Feasibility, Indications, and Prognostic Significance of Selective Lateral Pelvic Lymph Node Dissection After Preoperative Chemoradiotherapy in Middle/Low Rectal Cancer: Results of a Multicenter Lateral Node Study in China.

BACKGROUND: Lateral pelvic lymph node dissection after preoperative chemoradiotherapy can decrease local recurrence to lateral compartments, thereby providing survival benefits. OBJECTIVE: The safety of lateral pelvic lymph node dissection after preoperative chemoradiotherapy was investigated, and the surgical indications and survival benefits of lateral pelvic lymph node dissection were established on the basis of preoperative characteristics. DESIGN: A multicenter retrospective study. SETTINGS: Three hospitals in China. PATIENTS: Four hundred nine patients with clinical evidence of lateral pelvic lymph node metastasis. INTERVENTIONS: Patients who received lateral pelvic lymph node dissection were divided into 2 groups depending on whether they received chemoradiotherapy (n = 139) or not (n = 270). MAIN OUTCOME MEASURES: The safety, indications, and survival benefits of lateral pelvic lymph node dissection after preoperative chemoradiotherapy were investigated. RESULTS: The surgery times were significantly prolonged by preoperative chemoradiotherapy (291.3 vs 265.5 min; p = 0.021). Multivariate analysis demonstrated that poor/mucinous/signet-ring adenocarcinoma (OR = 4.42, 95% CI, 2.24-11.27; p = 0.031) and postchemoradiotherapy lateral pelvic lymph node short-axis diameter ≥7 mm (OR = 15.2, 95% CI, 5.89-53.01; p < 0.001) were independent predictive factors for lateral pelvic lymph node metastasis. Multivariate prognostic analysis showed that swollen lateral pelvic lymph nodes beyond the obturator or internal iliac as well as the involvement of 3 or more lateral pelvic lymph nodes were independent adverse prognostic factors. LIMITATIONS: The retrospective nature of the study and the small sample size were the limitations of this study. CONCLUSIONS: Preoperative chemoradiotherapy combined with lateral pelvic lymph node dissection is a practicable procedure with acceptable morbidity. Postchemoradiotherapy lateral pelvic lymph node short-axis diameter ≥7 mm and poor/signet/mucinous adenocarcinoma could be used for predicting lateral pelvic lymph node metastasis after chemoradiotherapy. However, lateral pelvic lymph node dissection should be carefully considered in patients with swollen lateral pelvic lymph nodes beyond the obturator or internal iliac region or involvement of multiple lateral pelvic lymph nodes. See Video Abstract at http://links.lww.com/DCR/C133 . VIABILIDAD, INDICACIONES E IMPORTANCIA PRONSTICA DE LA DISECCIN SELECTIVA DE GANGLIOS LINFTICOS PLVICOS LATERALES DESPUS DE QUIMIORRADIOTERAPIA PREOPERATORIA EN CNCER DE RECTO MEDIO/INFERIOR RESULTADOS DE UN ESTUDIO MULTICNTRICO DE GANGLIOS LATERALES EN CHINA: ANTECEDENTES:La disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria puede disminuir la recurrencia local en los compartimentos laterales, lo que brinda beneficios de supervivencia.OBJETIVO:Se investigó la seguridad de la disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria, y se establecieron las indicaciones quirúrgicas y los beneficios de supervivencia de la disección de los ganglios linfáticos pélvicos laterales en función de las características preoperatorias.DISEÑO:Estudio retrospectivo multicéntrico.ESCENARIO:Tres hospitales en China.PACIENTES:Cuatrocientos nueve pacientes con evidencia clínica de metástasis en los ganglios linfáticos pélvicos laterales.INTERVENCIONES:Los pacientes que recibieron disección de ganglios linfáticos pélvicos laterales se dividieron en dos grupos dependiendo de si recibieron quimiorradioterapia (n = 139) o no (n = 270).PRINCIPALES MEDIDAS DE RESULTADO:Se investigaron la seguridad, las indicaciones y los beneficios de supervivencia de la disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria.RESULTADOS:Los tiempos de cirugía se prolongaron significativamente con la quimiorradioterapia preoperatoria (291,3 vs 265,5 min, p = 0,021). El análisis multivariable demostró que el adenocarcinoma mal diferenciado/mucinoso/en anillo de sello (odds ratio = 4,42, intervalo de confianza del 95%, 2,24-11,27; p = 0,031) y el diámetro del eje corto de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia ≥7 mm (odds ratio = 15,2, intervalo de confianza del 95%, 5,89-53,01; p < 0,001) fueron factores predictivos independientes de metástasis en los ganglios linfáticos pélvicos laterales. El análisis pronóstico multivariable mostró que la inflamación de los ganglios linfáticos pélvicos laterales más allá del obturador o la ilíaca interna, así como la afectación de tres o más ganglios linfáticos pélvicos laterales, eran factores pronósticos adversos independientes.LIMITACIONES:La naturaleza retrospectiva del estudio y el pequeño tamaño de la muestra.CONCLUSIONES:La quimiorradioterapia preoperatoria combinada con la disección de los ganglios linfáticos pélvicos laterales es un procedimiento practicable con una morbilidad aceptable. Posterior a la quimiorradioterapia, el diámetro del eje corto de los ganglios linfáticos pélvicos laterales ≥7 mm y el adenocarcinoma pobre/en sello/mucinoso podrían usarse para predecir la metástasis en los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia. Sin embargo, la disección de los ganglios linfáticos pélvicos laterales debe considerarse cuidadosamente en pacientes con ganglios linfáticos pélvicos laterales inflamados más allá del obturador o de la región ilíaca interna o compromiso de múltiples ganglios linfáticos pélvicos laterales. Consulte Video Resumen en http://links.lww.com/DCR/C133 . (Traducción-Dr. Felipe Bellolio ).

