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Objective We conducted this multicenter cohort study to evaluate the current tumor‐node‐metastasis staging system and treatment modality by analyzing the survival outcomes of patient groups with stage III and IV colon cancer. Patients and Methods Stage III and IV colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database (SEER cohort) and prospectively maintained Sun Yat‐sen University (SYSU) cohort were included in this study. Kaplan‐Meier method was used to estimate the cumulative rate of overall survival (OS) between patient groups, and the inverse probability weighting method was used to calculated age and sex‐adjusted survival curves. The Cox regression model was used to identify the risk factors for OS. Results A total of 17,911 and 1135 stage III–IV cases were included in the SEER and SYSU cohorts, respectively. Among them, 1448 and 124 resectable stage IV cases underwent curative‐intent treatment in the SEER and SYSU cohorts, respectively. The T4N2b group showed a significantly worse survival outcome compared with the M1a subset receiving curative‐intent treatment (HR, 1.46; p, By analyzing the Surveillance, Epidemiology, and End Results database and in‐house cohorts, several stage III subgroups were identified in a high risk of death, especially the T4N2b group that had significantly worse overall survival than that of the M1a subset. When further categorized by risk factors, the survival of the high‐risk T4N2b patients was worse than that of the M1b subset.

Background The local recurrence of rectal cancer has been improved by total mesorectal excision following neoadjuvant chemoradiotherapy. However, in patients with low locally advanced rectal cancer, lateral pelvic recurrence remains to be addressed. Objective This study aimed to determine the efficiency of neoadjuvant radiotherapy in addressing lateral pelvic recurrence and which subgroup of patients might be optimal to receive lateral lymph node dissection. Design The MRI/CT images were reassessed for lateral lymph node status. The lateral lymph nodes with short axis ≥5 mm and ≥4 mm were considered positive in pretreatment and restaging MRI/CT. Setting This was a post hoc analysis of a prospective randomized controlled trial (FOWARC, NCT01211210). Patients A total of 495 patients with stage II or III rectal adenocarcinoma were included in the original trial. According to the excluding criteria, the finally included population consists of 253 patients; of these, 195 patients received neoadjuvant chemoradiotherapy and 94 received chemotherapy alone. Main outcomes and measures The primary outcome was the 5-year lateral pelvic recurrence rate. Results Compared with patients receiving chemotherapy alone, patients receiving additional radiotherapy had a marginal significance of lower lateral pelvic recurrence rate (6.6% vs 13.0%; p = 0.051). In the subset with pretreatment positive lateral lymph nodes, patients had a lateral pelvic recurrence rate of 22.6% and 45.1% after neoadjuvant chemoradiotherapy and chemotherapy alone. Of note, 34.9% of the pretreatment positive lateral lymph nodes were persistent after neoadjuvant chemoradiotherapy, culminating in a lateral pelvic recurrence rate of 63.3%. Limitations This is a post hoc analysis, and only the patients from the leading center were included, which limited the sample size. In addition, the lateral lymph node dissection was not performed in this cohort. Conclusions The addition of radiotherapy in neoadjuvant regimens could not address lateral pelvic recurrence adequately. Some subgroups of patients might need additional dissection. See Video Abstract at http://links.lww.com/DCR/B613. La inclusion de la radioterapia preoperatoria es insuficiiente en el control plvico lateral en un subgrupo de pacientes con cncer de recto inferior localmente avanzado un estudio posthoc controlado y randomizado ANTECEDENTES:La recurrencia local del cancer de recto ha disminuido al efectuar una excision mesorrectal total seguida de quimioradioterapia neoadyuvante. No obstante, en pacientes con cancer de tercio inferior de recto avanzado localmente, aun esta por controlarse la recurrencia pelvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pelvica lateral y en que subgrupo de pacientes seria conveniente efecutar una excision lateral de las cadenas ganglionares.DISENO:Se reevaluaron las imagenes tomograficas y de resonancia magnetica del status de las cadenas ganglionares linfaticas laterales. Los ganglios linfaticos laterales con un eje-corto > 5 mm y ≥ 4 mm se consideraron como positivos previo al tratamiento y reestadificados con RM y TAC respectivamente.ESCENARIO:Es un analisis post hoc de un studio prospectivo randomizado controlado (FOWARC, NCT01211210).PACIENTESSe incluyeron un total de 495 pacientes en estdio II o III con adenomcarcinoma rectal en el estudio original. De acuerdo a los criterios de exclusion, la poblacion final incluida consistio en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parametro mas importante fue la tasa de recurrencia pelvica lateral a cinco anos.RESULTADOS:En comparacion con los pacientes que recibieron quimioterapia sola, aquellos que ademas fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pelvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfaticos laterales positivos, los enfermos presentaron una tasa de recurrencia pelvica lateral de 22.6% y 45.1% despues de quimioradiaterapia neoadyuvante en comparacion con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfaticos laterales positivos antes del tratamiento persistieron despues de la quimioradioterapia neoadyuvante, reportandose finalmente una recurrencia pelvica lateral de un 63.3%.LIMITACIONES:Se trata de un analisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamano de la muestra. Ademas, no se efectuo la diseccion de los ganglios linfaticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pelvica lateral en forma adecuada. Algunos subgrupos de pacientes podria requerir de diseccion adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

Objective: The purpose of this study was to observe the factors related to T4 patients who underwent surgery for colorectal cancer (CRC) with peritoneal carcinomatosis. Methods: 154 T4 colorectal cancer patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University were included in the study between August, 1994 and December, 2005. Some clinical variables were selected and statistically correlated with prognosis. Results: The overall survival time was 91.7 months at the end of December of 2010 or death. The complete cytoreduction had significant survival benefit than the palliative surgery group. The age, location, histological grade, complete cytoreduction and liver metastasis were associated with overall survival time (OS) according to the univariate analysis (P < 0.05). In addition, Cox multivariate analysis showed that the complete cytoreduction (CCR) and liver metastasis were independent factor influencing survival. Conclusion: Compared with palliative surgery, the incomplete cytoreduction fails to improve patient prognosis. Patients performed completed cytoreduction have a relative good prognosis.

Background. The interventions for hemorrhoid increase access to rectal cancer screening and thus might reduce cancer death. We aimed to examine the impact of hemorrhoid on survival outcomes in rectal cancer. Methods. We identified 510 patients with stage I to III rectal cancer from a prospectively collected database. Patients were divided into hemorrhoid and non-hemorrhoid group. The primary endpoints were disease-free survival (DFS) and overall survival (OS). Results. Hemorrhoid group had significantly more stage I-II diseases in comparison to nonhemorrhoid group (71.1% vs. 55.9%, P = 0.049 ). The hemorrhoid group had significantly better DFS and OS compared to nonhemorrhoid group, the hazard ratios (HRs) of which were 0.39 (95% CI 0.17-0.88, P = 0.018 ) and 0.33 (95% CI 0.12-0.92, P = 0.034 ), respectively. Multivariate analysis revealed that hemorrhoid was independently associated with DFS [adjusted HR 0.43 (95% CI 0.17-0.95, P = 0.045 )]. A nomogram for predicting DFS outcome was generated based on hemorrhoid history, with a concordance index of 0.71 (95% CI 0.66-0.75, P < 0.001 ). Conclusions. There may exist a screening effect and survival benefit from hemorrhoid in rectal cancer, which supports the significance of rectal cancer screening in lowering its mortality.

