Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial.

BACKGROUND: The early-onset rectal cancer with rapidly increasing incidence is considered to have distinct clinicopathological and molecular profiles with high-risk features. This leads to challenges in developing specific treatment strategies for early-onset rectal cancer patients and questions of whether early-onset locally advanced rectal cancer (LARC) needs aggressive neoadjuvant treatment. METHODS: In this post hoc analysis of FOWARC trial, we investigated the role of preoperative radiation in early-onset LARC by comparing the clinicopathological profiles and short-term and long-term outcomes between the early-onset and late-onset LARCs. RESULTS: We revealed an inter-tumor heterogeneity of clinical profiles and treatment outcomes between the early-onset and late-onset LARCs. The high-risk features were more prevalent in early-onset LARC. The neoadjuvant radiation brought less benefits of tumor response and more risk of complications in early-onset group (pCR: OR = 3.75, 95% CI = 1.37-10.27; complications: HR = 11.35, 95% CI = 1.46-88.31) compared with late-onset group (pCR: OR = 5.33, 95% CI = 1.83-15.58; complications: HR = 5.80, 95% CI = 2.32-14.49). Furthermore, the addition of radiation to neoadjuvant chemotherapy didn't improve long-term OS (HR = 1.37, 95% CI = 0.49-3.87) and DFS (HR = 1.05, 95% CI = 0.58-1.90) for early-onset patients. CONCLUSION: Preoperative radiation plus chemotherapy may not be superior to the chemotherapy alone in the early-onset LARC. Our findings provide insight into the treatment of early-onset LARC by interrogating the aggressive treatment and alternative regimens.

Aberrant methylation in neurofunctional gene serves as a hallmark of tumorigenesis and progression in colorectal cancer.

BACKGROUND: DNA methylation is one of the most promising biomarkers in predicting the prognosis of colorectal cancer (CRC). We aimed to develop a DNA methylation biomarker that could evaluate the prognosis of CRC. METHODS: A promising DNA methylation biomarker was developed by hypermethylated genes in cancer tissue that were identified from Illumina EPIC methylation arrays. A cohort comprising 30 pairs of snap-frozen tumor tissue and adjacent normal tissue was used for correlation analysis between the methylation and expression status of the marker. The other cohort comprising 254 formalin-fixed paraffin-embedded (FFPE) tumor tissue from 254 CRC patients was used for prognosis analysis. RESULTS: Regulating synaptic membrane exocytosis 2 (RIMS2) was hypermethylated and lowly expressed in CRC comparing to adjacent normal tissue. Hypermethylation of RIMS2 in CRC was correlated with less frequent KRAS mutant and high differentiation. RIMS2 promoter methylation showed independent predictive value for survival outcome (P = 0.015, HR 1.992, 95% CI [(1.140-3.48)]), and a combination of RIMS2 methylation with KRAS status could predict prognosis better. CONCLUSIONS: RIMS2 is frequently hypermethylated in CRC, which can silence the expression of RIMS2. RIMS2 methylation is a novel biomarker for predicting the prognosis of CRC.

Prevalent Pseudoprogression and Pseudoresidue in Patients With Rectal Cancer Treated With Neoadjuvant Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitor (ICI) treatment in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors holds promise in reshaping organ preservation in rectal cancer. However, the benefits are accompanied by distinctive patterns of response, introducing a dilemma in the response evaluation for clinical decision-making. PATIENTS AND METHODS: Patients with locally advanced rectal cancer with MSI-H/dMMR tumors receiving neoadjuvant ICI (nICI) treatment (n=13) and matched patients receiving neoadjuvant chemoradiotherapy (nCRT; n=13) were included to compare clinical response and histopathologic features. RESULTS: Among the 13 patients receiving nICI treatment, in the final radiologic evaluation prior to surgery (at a median of 103 days after initiation of therapy), progressive disease (n=3), stable disease (n=1), partial response (n=7), and complete response (n=2) were observed. However, these patients were later confirmed as having pathologic complete response, resulting in pseudoprogression and pseudoresidue with incidences of 23.1% (n=3) and 76.9% (n=10), respectively, whereas no pseudoprogression was found in the 13 patients receiving nCRT. We further revealed the histopathologic basis underlying the pseudoprogression and pseudoresidue by discovering the distinctive immune-related regression features after nICI treatment, including fibrogenesis, dense lymphocytes, and plasma cell infiltration. CONCLUSIONS: Pseudoprogression and pseudoresidue were unique and prevalent response patterns in MSI-H/dMMR rectal cancer after nICI treatment. Our findings highlight the importance of developing specific strategies for response evaluation in neoadjuvant immunotherapy to identify patients with a good response in whom sphincter/organ-preserving or watch-and-wait strategies may be considered.