A Prospective Long-Term Follow-Up Study: The Application of Circulating Tumor Cells Analysis to Guide Adjuvant Therapy in Stage II Colorectal Cancer.

BACKGROUND: The efficacy of circulating tumor cells (CTCs) in the selection of stage II colorectal cancer (CRC) patients for adjuvant chemotherapy remains inconclusive. OBJECTIVE: The aim of this study was to validate the necessity of adjuvant chemotherapy for stage II CRC patients with positive postoperative CTCs. METHODS: The clinicopathological features and overall survival (OS) of a cohort of 70 patients with confirmed CRC were collected and analyzed. RESULTS: The total rate of positive CTCs was 55.7%, while the average OS was 70.8 months and the OS rate was 75.7% (53/70). These 70 patients were divided into four subgroups, including a CTC-negative group with non-adjuvant chemotherapy (CHEMO-/CTC-) versus a CTC-positive group with non-adjuvant chemotherapy (CHEMO-/CTC+), CHEMO+/CTC- versus CHEMO+/CTC+, CHEMO-/CTC- versus CHEMO+/CTC-, and CHEMO+/CTC+ versus CHEMO-/CTC+; the total numbers in each subgroup were 25 versus 32, 6 versus 7, 25 versus 6, and 7 versus 32, respectively. The average OS of the CHEMO-/CTC- and CHEMO-/CTC+ groups was 82.0 and 68.1 months, respectively (p = 0.020); the average OS of the CHEMO+/CTC- and CHEMO+/CTC+ groups was 83.6 months and 76.4 months, respectively (p = 0.963); the average OS of the CHEMO-/CTC- and CHEMO+/CTC- groups was 82.0 months and 83.6 months, respectively (p = 0.999); and the average OS of the CHEMO+/CTC+ and CHEMO-/CTC+ groups was 76.4 months and 68.1 months, respectively (p = 0.247). CONCLUSIONS: Positive CTCs are a potential prognostic marker for stage II CRC.

BRCA genes as candidates for colorectal cancer genetic testing panel: systematic review and meta-analysis.

BACKGROUND: Breast cancer susceptibility gene (BRCA) mutation carriers are at an increased risk for breast, ovarian, prostate and pancreatic cancers. However, the role of BRCA is unclear in colorectal cancer; the results regarding the association between BRCA gene mutations and colorectal cancer risk are inconsistent and even controversial. This study aimed to investigate whether BRCA1 and BRCA2 gene mutations are associated with colorectal cancer risk. METHODS: In this systematic review, we searched PubMed/MEDLINE, Embase and Cochrane Library databases, adhering to PRISMA guidelines. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Unadjusted odds ratios (ORs) were used to estimate the probability of Breast Cancer Type 1 Susceptibility gene (BRCA1) and Breast Cancer Type 2 Susceptibility gene (BRCA2) mutations in colorectal cancer patients. The associations were evaluated using fixed effect models. RESULTS: Fourteen studies were included in the systematic review. Twelve studies, including seven case-control and five cohort studies, were included in the meta-analysis. A significant increase in the frequency of BRCA1 and BRCA2 mutations was observed in patients with colorectal cancer [OR = 1.34, 95% confidence interval (CI) = 1.02-1.76, P = 0.04]. In subgroup analysis, colorectal cancer patients had an increased odds of BRCA1 (OR = 1.48, 95% CI = 1.10-2.01, P = 0.01) and BRCA2 (OR = 1.56, 95% CI = 1.06-2.30, P = 0.02) mutations. CONCLUSIONS: BRCA genes are one of the genes that may increase the risk of developing colorectal cancer. Thus, BRCA genes could be potential candidates that may be included in the colorectal cancer genetic testing panel.

Mesorectal excision with or without lateral lymph node dissection for elderly patients with mid-low rectal cancer: safety and feasibility analysis.

