3cm adjacent tissues and5 cm adjacent tissues were found no breast cancer cell infiltration.The results indicated that the open-ended coaxial line tumor sensor at radio frequency could be effective in detecting the differences in permittivity and conductivity between breast cancerous tissues and adjacent tissues and,therefore,it may have a potential prospect in making a final diagnosis to confirm whether the detected breast tissue is malignant or not.