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. Significance: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.

BACKGROUND Situs inversus totalis (SIT) is a rare anomaly in which structures are located opposite to their usual positions. It is not a premalignant condition and the association with colorectal cancer (CRC) is rare. We here report a patient with SIT who underwent laparoscopic radical resection of sigmoid colon cancer, and review the pertinent literature. CASE SUMMARY A 53-year-old woman presented with CRC and SIT and underwent a complete examination after admission. The patient then underwent laparoscopic radical resection of sigmoid colon cancer and hyperthermic intraperitoneal chemotherapy. The operation duration was 120 min, and no intraoperative complications occurred. The final pathological report showed stage T4aN0M0. Postoperative chemotherapy was administered and no evidence of recurrence was observed during 18 mo of follow-up. CONCLUSION Surgery in a patient with CRC and SIT can be safely performed on the basis of routine preoperative clinical examination.

Background Preoperative fluoropyrimidine with radiotherapy was regarded as the standard of care for locally advanced rectal cancer (LARC). The model for predicting pCR in LARC patients was based on standard treatment only. This study aimed to establish a nomogram with pretherapeutic parameters and different neoadjuvant regimens for predicting pathologic complete response (pCR) and tumor downstaging or good response (ypT0-2N0M0) after receiving neoadjuvant treatment in patients with LARC based on a randomized clinical trial. Methods Between January 2011 and February 2015, 309 patients with rectal cancer were enrolled from a prospective randomized study (NCT01211210). All pretreatment clinical parameters were collected to build a nomogram for predicting pCR and tumor downstaging. The model was subjected to bootstrap internal validation. The predictive performance of the model was assessed with concordance index (C-index) and calibration plots. Results Of the 309 patients, 53 (17.2%) achieved pCR and 132 (42.7%) patients were classified as tumor downstaging with ypT0-2N0M0. Based on the logistic-regression analysis and clinical consideration, tumor length (P = 0.005), tumor circumferential extent (P = 0.036), distance from the anal verge (P = 0.019), and neoadjuvant treatment regimen (P Conclusions The nomogram provided individual prediction responses to different preoperative treatment for patients with rectal cancer. This model might help physicians in selecting an optimized treatment, but warrants further external validation.

Summary Background PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. Methods The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18–75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3–T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov , NCT03926338 , and is ongoing. Findings Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8–17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64–99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38–86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1–2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. Interpretation Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. Funding The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. Translation For the Chinese translation of the abstract see Supplementary Materials section.

BackgroundTumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC).MethodsA CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score.ResultsThree CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts.ConclusionsThis study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.

Previously, we identified that sortilin related VPS10 domain containing receptor 1 (SorCS1) was hypermethylated in colorectal cancer (CRC) tissues. Here, we aimed to investigate the association between CRC and SorCS1. DNA methylation was determined by methylation-specific polymerase chain reaction (MSP) or quantitative real-time methylation analysis (MethyLight). Colorectal cancer tissue specimens from 239 patients that had undergone surgical treatment were evaluated using immunohistochemistry (IHC) analysis for the expression of SorCS1 and correlated with clinicopathological variables and prognosis. We found that SorCS1 was hypermethylated in CRC cell lines and 67.5% (27/40) CRC tumor tissues. The loss of SorCS1 mRNA (p

Background Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes. Methods Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype. Results The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively. Conclusion We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.

Objective: To retrospectively analyze the prognostic differences between LCC and RCC, and to explore the occurrence of such differences in the relevant factors. Provide clinical basis for the individualization and precise treatment of CRC. Methods: The clinical and follow-up data of 155 T4 CRC patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University between August, 1994 and December, 2005. The age, sex, family history, staging, pathologic features, DFS, OS and other information were collected. The survival of the LCC (Left colon cancer) and RCC (Right colon cancer) patients was analyzed by Kaplan-Meier method. The survival curves of the LCC and RCC patients were compared by log-rank test. Results: There are statistically significant differences in N stage, CCR, family history and histological grade between two groups. Gender, histological grade and CCR were factors associated with OS and DFS of the T4 LCC according to the univariate and multivariate analyses. In addition, only the CCR was found to be the factor associated with OS and DFS of the T4 RCC. The mean survival of the patients was 104.23 months (range, 87.32 - 121.15 months) in the T4 RCC and 76.96 months (range, 61.32 - 92.60 months) in the T4 LCC groups. The complete cytoreduction had significant survival benefit than the palliative surgery group. Conclusion: The T4 RCC patients with CCR had a relatively better prognosis than LCC. Compared with palliative surgery, the incomplete cytoreduction fails to improve the prognosis of patient.

Long non‐coding RNAs (lncRNAs) could regulate growth and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to investigate the mechanism of lncRNA F11‐AS1 in hepatitis B virus (HBV)–related HCC. The relation of lncRNA F11‐AS1 expression in HBV‐related HCC tissues to prognosis was analysed in silico. Stably HBV‐expressing HepG2.2.15 cells were established to explore the regulation of lncRNA F11‐AS1 by HBx protein, as well as to study the effects of overexpressed lncRNA F11‐AS1 on proliferation, migration, invasion and apoptosis in vitro. Subsequently, the underlying interactions and roles of lncRNA F11‐AS1/miR‐211‐5p/NR1I3 axis in HBV‐related HCC were investigated. Additionally, the influence of lncRNA F11‐AS1 and miR‐211‐5p on tumour growth and metastasis capacity of HepG2.2.15 cells were studied on tumour‐bearing nude mice. Poor expression of lncRNA F11‐AS1 was correlated with poor prognosis in patients with HBV‐related HCC, and its down‐regulation was caused by the HBx protein. lncRNA F11‐AS1 was proved to up‐regulate the NR1I3 expression by binding to miR‐211‐5p. Overexpression of lncRNA F11‐AS1 reduced the proliferation, migration and invasion, yet induced apoptosis of HepG2.2.15 cells in vitro, which could be abolished by overexpression of miR‐211‐5p. Additionally, either lncRNA F11‐AS1 overexpression or miR‐211‐5p inhibition attenuated the tumour growth and metastasis capacity of HepG2.2.15 cells in vivo. Collectively, lncRNA F11‐AS1 acted as a modulator of miR‐211‐5p to positively regulate the expression of NR1I3, and the lncRNA F11‐AS1/miR‐211‐5p/NR1I3 axis participated in HBV‐related HCC progression via interference with the cellular physiology of HCC.

Introduction Although neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC. Patients and Methods Patients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT0-2N0M0. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety. Results Overall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated. Conclusion Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.

BACKGROUND Carcinoembryonic antigen (CEA) is a commonly used biomarker in colorectal cancer. However, controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer. AIM To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer. METHODS We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. RESULTS In all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort (2/3 of 556, n = 371) and the validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, the presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P < 0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18, 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95%CI: 0.93-2.33, P = 0.096; validation cohort: HR = 2.61, 95%CI: 1.38-4.95, P = 0.003). CONCLUSION Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer. Higher CEA/tumor size is associated with worse OS and DFS.

PURPOSE In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% ( P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% ( P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% ( P = .971 by log-rank test), respectively. CONCLUSION mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.