OBJECTIVE: The perioperative safety and survival benefits of lateral lymph node dissection in elderly patients have been less reported. This study aimed to compare short-term and survival outcomes of total mesorectal excision and total mesorectal excision + lateral lymph node dissection in elderly patients. METHODS: A total of 444 elderly patients (≥65 years) with middle-low rectal cancer were enrolled in three institutions and divided into the total mesorectal excision + lateral lymph node dissection group (n = 110) and the total mesorectal excision group (n = 334). Eighty-three matched pairs were selected for evaluation after propensity matching. Data of 297 patients (age <65 years) with middle-low rectal cancer who underwent total mesorectal excision + lateral lymph node dissection were also collected and reviewed. Clinical and pathological features, postoperative outcomes and survival data were collected and analyzed. RESULTS: Compared with the total mesorectal excision group, the operation time of patients in the total mesorectal excision + lateral lymph node dissection group was significantly longer (277.6 vs. 171.4 min, P < 0.001), and the estimated blood loss was significantly more (119.6 vs. 57.5 ml, P = 0.014). Although there was no significant difference in overall complications (24.1% vs. 14.4%, P = 0.115) and grade 3-5 complications (9.6% vs. 7.2%, P = 0.576) between the two groups, the incidence of urinary retention (10.8% vs. 2.4%, P = 0.029) was higher in the total mesorectal excision + lateral lymph node dissection group. Two groups of patients achieve a similar 3-year overall survival (92.8% vs. 85.4%, P = 0.195) and 3-year disease-free survival (81.5% vs. 73.0%, P = 0.625). In addition, we compared long-term outcomes in 110 elderly patients with total mesorectal excision + lateral lymph node dissection and 297 non-elderly patients with total mesorectal excision + lateral lymph node dissection, and the results showed that 3-year (89.2% vs. 80.9%, P = 0.546) and disease-free survival (76.4% vs. 70.4%, P = 0.346) were similar between elderly and non-elderly patients. CONCLUSIONS: Although urinary retention is closely related to the implementation of lateral lymph node dissection in elderly patients, total mesorectal excision with lateral lymph node dissection could be performed safely with accepted overall and grade 3-5 postoperative complications in elderly patients with rectal cancer. Moreover, elderly patients with clinical lateral lymph node metastasis can also benefit from lateral lymph node dissection as well as younger patients. Prospective studies with large sample sizes are needed to verify our results further.

Feasibility and safety of lateral pelvic lymph node dissection for elderly patients with middle-low rectal cancer: results of a large multicenter lateral node collaborative group study in China.

BACKGROUND: Lateral pelvic lymph node (LPN) dissection can improve local control in certain rectal cancer patients with LPN metastasis. However, the effects of this technically complex procedure on perioperative safety and long-term survival of elderly patients (≥ 70 years) remain unclear. METHODS: Locally advanced middle-low rectal cancer patients diagnosed with LPN metastasis who underwent total mesorectal excision (TME) with LPN dissection at three institutions from January 2012 to December 2019 were included in this study. Additionally patients who had neoadjuvant chemoradiotherapy (nCRT) and those who did not were compared. RESULTS: In total there were 407 patients, including 49 elderly and 358 non-elderly patients, of which 249 were male, with a median age of 58 years (range:18-85 years). In the whole cohort, operation time (280.7 vs. 292.0 min, p = 0.498) and estimated blood loss (100 vs. 100 ml, p = 0.384) were comparable in the elderly and non-elderly groups. There was no significant difference in the incidences of overall complications (24.5% vs. 19.8%, p = 0.448) and severe (Clavien-Dindo grade 3-5) surgical complications (8.2% vs. 7.5%, p = 0.778) between the two groups. However, the incidence of urinary retention (14.3% vs. 5.6%, p = 0.032) and intensive care unit admission (16.3% vs. 6.1%, p = 0.018) was significantly higher in the elderly group compared with those in the non-elderly group. The 3-year overall survival (88.7% vs. 82.1%, p = 0.516) and disease-free survival (81.2% vs. 70.7%, p = 0.352) were comparable between the two groups. Moreover, results in the nCRT cohort were comparable to those in the overall cohort. CONCLUSIONS: Even with nCRT, TME combined with LPN dissection is safe and feasible for elderly patients, demonstrating low mortality and acceptable morbidity. Elderly and non-elderly patients with LPN metastasis who undergo LPN dissection can achieve comparable 3-year survival outcomes. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT04850027.

Risk factors and prognostic significance of postoperative complications following lateral pelvic lymph node dissection for rectal cancer: results of the multicenter lateral node study in China.