Current Surveillance After Treatment is Not Sufficient for Patients With Rectal Cancer With Negative Baseline CEA.

BACKGROUND: Serum CEA has been widely used to screen for potential recurrent disease after resection in rectal cancer. However, the influence of baseline CEA on the performance of CEA in recurrence surveillance needs to be investigated. PATIENTS AND METHODS: This longitudinal cohort study included 484 patients with nonmetastatic rectal cancer from 18,013 patients in a prospectively enrolled institutional database program of colorectal disease. Baseline CEA levels were determined before treatment, and CEA-based follow-up tests and examinations were applied in the surveillance after treatment. RESULTS: A total of 62.6% (62/99) overall, 53.5% (23/43) local, and 64.9% (50/77) distant recurrences were seen in patients who had similar CEA levels with their baseline statuses. The sensitivity of elevated CEA levels during surveillance for overall recurrence was significantly lower in patients with negative baseline CEA than in those with elevated baseline CEA levels (41.3% vs 69.4%; P =.007). Moreover, similar results were observed in the surveillance for local (50% vs 61.5%; P =.048) and distant (39.6% vs 72.4%; P =.005) recurrences between these 2 patient groups. However, CEA had comparable and excellent specificity during surveillance for recurrent disease in these groups. The addition of CA19-9 to the CEA assay significantly improved the sensitivity in recurrence surveillance for patients with negative baseline CEA (49.2% vs 41.3%; P =.037). Finally, we identified a subgroup of CEA-turn recurrences characterized by negative CEA at baseline, elevated CEA at recurrence, and worse survival outcomes after recurrence (hazard ratio, 1.88; 95% CI, 1.07-3.30; P =.026). CONCLUSIONS: In patients with rectal cancer with negative baseline CEA, serum CEA had insufficient sensitivity in recurrence surveillance after treatment, and additional surveillance may improve oncologic outcomes. Baseline CEA should be considered before CEA-based surveillance can be applied in the follow-up trials.

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer.

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.

Radiomic signature of the FOWARC trial predicts pathological response to neoadjuvant treatment in rectal cancer.

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.

The Addition of Preoperative Radiation Is Insufficient for Lateral Pelvic Control in a Subgroup of Patients With Low Locally Advanced Rectal Cancer: A Post Hoc Study of a Randomized Controlled Trial.

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, aún está por controlarse la recurrencia pélvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pélvica lateral y en que subgrupo de pacientes sería conveniente efecutar una excisión lateral de las cadenas ganglionares.DISEÑO:Se reevaluaron las imágenes tomográficas y de resonancia magnética del status de las cadenas ganglionares linfáticas laterales. Los ganglios linfáticos 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 análisis 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 exclusión, la población final incluida consistió en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parámetro mas importante fue la tasa de recurrencia pélvica lateral a cinco años.RESULTADOS:En comparación con los pacientes que recibieron quimioterapia sola, aquellos que además fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pélvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfáticos laterales positivos, los enfermos presentaron una tasa de recurrencia pélvica lateral de 22.6% y 45.1% después de quimioradiaterapia neoadyuvante en comparación con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfáticos laterales positivos antes del tratamiento persistieron después de la quimioradioterapia neoadyuvante, reportándose finalmente una recurrencia pélvica lateral de un 63.3%.LIMITACIONES:Se trata de un análisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamaño de la muestra. Además, no se efectuó la disección de los ganglios linfáticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pélvica lateral en forma adecuada. Algunos subgrupos de pacientes podría requerir de disección adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

High platelet-to-lymphocyte ratio predicts improved survival outcome for perioperative NSAID use in patients with rectal cancer.

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: Perioperative use of NSAIDs was associated with improved survival outcomes in rectal cancer patients with high PLR.

Early Versus Routine Stoma Closure in Patients With Colorectal Resection: A Meta-Analysis of 7 Randomized Controlled Trials.