BACKGROUND: Systemic inflammation markers have shown prognostic values with variability in rectal cancer. Considering the association of serum calcium with inflammation, we aimed to examine whether it could improve systemic inflammation markers for survival prediction. METHODS: We enrolled 508 patients with stage I to III rectal cancer who underwent curative resection. The cohort was grouped by corrected serum calcium (cCa), platelet-to-lymphocyte ratio (PLR), and CaPLR (a score model combining cCa with PLR) for survival analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare models in survival prediction. The primary endpoint was disease-free survival (DFS). RESULTS: A total of 26.7% (136/508) patients reached recurrence after curative surgery. Both high cCa (HR 1.486; 95% CI, 1.018–2.171; P=0.040) and high PLR (HR 1.452; 95% CI, 1.059–1.991; P=0.021) were significantly associated with worse DFS. In model comparison, the AIC and LR were improved after cCa was added to PLR model in DFS prediction (AIC: 1,704.83 vs. 1,707.14 vs. 1,707.15; LR: 8.68 vs. 4.37 vs. 4.36; P=0.037). The CaPLR was developed for DFS prediction with adjusted HRs of 2.216 (95% CI, 1.256–3.909; P=0.006) and 1.679 (95% CI, 1.004–2.836; P=0.047) for high and intermediate score group respectively compared to low score group. A nomogram for predicting DFS was generated by using CaPLR and other clinical predictors, with a concordance index of 0.705 (95% CI, 0.620–0.789; P

Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

Background We aimed to develop a radiomic model based on pre-treatment computed tomography (CT) to predict the pathological complete response (pCR) in patients with rectal cancer after neoadjuvant treatment and tried to integrate our model with magnetic resonance imaging (MRI)-based radiomic signature. Methods This was a secondary analysis of the FOWARC randomized controlled trial. Radiomic features were extracted from pre-treatment portal venous-phase contrast-enhanced CT images of 177 patients with rectal cancer. Patients were randomly allocated to the primary and validation cohort. The least absolute shrinkage and selection operator regression was applied to select predictive features to build a radiomic signature for pCR prediction (rad-score). This CT-based rad-score was integrated with clinicopathological variables using gradient boosting machine (GBM) or MRI-based rad-score to construct comprehensive models for pCR prediction. The performance of CT-based model was evaluated and compared by receiver operator characteristic (ROC) curve analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare CT-based rad-score, MRI-based rad-score and the combined rad-score. Results We developed a CT-based rad-score for pCR prediction and a gradient boosting machine (GBM) model was built after clinicopathological variables were incorporated, with improved AUCs of 0.997 [95% CI 0.990–1.000] and 0.822 [95% CI 0.649–0.995] in the primary and validation cohort, respectively. Moreover, we constructed a combined model of CT- and MRI-based radiomic signatures that achieve better AIC (75.49 vs. 81.34 vs.82.39) than CT-based rad-score (P = 0.005) and MRI-based rad-score (P = 0.003) alone did. Conclusions The CT-based radiomic models we constructed may provide a useful and reliable tool to predict pCR after neoadjuvant treatment, identify patients that are appropriate for a 'watch and wait' approach, and thus avoid overtreatment. Moreover, the CT-based radiomic signature may add predictive value to the MRI-based models for clinical decision making.

OBJECTIVE To compare the outcomes of laparoscopic total mesorectal excision (L-TME) with Denonvilliers' fascia (DVF) preservation versus resection on urogenital function of male patients with rectal cancer. BACKGROUND The protective effect of DVF during L-TME on pelvic autonomic nerves and postoperative urogenital function remains controversial. METHODS Between August 26, 2015 and July 18, 2019, 253 male patients with cT1-4 (T1-2 for anterior wall) N0-2M0 rectal cancer from 11 institutions were enrolled, and randomly assigned to L-TME with DVF preservation (Exp-group, n = 123) or resection procedures (Con-group, n = 130). Urinary function was assessed by residual urine volume, maximal flow rate, and International Prostate Symptom Score; sexual function was assessed by 5-item version of the International Index of Erectile Function (IIEF-5) and ejaculation grading. RESULTS The Exp-group patients showed a lower urinary dysfunction rate (6.8% vs 25.4%, P = 0.003), higher maximal flow rate (16.25 ± 8.02 vs 12.40 ± 7.05 mL/s, P = 0.007), and lower International Prostate Symptom Score (6.55 ± 5.86 vs 8.57 ± 5.85, P = 0.026) than the Con-group patients at 2 weeks after surgery. The incidence of erectile dysfunction (IIEF-5 ≤ 11) at 12 months after surgery was lower in the Exp-group than in the Con-group (12.5% vs 34.2%, P = 0.023); Exp-group manifested superior IIEF-5 (16.63 ± 6.28 vs 12.26 ± 6.83, P = 0.018). The incidence of ejaculation dysfunction was lower in the Exp-group than in the Con-group at 12 months after surgery (10.0% vs 29.4%, P = 0.034). CONCLUSIONS DVF preservation during L-TME revealed protective effects on postoperative urogenital function, and could be a better choice for male rectal cancer patients with specific staging and location. TRIAL REGISTRATION NUMBER NCT02435758.

Background The clinical incidence of appendiceal mucinous adenocarcinoma is low. Moreover, the case reports of postoperative relapse after surgery are rarely based on literature search results. Here, we report such a case spanning nearly 7 years and and review the relevant literature. Case presentation A 50-year-old female underwent additional surgery after appendectomy, and pathological examination confirmed mucinous adenocarcinoma. The patients underwent HIPEC (hyperthermic intraoperative chemotherapy) and adjuvant chemotherapy. Twenty-six months after the previous surgeries, another surgery, HIPEC, and adjuvant chemotherapy were performed again due to tumour recurrence. To date, the follow-up time is 43 months, and no recurrence or metastasis has been found. Conclusions Appendix mucinous adenocarcinoma has a poor prognosis and the diagnosis depends on pathological and immunohistochemical examinations. Its clinical manifestations are non-specific, and CRS + HIPEC should be used for treatment, which is safe and effective.

Background The incidence of anal squamous cell carcinoma (SCC) has been steadily growing globally in the past decade. Clinical data on anal SCC from China are rare. We conducted this study to describe the clinical and epidemiological characteristics of anal SCC in China and explore prognostic factors of outcomes among patients with anal SCC. Methods We audited demographic characteristics, relevant symptoms, risk factors, treatment modalities and outcomes for patients diagnosed with anal SCC at 11 medical institutions in China between January 2007 and July 2018. Results A total of 144 patients (109 females) were diagnosed with SCC during this period. Median age at initial diagnosis was 52.0 (interquartile range: 46.0–61.8) years. The most common symptoms were bleeding (n = 93, 64.6%), noticing a lump (n = 49, 34.0%), and pain (n = 47, 32.6%). The proportion of patients at the American Joint Committee on Cancer (AJCC) stages I-IV were 10 (6.9%), 22 (15.3%), 61 (42.4%) and 8 (5.6%), respectively, and AJCC stages in 43 (29.9%) patients were unknown. Thirty-six patients (25.0%) underwent abdominoperineal resection initially. Univariable analysis showed that T stage predicted recurrence-free survival (RFS) (Hazard ratio [HR] = 3.03, 95% Confidence interval [CI]: 1.10–8.37, p = 0.032), and age group (HR = 2.90, 95% CI: 1.12–7.49, p = 0.028), AJCC stage (HR = 4.56, 95% CI: 1.02–20.35, p = 0.046), and N stage (HR = 3.05, 95% CI: 1.07–8.74, p = 0.038) predicted overall survival (OS). Conclusions T stage was identified as prognostic factor of RFS, and age, AJCC stage, and N stage were identified as prognostic factors of OS. Improving symptom awareness and earlier presentation among patients potentially at risk for anal SCC should be encouraged. Familiarity with the standard treatment among health care providers in China should be further improved.