OBJECTIVE: Total mesorectal excision (TME) plus lateral pelvic lymph node (LPN) dissection (LPND) is a technically complex and challenging procedure with higher morbidity than TME alone. We aimed to investigate the risk factors for postoperative complications after TME + LPND, and the impact of complications on patient prognosis. METHODS: A total of 387 rectal cancer patients with clinical LPN metastasis (LPNM) who underwent TME + LPND at three institutions affiliated with the Chinese Lateral Node Collaborative Group were included. Logistic regression models were used to identify the risk factors for post-surgical complications, and the log-rank test was used to compare the prognosis. Severe complications were described as grade III-V. RESULTS: The incidence rates of overall complications and severe complications after TME + LPND were 15.2% (59/387) and 7.8% (30/387), respectively. Multivariate analysis showed that a duration of operation ≥260 min was an independent risk factor for both overall (odds ratio [OR] = 3.03, 95% confidence interval [CI] = 1.57-5.85, P = 0.001) and severe postoperative complications (OR = 2.67, 95% CI = 1.06-6.73, P = 0.037). The development of overall postoperative complications (P = 0.114) and severe postoperative complications (P = 0.298) had no significant impact on the overall survival. However, patients with overall complications (P = 0.015) or severe complications (P = 0.031) with a postoperative hospital stay >30 days had significantly an overall worse survival. CONCLUSION: A surgical duration of ≥260 min is a significant risk factor for both overall and severe postoperative complications after TME + LPND for middle-low rectal cancer. Furthermore, the development of overall complications or severe complications that require a postoperative hospital stay >30 days significantly worsens the prognosis.

Short- and long-term outcomes of laparoscopic versus open selective lateral pelvic lymph node dissection for locally advanced middle-low rectal cancer: Results of a multicentre lateral node study in China.

AIM: Lateral pelvic lymph node dissection (LPND) is a technically challenging procedure, and the safety and feasibility of laparoscopic LPND remains undetermined. Here, we compared the short- and long-term survival outcomes of laparoscopic LPND with those of open LPND. METHODS: From January 2012 to December 2019, locally advanced middle-low rectal cancer patients with clinical evidence of lateral pelvic lymph node metastasis (LPNM) who underwent total mesorectal excision with LPND at three institutions were included. Propensity score matching was used to minimize selection bias. The short-term and oncological outcomes of open and laparoscopic LPND were compared. RESULTS: Overall, 384 patients were enrolled into the study including 277 and 107 patients who underwent laparoscopic and open LPND, respectively. After matching, patients were stratified into laparoscopic (n = 100) and open (n = 100) LPND groups. Patients in the laparoscopic LPND group had a shorter operation time (255 vs. 300 min, p = 0.001), less intraoperative blood loss (50 vs. 300 ml, p < 0.001), lower incidence of postoperative complications (32.0% vs. 15.0%, p = 0.005), shorter postoperative hospital stay (8 vs. 14 days, p < 0.001), and excision of more lateral pelvic lymph nodes (9 vs. 7, p = 0.025) than those in the open LPND group. The 3-year overall survival (p = 0.581) and 3-year disease-free survival (p = 0.745) rates were similar between the groups, and LPNM was an independent predictor of survival. CONCLUSION: Laparoscopic LPND is technically safe and feasible with favourable short-term results and similar oncological outcomes as open surgery in selected patients.

Prophylactic subcutaneous drainage reduces post-operative incisional infections in colorectal surgeries: a meta-analysis of randomized controlled trials.

BACKGROUND: Due to lack of high-level evidences, prophylactic subcutaneous drainage has so far not been recommended in relevant guidelines as a countermeasure against incisional infections. This meta-analysis aims to clarify the efficacy of subcutaneous drainage in reducing incisional infections in colorectal surgeries. METHODS: Cochrane Library, Embase, and PubMed were searched for randomized controlled trials comparing the incidence rate of incisional infections between patients receiving prophylactic subcutaneous drainage (interventions) and those not receiving (controls) after digestive surgeries. Results from included RCTs were pooled multiple times according to different surgical types. Heterogeneity, publication bias, and certainty of evidences were estimated. RESULTS: Eight randomized controlled trials were included. Three RCTs each included patients receiving all sorts of digestive surgeries (gastrointestinal, hepatobiliary, and pancreatic); pooled incisional infection rates between the drainage group and the control group were not significantly different (RR = 0.76, 95%CI: 0.48-1.21, p = 0.25). Four RCTs included patients receiving colorectal surgeries; pooled incisional infection rate in the drainage group was significantly lower than that in the control group (RR = 0.34, 95%CI: 0.19-0.61, p = 0.0004). Four RCTs included patients receiving upper GI and/or HBP surgeries; pooled incisional infection rates in the drainage group and the non-drainage group were not significantly different (RR = 0.85, 95%CI: 0.54-1.34, p = 0.49). CONCLUSIONS: Prophylactic subcutaneous drainage significantly reduces post-operative incisional infections in colorectal surgeries but was not efficacious in digestive surgeries in general.

Prognostic value of leukemia inhibitory factor and its receptor in pancreatic adenocarcinoma.