Objective: To observe the factors related to survival and prognosis of patients with resectable stage T4 colorectal cancer. Methods : 148 patients with resectable stage T4 colorectal cancer who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University between August, 1994 and December, 2005 were retrospectively analyzed. Univariate and multivariate analyses of associations between clinicopathological variables and survival were analyzed using the Cox regression model. Results: At the end of December of 2010 or death, the 5-year and 10 years OS rates were 49.0% and 32.2% respectively, the median OS was 25 months. The disease free survival rates (DFS) at 5 and 10 years were 44.2% and 30.3% respectively. In univariate analysis, patients with postoperative pathology lymph node metastasis was associated with the prognosis of patients with OS (all P< 0.01), postoperative adjuvant therapy failed to improve OS and DFS (P>0.05). Postoperative pathology lymph node metastasis was associated with DFS too (all P< 0.01). In multivariate analysis, postoperative pathology lymph node metastasis was independent factor affected OS and DFS in colorectal cancer patients. Conclusion: Postoperative prognosis of T4 colorectal cancer patients is poor, postoperative pathology lymph node positive was an independent factor affect OS and DFS.

Purpose This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. Patients and Methods Patients were enrolled to receive cetuximab (500 mg/m2) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. Results Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%–48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%–36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. Conclusion Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. Implications for Practice This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.

Background: The case–control study aimed to investigate the association between the −31G>C polymorphism in the promoter of survivin gene and the susceptibility to sporadic colorectal cancer (CRC) in a Southern Chinese population. Materials and Methods: The study was carried out on 711 healthy controls and 702 CRC cases of a Southern Chinese population. Survivin gene −31G>C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The association between CRC risk and −31G>C genetic polymorphism was estimated using an unconditional logistic regression model. Results: The number of CC genotype carried in CRC patients was much higher than those of controls (P < 0.001). Compared with CC genotypes, GC, GG genotypes and −31G wild-type genotypes (i.e., GC + GG) had a significantly decreased risk of CRC (P < 0.001). In addition, survivin −31G wild-type genotypes were not associated with decreased risk of sporadic CRC patients with body mass index (BMI) ≥28.0 kg/m2, family cancer history, and premenopausal. Conclusion: Survivin −31G>C polymorphism is associated with sporadic CRC risk in the Southern Chinese population. The −31G wild-type genotypes and GC, GG genotypes are the independent protective factors against sporadic CRC excluding those with a BMI ≥28.0 kg/m2, family cancer history, and premenopausal.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to block tumor-associated inflammation in rectal cancer. However, the perioperative use of NSAIDs remains controversial. This study was designed to investigate whether the perioperative use of NSAIDs influences outcomes and to provide a predictive marker to identify patients who would benefit from NSAIDs. We enrolled 515 patients with stage I to III rectal cancer in this retrospective study. Patients were classified into the NSAID and non-NSAID groups according to their perioperative use of NSAIDs. The whole cohort was stratified by platelet-to-lymphocyte ratio (PLR). The primary endpoints were disease-free survival (DFS) and overall survival (OS). The NSAID group had a 12.6% lower risk of recurrence than the non-NSAID group (P = 0.015), while the association with survival was nonsignificant. In the high-PLR subset, the NSAID group had a 17.3% lower risk of recurrence (P = 0.003) and a better DFS (P = 0.033) outcome than the non-NSAID group. Multivariate analysis confirmed this independent significant association with DFS (P = 0.023). In the low-PLR subset, the association of NSAID use with survival was nonsignificant. Perioperative use of NSAIDs was associated with improved survival outcomes in rectal cancer patients with high PLR.

Purpose: To investigate the clinical effectiveness and safety of ultrasound (US)-guided percutaneous microwave ablation (MWA) for colorectal liver metastasis (CRLM) and evaluate the influencing factors of local efficacy. Methods: From January 2013 to January 2017, 137 CRLM patients accepting US-guided percutaneous MWA were included. The 2450-MHz microwave ablation system and a cooled-shaft antenna were used. All patients were regularly followed up for at least 6 months. Technical success, complete ablation, local tumor progression (LTP), complications and side effects were assessed. Logistic regression analysis was used to identify the independent prognostic factors for LTP. Results: In total, 411 lesions (mean diameter 15.4 ± 7.2 mm, range 5–67 mm) were treated. Complete ablation was achieved in 99.27% (408/411) of lesions and 97.81% (134/137) of patients. LTP occurred in 5.35% (22/411) of lesions and 16.06% (22/137) of patients. LTP was more likely to occur in lesions larger than 3 cm in diameter (OR: 14.71; p

With the increase in sphincter preserving rate of rectal cancer (RC) cancer, postoperative quality-of-life, such as genital dysfunction, has become a major issue in the patient management. In this study, we proposed a measurement, namely, the sphincter preserving length (SPL), and investigated the relationship between SPL and postoperative genital function and survival in RC patients.A total of 536 male patients who had a diagnosis of RC and underwent sphincter preserving rectal resection in the Sixth Affiliated Hospital of Sun Yat-sen University and the First Affiliated Hospital of Sun Yat-sen University between October 1997 and December 2013 were included in our study. SPL was defined as the distance between the lowest edge of the tumor to dentate line. Postoperative genital function was evaluated by erection function and ejaculation function. Five-year survival status was extracted from the hospital database.Larger SPL was significantly associated with poorer postoperative erection and ejaculation function. For a SPL of 7.25 cm, the sensitivity and specificity of the diagnosis of erection dysfunction was 68.6% and 68.8%, respectively. The corresponding sensitivity and specificity for the diagnosis of ejaculation dysfunction was 70.9% and 75.7%, respectively. SPL was also negatively associated with survival rate. Compared with lower anterior resection, patients with lower RC who underwent local resection or draw-out colon-anal anastomosis had better postoperative genital function.SPL might be a useful measurement to assess the risk of postoperative genital dysfunction and survival status and an indicator for initiation of early preventative treatment in patients with RC.

Purpose The prognostic value of the tumor-to-liver uptake ratio (TLR) from 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F–FDG-PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from 18F–FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection. Methods From April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent 18F–FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative 18F–FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS). Results ROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P 6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with elevated TLR. Cox regression analysis showed that elevated TLR [>6.2; hazard ratio (HR): 3.109–57.463; P 4.4 cm; HR: 1.636–19.155; P = 0.006) were independent risk factors for DFS. Meanwhile, elevated TLR (>6.2; HR: 1.398–84.945; P = 0.023) and lymphovascular/neural invasion (positive; HR: 1.278–12.777; P = 0.017) were independent risk factors for OS. Conclusion Elevated TLR predicted worse DFS and OS for stage IIA CRC patients and might serve as a potential radiological index to identify candidates for neoadjuvant or adjuvant chemotherapy. Stage IIA CRC patients with elevated TLR should be monitored carefully for early detection of possible recurrence.