Currently, the prognostic effects of leukemia inhibitory factor (LIF) and LIF receptor (LIFR) in pancreatic adenocarcinoma (PAAD) are not clear. In the present study, we utilized the large datasets from four public databases to investigate the expression of LIF and LIFR and their clinical significance in PAAD. Eight cohorts containing 1278 cases with PAAD were identified and the analysis results suggested that LIF was highly expressed while LIFR was lowly expressed in PAAD tissues compared with adjacent or normal tissues. Kaplan-Meier plot curves and univariate and multivariate Cox proportional hazards regression analyses indicated high LIF expression was associated with shorter overall survival (adjusted hazard ratio = 1.641, 95% CI: 1.399-1.925, p < 0.001) whereas high LIFR expression was associated with longer overall survival (adjusted hazard ratio = 0.653, 95% CI: 0.517-0.826, p < 0.001).

The MiR-495/Annexin A3/P53 Axis Inhibits the Invasion and EMT of Colorectal Cancer Cells.

BACKGROUND/AIMS: More and more reports have shown that the dysregulation of miRNAs can contribute to the progression and metastasis of human cancers. Many studies have shown that the down-regulation of the miR-495 level occurs in a variety of cancers, including colorectal cancer (CRC). However, the precise molecular mechanisms of miR-495 in CRC have not been well clarified. In the current study, we investigated the biological functions and molecular mechanisms of miR-495 in CRC cell lines. METHODS: qRT-PCR was used to determine the level of miR-495 in CRC cell lines and tissues. A miR-495 mimic and inhibitor were transfected into CRC cells, and the effects of miR-495 on the invasion and EMT were explored by qRT-PCR as well as transwell and Western blot assays. Meanwhile, luciferase assays were performed to validate Annexin A3 as a miR-495 target in CRC cells. RESULTS: In our study, we found that miR-495 is down-regulated in CRC tissues and cell lines. Moreover, the low level of miR-495 was associated with increased expression of Annexin A3 in CRC tissues and cell lines. The invasion and EMT of CRC cells were suppressed by the overexpression of miR-495. However, the down-regulation of miR-495 promoted the invasion and EMT of CRC cells. Bioinformatics analysis predicted that Annexin A3 was a potential target gene of miR-495. Next, the luciferase reporter assay confirmed that miR-495 could directly target Annexin A3. Consistent with the effect of miR-495, the down-regulation of Annexin A3 by siRNA inhibited the invasion and EMT of CRC cells through the up-regulation of p53. The introduction of Annexin A3 in CRC cells partially blocked the effects of the miR-495 mimic. CONCLUSION: The introduction of miR-495 directly targeted Annexin A3 to inhibit the invasion and EMT of CRC cells by up-regulating p53, and the down-regulation of Annexin A3 was essential for inhibiting the invasion and EMT of CRC cells by overexpressing miR-495. Overall, the re-activation of the miR-495/Annexin A3/ p53 axis may represent a new strategy for overcoming metastasis of CRC.

High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer.

Heat shock factor 4 (HSF4) is a member of the HSF family. In this study, by using data from the Cancer Genome Atlas-Colorectal Cancer (TCGA-CRC), we investigated the expression profile and the prognostic value of the HSF4 in terms of overall survival (OS) and recurrence free survival (RFS) in CRC patients. RNA-Seq data showed that HSF4 RNA expression was significantly higher in CRC tissues (N = 380) than in the corresponding normal tissues (N = 51) (mean ± SD: 3.56 ± 1.28 vs. 1.85 ± 0.87, P < 0.0001). High HSF4 expression group had significantly higher ratio of stages III/IV patients (52/86, 60.5%) than low HSF4 expression group (110/264, 41.7%; P = 0.0024). Besides, the high HSF4 expression group also had significantly increased expression of CEA (CEA ≥ 5, 26/51, 51.0% vs. 64/186, 34.4%), higher proportion of recurrence (32/86, 37.2% vs. 48/254, 18.9%, P = 0.0005) and death (36/90, 40.0% vs. 49/277, 17.7%, P < 0.0001) compared with the low HSF4 expression group. Multivariate analysis confirmed that high HSF4 expression was an independent prognostic factor of poor OS (HR = 2.111, 95%CI: 1.350-3.302, P = 0.001) and RFS (HR = 1.958, 95%CI: 1.224-3.131, P = 0.005). Bioinformatic analysis showed that HSF4 can directly interact with DUSP26, ZBED8, and MAPK14. It is also coexpressed with PTGER1, COL11A2, CLPS, and ARSA and colocalized with PTGER1, ADRB1, PEX12, CLPS, PSEN2, KCNJ5, CPA1, ARSA, PNLIP, IRX4, CPA2, IDUA, BCKDHA, and CTRL. We hypothesized that HSF4 might exert its oncogenic effects in CRC via some of these genes. © 2017 IUBMB Life, 69(12):956-961, 2017.

UBR5 Contributes to Colorectal Cancer Progression by Destabilizing the Tumor Suppressor ECRG4.

BACKGROUND: The E3 ligase UBR5 is aberrantly expressed in diverse types of cancer. However, its expression pattern and biological function in colorectal cancer (CRC) remain unclear. METHODS: We used RT-PCR, Western blot, and immunohistochemistry to measure UBR5 expression in CRC tissues and corresponding non-tumor tissues. The expression pattern of UBR5 in CRC tissues was determined by scoring system of immunohistochemical analysis and mRNA level by RT-PCR. The statistical analyses were applied to evaluate the associations of UBR5 expression with survival rate of patients. The UBR5 gene was overexpressed or silenced with lentiviral vectors in CRC cells. And, cell proliferation and apoptosis were measured using CCK8 assay and flow cytometry. RESULTS: We found that UBR5 is abundantly overexpressed in CRC tissues than adjacent non-cancerous tissues. We also found that high UBR5 level is positively correlated with progression and poor survival in CRC patients. In addition, further multivariate analysis indicated that UBR5 and TNM stage were independent prognostic factors for overall survival in patients with CRC. Furthermore, we demonstrated that the expression of UBR5 was significantly elevated in CRC cell lines. Overexpression of UBR5 enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing UBR5 suppressed growth of CRC cells. Moreover, our findings show that UBR5 promotes CRC cell proliferation by inducing cell cycle progression and suppressing cell apoptosis. Finally, we found that UBR5 directly binds to the tumor suppressor esophageal cancer-related gene 4 (ECRG4) and increased its ubiquitination to reduce the protein stability of ECRG4. CONCLUSIONS: We identified a tumorigenic role of UBR5 in CRC and provided a novel therapeutic target for CRC patients.

[The clinical and pathological research of complete mesocolic excision on the treatment of right colon cancer].

OBJECTIVE: To verify the clinical safety of complete mesocolic excision (CME) and manufacture pathological large slices. METHODS: A prospective analysis clinical data of 85 right colon cancer in patients by the same group of surgeons at the Department of General Surgery, Beijing Friendship Hospital, Capital Medical University from January 2012 to December 2013 which were divided into two groups: CME group (n=39) and traditional radical operation group (n=46) by surgical approach. CME group and control group were compared the differences of clinic and pathologic variables, precise tissues morphometry, lymph nodes harvest, mesocolic area and so on. By comparison to operation time, blood loss, postoperative complications, flatus restoring time, drainage removal time and length of stay, the security of CME was analyzed. Statistical methods included independent sample t-test, Wilcoxon rank sum test and χ(2) test. In order to manufacture pathological large slices, the CME operation specimens were fixed. The large slices were stained by routine HE staining to detection of circumferential resection margin. RESULTS: Mean number of total lymph nodes was increased obviously in CME group (26.8±1.9 vs. 23.2±3.4, t=4.261, P=0.000). Mean number of lymph nodes of stage Ⅰ, Ⅱ were different between two groups (25.8±3.6 vs. 18.2±4.5, 26.8±7.7 vs. 24.9±6.2, t=8.776, 2.802, P=0.000). The positive lymph nodes of CME group was higher than control group (4(7) vs. 1.5(2), P=0.032), above all with statistically significant difference. Comparing CME group with the control group, there were the larger area of mesentery ((15 555±1 263) mm(2) vs. (12 493±1 002) mm(2,) t=12.456, P=0.000), the greater distance between the tumor and the high vascular tie ((116±22) mm vs. (82±11) mm, t=9.295, P=0.000), the greater distance between the normal bowel and the high vascular tie ((92±17) mm vs. (74±10) mm, t=8.132, P=0.000) of CME, with statistically significant difference. There were no statistically significant differences from operation safety when CME group was compared with the control group. The pathological large slices of colon cancer were prepared successfully and dyed evenly than those large slices were used to observe whether the lymph tube and lymph node metastasis inside the mesocolon. Existence of direct tumor invasion could be confirmed by investigating the large slices. Cancer embolus in intravascular and micro infiltration in mesocolon also could be found. CONCLUSIONS: CME operation can get the standard excision according the mesocolic area and integrity, as well as to harvest the maximum number of lymph node. The clinical application of CME is safe and does not increase the risk of operation. Circumferential resection margins can be detected by pathological large slices.

Preoperative electroacupuncture versus sham electroacupuncture for the treatment of postoperative ileus after laparoscopic surgery for colorectal cancer in China: a study protocol for a multicentre, randomised, sham-controlled trial.