// Pu-Ning Wang 1, * , Jun Huang 1, * , Ying-Hua Duan 2, * , Jia-Min Zhou 1 , Pin-Zhu Huang 1 , Xin-Juan Fan 3 , Yan Huang 3 , Lei Wang 1 , Huan-Liang Liu 4 , Jian-Ping Wang 1 , Mei-Jin Huang 1 1 Department of Colorectal Surgery, The 6th Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 2 Department of Traditional Chinese Medicine, The 1st Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 3 Department of Pathology, The 6th Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 4 Gastrointestinal Diseases Research Institute of Guangdong Province, The 6th Affiliated Hospital, Sun Yat-sen University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Mei-Jin Huang, email: maymay0129@139.com Keywords: phosphorylated mitogen-activated protein kinase kinase 4, colorectal cancer, metastasis Received: September 20, 2016 Accepted: February 01, 2017 Published: March 11, 2017 ABSTRACT Mitogen-activated protein kinase kinase 4 (MKK4) is a key mediator of Jun N-terminal kinase signaling and influences malignant metastasis. Here, we used immunohistochemistry to assess phosphorylated MMK4 (pMKK4) levels and examine their association with the clinicopathological features of a pilot set of patient samples consisting of normal colonic mucosa (NCM), colorectal adenoma (CA), and colorectal cancer (CRC) tissues. pMKK4 levels were also assessed in a validation set of CRC cases with accompanying follow-up data to confirm their clinicopathological and prognostic significance. pMKK4 levels, which were high in 79.17% of NCM samples, were downregulated in 33.33% of CA and 63.54% of CRC samples. pMKK4 downregulation was associated with metastasis, especially to the liver. In the validation set, pMKK4 downregulation was associated with increases in invasive depth, lymph node metastasis, distant metastasis, and TNM stage. Univariate analysis indicated that pMKK4 score, tumor differentiation, and TNM stage were correlated with disease-free survival and overall survival. Multivariate analysis indicated that decreased pMKK4 expression was an independent risk factor for disease-free survival in CRC patients. These results suggest that CRC patients with low pMKK4 immunochemistry scores should be monitored carefully for early detection of possible recurrences, especially liver metastasis.

Although abnormal expression of eukaryotic initiation factor 6 (eIF6) has been found in several human solid tumors, the functions and underlying mechanisms of eIF6 in the progression of colorectal cancer (CRC) still needs further elucidation. In the present study, large-scale gene analysis based on Oncomine and The Cancer Genome Atlas (TCGA) database revealed significantly higher baseline expression of eIF6 in colorectal cancer than in normal tissues. Furthermore, our Chinese cohort study revealed that high expression of eIF6 was correlated with aggressive characteristics and poor survival in CRC patients. Functional studies using magnetic nanoparticle extraction indicated that eIF6 was an oncogene in CRC cells. Regarding its mechanism, through Gene ontology (GO) and KEGG pathway analysis based on TCGA RNAseq database, we found that eIF6 can activate multiple AKT-related cancer signaling pathways, such as p-AKT\MMP1\cyclinD1\Bcl2-related signaling, to regulate cell proliferation, invasion, cell cycle and apoptosis in CRC. Collectively, these findings suggested that eIF6 can positively regulate AKT-related cancer signaling and enhance tumorigenicity in CRC, and may serve as a potential prognostic indicator and therapeutic target in CRC.

Skin rash, diarrhea and hepatotoxicity are the most common toxicities of Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study investigated the effects of genetic polymorphisms of drug target, metabolizing enzymes and transporters on Gefitinib toxicities. Thirty single-nucleotide polymorphisms, including EGFR, cytochromes P450 and ATP-binding cassette (ABC), were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform in 59 non-small cell lung cancer patients treated with Gefitinib. Correlation analyses were performed to evaluate their effects on Gefitinib-induced toxicities. ABCB1 rs1128503 TT genotype was a significant high-risk determinant of both skin rash and diarrhea, with 15.78- and 10.78-fold of incident risk increased, respectively. (odds ratio (OR)=15.78, 95% confidence interval (CI) 2.01-124.1, P=0.0087; OR=10.78, 95% CI 1.54-75.40, P=0.0166 vs non-TT genotypes). Patients with ABCB1 rs1128503 TT genotype had greater risk of skin rash and diarrhea. Therefore, polymorphism analyses of ABCB1 might be beneficial to optimize Gefitinib treatment.

Background: Neoadjuvant chemoradiotherapy induced pathologic complete response (pCR) is associated with an excellent outcome for locally advanced rectal cancer (LARC) patients. However, it is unclear if patients achieving a pCR could further benefit from adjuvant chemotherapy (ACT). Methods: This retrospective study recruited consecutive LARC patients who received neoadjuvant therapy and total mesorectal excision from 2010 to 2018. The pCR patients who received different ACT cycles were compared by propensity score matching. Overall survival (OS), disease free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by the Kaplan-Meier method and log-rank test. Findings: In total, 1041 consecutive pCR patients (median age, 55.0 years; 56.9% male) were included. Of whom, 303 (29.1%) patients received non-ACT treatment, and 738 patients (70.9%) received fluoropyrimidine-based ACT (range, 1-12 cycles; median, 4 cycles). Specifically, 57.6% of patients (425/738) received 1-4 cycles of ACT, and 42.4% of patients (313/738) received 5 or more cycles of ACT. After 1:3 propensity matching, 712 patients who received ACT were matched to 297 patients who did not receive ACT. The 3-year outcomes (OS, DFS, LRFS, and DMFS) of the ACT and non-ACT subgroups were similar (all P > 0.05). Moreover, the subsets of patients who received different ACT cycle(s) (0 vs. 1-4 cycles and 0 vs. ≥ 5 cycles) also had similar 3-year OS, DFS, LRFS, and DMFS (all P > 0.05). In a stratified analysis, ACT treatment did not improve the survival outcomes (OS, DFS, LRFS and DMFS) of the high-risk patients who with baseline cT3-4 and/or cN1-2 (all P > 0.05). Interpretation: ACT administration could not provide additional survival benefits for neoadjuvant treatment-induced pCR LARC patients, even if is given much more cycles. Particularly, for the baseline high-risk subset patients, a pCR status is a guarantee of excellent outcome and ACT would be unnecessary. Funding Statement: This study was supported by Natural Science Foundation of China (No. 81872188), International Centre for Genetic Engineering and Biotechnology Research Grant (No. CRP/CHN16-04_EC), Guangdong Natural Science Foundation for Distinguished Young Scholar (No. 2014A030306016), the Science and Technology Planning Project of Guangdong Province (No. 2017B090901065). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This study was approved by the Clinical Ethics Review Committee at the Sixth Affiliated Hospital of Sun Yat-sen University.