INTRODUCTION: Postoperative ileus (POI) is a postoperative complication that can cause lingering recovery after colorectal resection and a heavy healthcare system burden. Acupuncture aims to prevent postoperative complications, reduce the duration of POI, help recovery and shorten hospital stays. We hypothesise that preoperative electroacupuncture (EA) can promote POI recovery under the enhanced recovery after surgery protocol after laparoscopic surgery in patients with POI. METHODS AND ANALYSIS: This is a multicentre, randomised, sham-controlled trial. A total of 80 patients will be enrolled and randomly assigned to the EA or sham electroacupuncture (SA) group. The eligible patients will receive EA or SA for one session per day with treatment frequency starting on preoperative day 1 for four consecutive days. The primary outcome is the time to first defecation. The secondary outcomes include the time to first flatus, length of postoperative hospital stay, time to tolerability of semiliquid and solid food, postoperative nausea, vomiting, pain and extent of abdominal distention, time to first ambulation, preoperative anxiety, 30-day readmission rate, the usage of anaesthetics and analgesics during operation, length of postanaesthesia care unit stay. A mechanistic study by single-cell RNA sequencing in which postintervention normal intestinal tissue samples will be collected. The results of this study will provide evidence of the effects of acupuncture on POI and promote good clinical decision to millions of patients globally every year. ETHICS AND DISSEMINATION: This study has been approved by the ethical application of Beijing University of Chinese Medicine (2022BZYLL0401), Beijing Friendship Hospital Affiliated to Capital Medical University(2022-P2-368-02), Cancer Hospital Chinese Academy of Medical Science (23/175-3917), Huanxing Cancer Hospital (2023-002-02). The results will be published in a medical journal. In addition, we plan to present them at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300077633.

Preservation of left colic artery in laparoscopic colorectal operation: The benefit challenge.

BACKGROUND: During laparoscopic resection for colorectal cancer, there is controversy regarding whether the left colic artery (LCA) should be preserved at its origin. AIM: To investigate the prognostic significance of preservation of the LCA in colorectal cancer surgery. METHODS: Patients were divided into two groups. The high ligation (H-L) technique (refers to ligation performed 1 cm from the beginning of the inferior mesenteric artery) group consisted of 46 patients, and the low ligation (L-L) technique (refers to ligation performed below the initiation of the LCA) group consisted of 148 patients. Operative time, blood loss, lymph nodes with tumor invasion, postoperative complications and recovery time, recurrence rate, and 5-year survival rate were compared between the two groups. RESULTS: The average number of lymph nodes detected in postoperative pathological specimens was 17.4/person in the H-L group and 15.9/person in the L-L group. There were 20 patients (43%) with positive lymph nodes (lymph node metastasis) in the H-L group and 60 patients (41%) in the L-L group. No statistical differences were found between the groups. Complications occurred in 12 cases (26%) in the H-L group and in 26 cases (18%) in the L-L group. The incidences of postoperative anastomotic complications and functional urinary complications were significantly lower in the L-L group. The 5-year survival rates in H-L and L-L groups were 81.7% and 81.6%, respectively, and relapse-free survival rates were 74.3% and 77.1%, respectively. The two groups were similar statistically. CONCLUSION: Complete mesenteric resection combined with lymph node dissection around the inferior mesenteric artery root while preserving the LCA is a beneficial surgical approach during laparoscopic resection for colorectal cancer.

Establishing and validating predictive nomograms for lateral pelvic lymph node metastasis in patients with rectal cancer based on radiologic factors and clinicopathologic characteristics.

INTRODUCTION: It is critical to accurately predict the occurrence of lateral pelvic lymph node (LPN) metastasis. Currently, verified predictive tools are unavailable. This study aims to establish nomograms for predicting LPN metastasis in patients with rectal cancer who received or did not receive neoadjuvant chemoradiotherapy (nCRT). MATERIALS AND METHODS: We carried out a retrospective study of patients with rectal cancer and clinical LPN metastasis who underwent total mesorectal excision (TME) and LPN dissection (LPND) from January 2012 to December 2019 at 3 institutions. We collected and evaluated their clinicopathologic and radiologic features, and constructed nomograms based on the multivariable logistic regression models. RESULTS: A total of 472 eligible patients were enrolled into the non-nCRT cohort (n = 312) and the nCRT cohort (n = 160). We established nomograms using variables from the multivariable logistic regression models in both cohorts. In the non-nCRT cohort, the variables included LPN short diameter, cT stage, cN stage, histologic grade, and malignant features, and the C-index was 0.930 in the training cohort and 0.913 in the validation cohort. In the nCRT cohort, the variables included post-nCRT LPN short diameter, ycT stage, ycN stage, histologic grade, and post-nCRT malignant features, and the C-index was 0.836 in the training dataset and 0.827 in the validation dataset. The nomograms in both cohorts were moderately calibrated and well-validated. CONCLUSIONS: We established nomograms for patients with rectal cancer that accurately predict LPN metastasis. The performance of the nomograms in both cohorts was high and well-validated.

Sarcobesity, but not visceral fat, is an independent risk factor for complications after radical resection of colorectal cancer.

Background: The influence of body composition on the outcome of colorectal cancer surgery is controversial. The aim of this study was to evaluate the effects of visceral obesity and sarcobesity on the incidence of total and surgical complications after radical resection of colorectal cancer. Methods: We collected a total of 426 patients who underwent elective radical resection of colorectal cancer at Beijing Friendship Hospital, Capital Medical University from January 2017 to May 2018. According to the inclusion and exclusion criteria, 387 patients were finally included. A CT scan at the level of the L3-L4 intervertebral disk was selected to measure the values of visceral fat area and skeletal muscle area. Multivariate analysis was used to explore the independent risk/protective factors affecting postoperative complications. Results: 128 (33.1%) patients developed complications, and 44 (11.4%) patients developed major complications. Among them, 111 patients developed surgical complications and 21 developed medical complications. Visceral fat area (Z = -3.271, p = 0.001), total fat area (Z = -2.613, p = 0.009), visceral fat area to subcutaneous fat area ratio (V/S, Z = -2.633, p = 0.008), and sarcobesity index (Z = -2.282, p = 0.023) were significantly associated with total complications. Visceral fat area (Z = -2.119, p = 0.034) and V/S (Z = -2.010, p = 0.044) were significantly associated with total surgical complications. Sarcobesity index, smoking, stoma, blood loss, surgery time, and American Society of Anesthesiology (ASA) score were selected as risk factors for total postoperative complications according to LASSO regression. Multivariate logistic regression analysis suggested that sarcobesity index was an independent risk factor for postoperative total complications and surgical complications. Subgroup analysis suggested that albumin level was an independent protective factor for postoperative total complications in male patients. Smoking, operative time, and sarcobesity index were independent risk factors, and cholesterol was an independent protective factor for total postoperative complications in female patients. Conclusion: Increased sarcobesity index is an independent risk factor for postoperative complications in patients with colorectal cancer, while visceral fat area is not. For female patients, smoking, operation time, and obesity index are independent risk factors for postoperative complications, while cholesterol is an independent protective factor. For male patients, serum albumin is an independent protective factor for postoperative complications.

A cuproptosis-related lncRNA signature to predict prognosis and immune microenvironment of colon adenocarcinoma.

Cuproptosis is a novel cell death modality but its regulatory role in the colon cancer remains obscure. This study is committed to establishing a cuproptosis-related lncRNA (CRL) signature to forecast the prognosis for colon adenocarcinoma (COAD). The Cancer Genome Atlas (TCGA) samples were randomly divided into training and validation cohorts. LASSO-COX analysis was performed to construct a prognostic signature consisting of five CRLs (AC015712.2, ZEB1-AS1, SNHG26, AP001619.1, and ZKSCAN2-DT). We found the patients with high-risk scores suffered from poor prognosis in training cohort (p < 0.001) and validation cohort (p = 0.004). Nomogram was created based on the 5-CRL signature. Calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) demonstrated the nomogram performed well in 1­, 3­, and 5­year overall survival (OS). Subsequently, we observed increased infiltration of multiple immune cells and upregulated expression of immune checkpoints and RNA methylation modification genes in high-risk patients. Additionally, gene set enrichment analysis (GSEA) revealed two tumor-related pathways, including MAPK and Wnt signaling pathways. Finally, we found AKT inhibitors, all-trans retinoic acid (ATRA), camptothecin, and thapsigargin had more sensitivity to antitumor therapy in high-risk patients. Collectively, this CRL signature is promising for the prognostic prediction and precise therapy of COAD.

Inhibition of neuroactive ligand-receptor interaction pathway can enhance immunotherapy response in colon cancer: an in silico study.

BACKGROUND: The potential mechanism underlying the association between Homologous recombination deficiency (HRD) and immunotherapy in colon cancer has not been investigated. METHODS: The exon sequencing data and transcriptome data of 456 colon adenocarcinoma (COAD) patients were obtained from the TCGA database. Pathway activity score was calculated by GSVA methods and engaged in further survival analysis. The prognostic value of the candidate pathways was validated in an external GEO cohort and an immunotherapy cohort. RESULTS: Patients with high HRD were associated with poor prognosis, lower tumor mutation burden and microsatellite instability, higher fraction genome alteration, and less sensitivity to immunotherapy in COAD. And then, the neuroactive ligand-receptor interaction pathway was over-activated in high-HRD tumors and associated with immunosuppression in colon cancer with high HRD. Besides, the pathway was associated with prognosis and immunotherapy response in COAD. Moreover, genes in this pathway such as LTB4R2 can be used as a novel target for therapy development in colon cancer. CONCLUSION: Our study not only revealed the potential mechanism of HRD and the function of the neuroactive ligand-receptor interaction pathway in colon cancer but also provided new clues for the improvement of immunotherapy response in colon cancer.