99 Background: Conversion therapy for unresectable colorectal liver metastases (LM) can downsize tumours and create a situation where the patient has no evidence of disease (NED). We assessed the effectiveness of cetuximab plus mFOLFOXIRI or mFOLFOXIRI in this setting. Methods: FOCULM was a prospective 2:1 controlled, multicenter, phase II trial. Given no free drugs offered and the patients' affordability for cetuximab, the study design has been amended from randomization to non-randomization since September, 2016. Patients with unresectable LM were assigned to receive cetuximab (500mg/m2) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 2800mg/m2 46h infusion, every 2 weeks) (group A) or mFOLFOXIRI (group B). Primary endpoint was the rate of NED achieved, secondary endpoints were ORR, resection rate, the rate of local and ablative treatment (LAT), OS, PFS and DpR. Results: From February 2014 to July 2019, 114 patients were enrolled at 6 centers in China and 101 patients were in the ITT population (67 group A, 34 group B). Treatment groups were generally well balanced, although more patients with ≥5 LM were in group A. The rate of NED achieved was 62.7% in group A and 38.2% in group B (P = 0.020). At a median follow-up of 19.4 months, patients in group A had significantly prolonged the mOS, increased ORR, the rate of LAT and DpR compared with those in group B (Table). Patients with NED achieved yielded a significant survival benefit, whether in group A (Not reached vs. 49.4 months; P = 0.001) or group B (Not reached vs. 25.1 months; P = 0.007). Conclusions: The addition of cetuximab to a mFOLFOXIRI in patients with RAS/BRAF wild-type unresectable LM colorectal cancer significantly improved the rate of NED achieved, ORR and OS. Clinical trial information: NCT02063529. [Table: see text]

Background Thiopurine drugs plays an important role for immunosuppressive therapy in inflammatory bowel disease. The molecular mechanism of the thiopurine toxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to assess the impact of DNA-TGN levels on thiopurine-induced toxicity. Methods Patients over 18 years who were diagnosed with IBD and prescribed on thiopurines from February 2019 to August 2019 were recruited. All of them were genotyped with NUDT15 R139C before the thiopurine therapy. A novel assay was established to measure levels of DNA-TGN in blood leucocytes. The DNA-TGN and 6TGN levels were correlated with clinical toxicity. Results 185 patients with Crohn’s disease and 5 patients with ulcerative colitis were included in this study. DNA-TGN and 6TGN levels could be quantified in 229 patients’ blood samples. Thiopurine-induced leukopoenia (TIL) arose in 19 individuals with the median 6TGN level of 308.0 pmol/8×108 RBC which was not significantly different from the patients without TIL (p = 0.050). However, there was a significant association between DNA-TGN levels and TIL. Patients who developed TIL were identified with a higher DNA-TGN levels compared with those who did not (p = 0.00030, 456.9 (63.3–879.2) vs. 268.9 (45.6–916.8) fmol/μg DNA). The area under the ROC curves of the continuous DNA-TGN concentration to predict TIL was 0.75 (95% CI: 0.63~0.87) and almost 84% (16/19) of the TIL could be explained based on the DNA-TGN cut-off value of 343.9 fmol/μg DNA Conclusion This study shows that quantification of DNA-TGN levels can be applied to gauge thioprine therapy and avoid TIL after pre-genotyping NUDT15 R139C in inflammatory bowel disease patients.

Background The clinical factors that accurately predict the response to preoperative treatment in rectal cancer were yet unknown. The carcinoembryonic antigen (CEA) clearance pattern during neoadjuvant treatment has been developed and the predictive value explored in rectal cancer patients with elevated CEA levels (> 5 ng/mL). Methods The training cohort was derived from the FOWARC prospective phase III trial, and 71/483 eligible patients were included. The validation cohort consisted of 75/587 consecutive rectal cancer patients from Xiangya Hospital between 2014 and 2015. The kinetic changes in serum CEA were measured at different time points during the neoadjuvant treatment. An exponential trend line was drawn using the CEA values. The patients were categorized into two groups based on the R2 value of the trend line, which indicates the correlation coefficient between the exponential graph and measured CEA values: exponential decrease group (0.9

// Jianwei Zhang 1,* , Yue Cai 1,* , Huabin Hu 1 , Ping Lan 2 , Lei Wang 2 , Meijin Huang 2 , Liang Kang 2 , Xiaojian Wu 2 , Hui Wang 2 , Jiayu Ling 1 , Jian Xiao 1 , Jianping Wang 2 and Yanhong Deng 1 1 Department of Medical Oncology, The Sixth Affiliated Hospital of Sun-Yat Sen University, Guangzhou, Guangdong, P.R. China 2 Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun-Yat sen University, Guangzhou, Guangdong, P.R. China * These authors have contributed equally to this work Correspondence to: Jianping Wang, email: // Yanhong Deng, email: // Keywords : neoadjuvant chemotherapy, nomogram, predictive, rectal cancer Received : September 01, 2015 Accepted : November 25, 2015 Published : December 04, 2015 Abstract Objective: To develop an accurate model with pre-treatment parameters to predict tumor regression and down-staging in locally advanced rectal cancer patients, basing the cohort of preoperative chemotherapy alone in FOWARC study. Patients and Methods: From Jan 2011 to Feb 2015, complete data was available for 137 out of 165 patients who received preoperative chemotherapy alone. All pre-treatment clinical parameters were collected. Tumor regression grade (TRG) 0-1 was defined as good regression, and pathological TNM stage (ypTNM) 0-I after neoadjuvant treatment was defined as good down-staging. Nomogram was established to predict tumor regression and down-staging. The predictive performance of the model was assessed with concordance index and calibration plots. Results: Of the 137 patients, 10 had TRG 0 (complete regression); 32 patients, TRG 1; and 95 patients, TRG 2 and 3 (poor regression); 56 (40.9%) patients were classified as good down-staging with ypTNM stage 0-I. The predictive nomograms were developed to predict the probability of TRG 0-1 and good down-staging with a C-index of 0.72 (95% CI: 0.604-0.797) and 0.76 (95% CI: 0.681-0.844). Calibration plots showed good statistical performance on internal validation. Predictive factors in the models included tumor length, tumor circumferential extent, age, and ApoA1. Conclusions: The model based on available clinical parameters could accurately predict early efficacy with neoadjuvant mFOLFOX6 chemotherapy alone, which might help in patient selection for optimized treatment.

PURPOSE To evaluate retrospectively the postoperative genital function, the local recurrence, and the survival rate impacted by laparoscopic or open surgery for rectal cancer (RC) in male patients. METHODS A total of 398 male RC patients after laparoscopic or open total mesorectal excision (TME) of rectomy (205 patients in the TME with laparoscopy group, and 193 patients in the control group) were included in our study, between October 1997 and December 2013. Postoperative genital function, local recurrence, and the 5-year survival rate were analyzed, retrospectively. RESULTS The rate of erection dysfunction was lower in the laparoscopic group (60.0%) than in the open group (82.4%, P

Currently, the majority cases of the novel down-to-up transanal total mesorectal excision (TaTME) were performed in a hybrid approach with conventional laparoscopic assistance because of less operative difficulty. However, although cases are limited, the successes of TaTME in a pure approach (without laparoscopic assistance) indicate that the costly and less mini-invasive hybrid TaTME could be potentially avoided. In the present single institutional, prospective study, we attempted to demonstrate the safety and feasibility of this approach in rectal cancer by evaluating the short-term results of our first 20 TaTME cases. For the majority of cases, we adopted a strategy that laparoscopic assistance was not introduced unless it was required during the planned pure TaTME procedure. A total of 20 patients (12 males and 8 females) were analyzed in this study, including 11 cases (55 %) of pure TaTME and 9 cases (45 %) of hybrid TaTME. Overall, the median operative time was 200 min (range 70–420), along with a median estimated blood loss of 50 ml (range 20–800). Morbidity rate was 20 % (one urethral injury, two urinary retentions, one anastomotic hemorrhage and one mild anastomotic leak). The median number of harvested lymph nodes was 12 (range 1–20). All specimens were intact in mesorectum without positive distal and circumferential resection margins. Among the 15 patients who were preoperatively scheduled to undertake pure TaTME, four patients (26.7 %) required converting to laparoscopic assistance. Moreover, among these 15 patients, the results of the comparative analysis between female and male subgroups favor the former, suggesting easier operation in them. This preliminary study demonstrates that TaTME in rectal cancer is safe and feasible. The strategy of not introducing laparoscopic assistance unless it is required while performing the planned pTaTME should be cautiously explored. Further studies with larger sample size and longer follow-up are warranted.

Background Perioperative administration of dexamethasone may augment recurrence and mortality after tumor resection possibly by immunosuppression, which, unfortunately, has never been noted. We therefore carried out a retrospective study in rectal cancer to validate the hypothesis. Methods Five hundreds and fifteen patients with stage I to III rectal cancers who underwent a curative resection from June 2007 and June 2011 were enrolled in the current study. Patients who had been given intravenous (IV) dexamethasone (4–10 mg) postoperatively and/or intraoperatively were assigned to dexamethasone group. The outcome of dexamethasone group and non-dexamethasone group were compared. The primary outcome was disease-free survival (DFS) and overall survival (OS). Results dexamethasone group had significant lower three-year DFS (62.3% vs 71.8%, P = 0.026) and OS (74.1% vs 82.9%, P = 0.031) rate in comparison to non-dexamethasone group, the hazard ratios (HRs) of which were 1.59 (95% CI 1.05–2.39, P = 0.028) and 1.77 (95% CI 1.05–3.01, P = 0.034), respectively. Multivariate analysis revealed that administration of systemic dexamethasone were independently associated with DFS [adjusted HR 1.60 (95% CI 1.03–2.49, p = 0.039)], but for OS, dexamethasone didn't remain significant in this model. In the analyses of a subgroup of 428 patients (55/428 in dexamethasone group) without perioperative blood transfusion, dexamethasone had independently impact on both DFS and OS. Conclusion Patients not given dexamethasone had better three-year survival outcomes compared with patients given dexamethasone perioperatively. Our results indicate that rectal cancer patients treated with curative surgery may get survival benefit from avoiding low-dose perioperative dexamethasone.

Long noncoding RNAs (lncRNAs) play a critical role in the initiation and progression of colorectal cancer (CRC), but little is known about the function of lncRNAs in the colorectal liver metastasis (CLM). This study was designed to identify specific lncRNAs correlating to liver metastasis of CRC, and to further assess their clinical value. Seventeen patients with primary CRC lesions, adjacent normal mucosa, and synchronous liver metastases lesions were divided into discovery set (six patients) and test set (11 patients). Transcriptome sequencing (RNAseq) was used to screen differential expression of lncRNAs in the discovery set. Based on bioinformatics data, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to verify the target lncRNA in test set. The relationships between target lncRNA and clinical values were analysed in an expanded validation set of additional 91 patients. 23 upregulated and 14 downregulated lncRNAs were detected for distinguishing synchronous liver metastases, primary CRC lesions from adjacent normal mucosa in the RNAseq set. The expression levels of four lncRNAs in the 37 lncRNA signature were verified by qRT-PCR in the test set. Compared with the paired normal mucosa, high expression levels of lnc-small-nucleolar RNA host gene 15 (SNHG15) were detected not only in primary CRC lesions but also in liver metastases lesions in the test set. Furthermore, in the expanded validation set, high expression of lnc-SNHG15 was significantly associated with lymph-node metastasis and liver metastasis (p < 0.05), and patients displaying high lncRNA-SNHG15 expression exhibited a shorter median overall survival duration than those displaying low expression (30.7 vs. 35.2 months; p = 0.003). Multivariate analyses demonstrated that lncRNA-SNHG15 overexpression may serve as a poor prognostic biomarker for CRC patients (p = 0.049; Cox's regression: 2.731). Lnc-SNHG15 overexpression was significantly associated with CLM and high-expression of lnc-SNHG15 in CRC was an independent predictor of poor survival. Refereed/Peer-reviewed

PEAK1 is upregulated in multiple human malignancies and has been associated with tumor invasion and metastasis, but little is known about the role of PEAK1 in colorectal cancer (CRC) progression. We investigated the expression pattern, function and regulatory mechanisms of PEAK1 in CRC. Here, we found that PEAK1 is overexpressed in CRC tissues and that high PEAK1 expression predicts poor survival in colon cancer but not rectal cancer. Functionally, silencing PEAK1 inhibits cell proliferation, migration, and invasion in vitro and inhibits the growth of tumor xenografts in nude mice. Mechanistic studies revealed that PEAK1 is induced by epidermal growth factor receptor (EGFR) signaling and that PEAK1 is required for KRas-induced CRC cell growth and metastasis. Furthermore, we demonstrated that miR-181d directly targets PEAK1. Ectopic expression of miR-181d reduces the expression of PEAK1 and inhibits the growth and metastasis of CRC cells in vitro. Clinically, miR-181d is downregulated in CRC samples, and low miR-181d is correlated with poor patient survival. Our study demonstrates the importance of PEAK1 in CRC progression and suggests a potential mechanism by which increasing PEAK1 expression in CRC might be the result of EGFR/KRas signal activation and consequent miR-181d repression.

1574 Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are primarily tested in colorectal (CRC) and endometrial cancer (EC) to aid Lynch Syndrome (LS) diagnosis. A pan-cancer study presented at 2018 ASCO, however, revealed that up to 50% of LS patients had tumors not typically associated with LS, suggesting that patients with an MSI-high (MSI-H) phenotype should proceed to germline testing regardless of tumor type or family history. We thus set out to examine this potentially practice changing notion in Chinese population. Methods: MSI status and germline mutations in MLH1, MSH2, MSH6 and PMS2 genes were determined using a targeted next generation sequencing panel covering 100 MSI loci as well as MMR genes. Tumor mutation burden (TMB) levels were calculated for LS patients with MSI-H and MSS tumors, and intergroup differences were assessed using Mann Whitney U test or Fisher’s exact test. Results: Of 6,288 advanced tumors spanning > 27 cancers, 0.8% (48/6,288) were EC, 21.6% (1,362/6,288) were CRC, and 77.6% (4,878/6,288) were other malignancies. 3.6% (224/6,288) of the samples were found to be MSI-H and 3.5% (217/6,288) harbored MMR mutations (somatic and germline). Germline mutations indicative of LS were identified in 0.1% (8/6,064) of the MSS group and 17% (38/224) of the MSI-H group (p < 0.001). In contrast with the 2018 ASCO report, up to 63.8% of the 224 MSI-H tumors were CRC/EC, and only 8.9% (3/38) of the LS patients had MSI-H non-CRC/EC tumors (1 ovarian clear cell, 1 small bowel, and 1 gastric cancer). LS patients with non-CRC/EC tumors were more likely to be MSS compared to those with CRC/EC (70.0% vs 2.7%, p < 0.001). Alterations in MLH1/ MSH2 were present in 78.3% (36/46) of the LS patients, and they demonstrated significantly better correlation with a MSI-H phenotype than MSH6/PMS2 alterations (94.4% vs. 40.0%, p = 0.0005). Additionally, in line with previous reports showing co-ocurrence of MSI-H and high TMB in gastrointestinal cancers, the LS patients with MSS tumors had a significantly lower median TMB compared with the MSI-H population (4.6 muts/Mb vs. 91.8 muts/Mb, p < 0.001). Conclusions: Our study showed that in Chinese population, CRC/EC still predominated among LS-associated cancers, while non-CRC/EC LS patients were more likely to present with an MSS phenotype. The value of MSI-H/dMMR as a predictor of LS across different tumor types warrant further investigation.

The impact of complete and incomplete colonic obstruction on the short- and long-term outcomes of malignant colorectal cancer has not yet been elucidated. The aim of this study was to investigate whether there was a difference in the impacts of the 2 types of obstruction on the short- and long-term outcomes of colorectal resection. This study included 224 colorectal cancer patients (162 patients with incomplete obstruction and 62 with complete obstruction) with left-sided malignant colonic obstruction who underwent surgical therapy between February 2007 and September 2012. The short- and long-term outcomes of surgical therapy were analyzed. No significant difference was found between the 2 groups with regard to short-term outcomes such as the curative resection rate (80.86 vs 70.97%, P = 0.109), hospital stay time (24.20 ± 16.01 vs 24.19 ± 12.06, P = 0.999), and the overall and respective complications (32.72 vs 46.77%, P = 0.051). Furthermore, no significant difference was found between the 2 groups with regard to long-term outcomes including the 1-, 3-, and 5-year survival rates (P = 0.089), recurrence rates (P = 0.711), and recurrence-free survival rates (P = 0.440). The 2 types of obstruction, i.e., complete and incomplete left-sided malignant colonic obstruction, had no impact on the short- and long-term outcomes of colorectal resection. Similar therapeutic methods can be used for treating both types of obstruction.

Mitogen-activated protein kinase kinase kinase 2 (MEKK2) is an important upstream mediator of the extracellular signal-regulated kinase 5 signaling cascade that is essential for a number of cellular functions, including mitogenesis, differentiation and oncogenic transformation. Using western blotting to examine MEKK2 expression in 16 cases of primary colorectal cancer (CRC) lesions with paired normal mucosa, it was identified that MEKK2 is highly expressed in CRC lesions compared with that of the normal mucosa. Immunohistochemistry of 24 normal mucosa, 24 adenoma and 96 adenocarcinoma colorectal specimens indicated that the expression of MEKK2 was significantly increased in the adenoma and carcinoma specimens compared with that of the normal mucosa cases (P0.05). The present study demonstrated that MEKK2 functions as a promotive factor in CRC.

Over expression of tissue factor (TF) occurs in more than 50 % of colorectal cancer (CRC). Therefore, TF represents an attractive target antigen for immunotherapy in CRC. Here, we assessed the safety and efficacy of a recombinant adenovirus vector encoding the light chain of human coagulation factor VII (hfVII-LC) and human IgG1 Fc fragment (hIgG1-Fc), termed “benc vector,” by targeting TF in the mouse model with colon cancer. Benc vector was administered intravenously or intratumorally in SCID mice with TF over-expressing HT-29 colon cancer. The safety and efficacy of benc vector were observed during animal experiments. Complete inhibition of tumor growth (5/5) was observed not only in the intravenously injection of benc vector group but also in the intratumorally of benc vector group. We also observed a precautionary effect on lung metastases of HT-29 cells by intratumoral injection of benc vector. In the control group of animals given empty control vector, all animals (5/5) developed lung tumors and exhibited a higher number of nodules after injection with HT-29 cells via the tail vein. In contrast, only three animals (3/5) in the treatment group receiving benc vector had any observable lung metastases and a lower number of nodules. No animals died and no bleeding was observed both in treatment groups and control groups. Moreover, only moderate liver damage was detected in mice receiving benc vector by intravenous injections. Benc vector encoding hfVII-LC and hIgG1-Fc can effectively inhibit tumor growth and metastases in SCID mice with TF over-expressing colon cancer and shows promise as an agent for CRC immunotherapy.

Background: Zonulin is a newly discovered protein that has an important role in the regulation of intestinal permeability. Our previous study showed that probiotics can decrease the rate of infectious complications in patients undergoing colectomy for colorectal cancer.Objective: The objective was to determine the effects of the perioperative administration of probiotics on serum zonulin concentrations and the subsequent effect on postoperative infectious complications in patients undergoing colorectal surgery.Design: A total of 150 patients with colorectal carcinoma were randomly assigned to the control group (n = 75), which received placebo, or the probiotics group (n = 75). Both the probiotics and placebo were given orally for 6 d preoperatively and 10 d postoperatively. Outcomes were measured by assessing bacterial translocation, postoperative intestinal permeability, serum zonulin concentrations, duration of postoperative pyrexia, and cumulative duration of antibiotic therapy. The postoperative infection rate, the positive rate of blood microbial DNA, and the incidence of postoperative infectious complications—including septicemia, central line infection, pneumonia, urinary tract infection, and diarrhea—were also assessed.Results: The infection rate was lower in the probiotics group than in the control group (P < 0.05). Probiotics decreased the serum zonulin concentration (P < 0.001), duration of postoperative pyrexia, duration of antibiotic therapy, and rate of postoperative infectious complications (all P < 0.05). The p38 mitogen-activated protein kinase signaling pathway was inhibited by probiotics.Conclusions: Perioperative probiotic treatment can reduce the rate of postoperative septicemia and is associated with reduced serum zonulin concentrations in patients undergoing colectomy. We propose a clinical regulatory model that might explain this association. This trial was registered at http://www.chictr.org/en/ as ChiCTR-TRC-00000423.

The aim was to evaluate erectile and urinary function of male patients with rectal cancer treated by neoadjuvant (NA) chemoradiotherapy (CRT) or NA chemotherapy only. In this prospective randomized trial (ClinicalTrials.gov NCT01211210; “FOWARC”), we included 102 men who received NA therapy for stage II–III rectal cancer between January 2011 and June 2013. Before surgery, patients received either NA mFOLFOX6 chemotherapy with radiation (RCS group, n = 54) or NA mFOLFOX6 chemotherapy alone (CS group, n = 48). Erectile and urinary dysfunctions were assessed with the five-item International Index of Erectile Function (IIEF-5) scale and the International Prostatic Symptom Score (IPSS), respectively. Questionnaires were completed at baseline and at 3, 6, and 12 months (t0–t3, respectively) after surgery. At t3, mean IIEF-5 score was significant higher in the CS group (15.3 ± 5.5) than in the RCS group (12.6 ± 5.7; P

Background To retrospectively evaluate postoperative genital function, local recurrence rate and survival rate after total mesorectal excision (TME) combined with or without pelvic autonomic nerve preservation (PANP) in male patients with rectal cancer. Methods A total of 953 male patients with rectal cancer after TME (518 patients received TME combined with PANP [PANP group] and 434patients received TME alone [TME group]) were included. Assessments of postoperative genital function, local recurrence rate, and 5 year survival rate were collected. Results Rate of erection dysfunction in PANP group (41.9 %) was significantly lower than that in TME group (76.7 %, P