Background. A substantial proportion of patients undergoing colorectal surgery receive a temporary stoma, and the timing for stoma closure remains unclear. The aim of this study was to evaluate the safety and feasibility of early stoma closure (ESC) compared with routine stoma closure (RSC) after colorectal surgery. Methods. We comprehensively searched PubMed, Embase, and the Cochrane Library for randomized controlled trials that compared ESC and RSC after colorectal surgery. Results. A total of 7 randomized controlled trials with 814 enrolled patients were identified for this meta-analysis. There were no significant differences between the ESC and RSC groups regarding the complications of stoma closure (26.8% and 16.6%, respectively; odds ratio [OR]: 1.30; 95% confidence interval [CI]: 0.89-1.90; P = .17). A subgroup analysis was conducted by Clavien-Dindo grade of complication, and no significant difference was observed in any subgroup (P > .05). However, the ESC group had a significantly higher risk of wound complications than the RSC group (17.6% and 7.8%, respectively; OR: 2.61; 95% CI: 1.43-4.76; P = .002), and the RSC group had more cases of small bowel obstruction than the ESC group (3.1% and 8.4%, respectively; OR: 0.37; 95% CI: 0.15-0.87; P = .02). Conclusions. ESC is a safe and effective therapeutic approach in patients who have undergone colorectal surgery; it is associated with a reduced risk of bowel obstruction but a higher risk of wound complications.

Novel Assay for Quantitative Analysis of DNA Methylation at Single-Base Resolution.

BACKGROUND: The DNA methylation profile provides valuable biological information with potential clinical utility. Several methods, such as quantitative methylation-specific PCR (qMSP), have been developed to examine methylation of specific CpG sites. Existing qMSP-based techniques fail to examine the genomic methylation at a single-base resolution, particularly for loci in gene bodies or extensive CpG open seas lacking flanking CpGs. Therefore, we established a novel assay for quantitative analysis of single-base methylation. METHODS: To achieve a robust single-base specificity, we developed a PCR-based method using paired probes following bisulfite treatment. The 6-carboxyfluorescein- and 2'-chloro-7'phenyl-1,4-dichloro-6-carboxy-fluorescein-labeled probes conjugated with minor groove binder were designed to specifically bind to the methylated and unmethylated allele of targeted single CpGs at their 3' half regions, respectively. The methylation percentage was calculated by values of methylation / (methylation + unmethylation). RESULTS: In the detection of single CpGs within promoters or bodies of 4 human genes, the quantitative analysis of the single-base methylation assay showed a detection capability in the 1 to 1:10000 dilution experiments with linearity over 4 orders of magnitude (R 2 = 0.989-0.994; all P < 0.001). In a cohort of 10 colorectal cancer samples, the assay showed a comparable detection performance with bisulfite pyrosequencing (R 2 = 0.875-0.990; all P < 0.001), which was better than conventional qMSP methods normalized by input control reaction (R 2 = 0.841 vs 0.769; P = 0.002 vs 0.009). CONCLUSIONS: This assay is highly specific and sensitive for determining single-base methylation and, thus, is potentially useful for methylation-based panels in diagnostic and prognostic applications.

Comparison of three-dimensional versus two-dimensional laparoscopic surgery for rectal cancer: a meta-analysis.

PURPOSE: Three-dimensional (3D) vision technology has recently been validated for the improvement of surgical skills in a simulated setting. This study assessed the current evidence regarding the efficiency and potential advantages of 3D compared with two-dimensional (2D) laparoscopic rectal surgery for rectal cancer. METHODS: We comprehensively searched PubMed, EMBASE and the Cochrane Library and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and non-randomized controlled trials (nRCTs) assessing the two approaches. RESULTS: Four trials including a total 331 cases were identified. The positive circumferential resection margins (CRMs) were significantly lower for the 3D group (P = 0.02). The operative time was significantly shorter in the 3D group than in the 2D group (P < 0.00001). There was less estimated blood loss (EBL) in the 3D group than in the 2D group (P = 0.02). Perioperative complication rates, conversion rate, harvested lymph nodes, first flatus, length of stay, pneumonia, wound infection, ileus, anastomotic fistula and urinary retention did not differ significantly between the two groups (P > 0.05). CONCLUSIONS: In summary, 3D laparoscopic rectal surgery appears to have advantages over 2D laparoscopic rectal surgery in terms of positive CRM and operation time; however, it is not better than 2D laparoscopic rectal surgery in terms of the conversion rate and postoperative complications.

The local efficacy and influencing factors of ultrasound-guided percutaneous microwave ablation in colorectal liver metastases: a review of a 4-year experience at a single center.

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 < .001; 95% CI: 3.7 3-57.92), near a large vascular structure (OR: 7.04; p < .001; 95% CI: 2.41-20.60), near the diaphragm (OR: 4.02; p = .049; 95% CI: 1.05-16.11) and in patients with no response to chemotherapy before MWA (OR: 3.25; p = .032; 95% CI: 1.14-15.30). MWA was well tolerated, with a major complication rate of 3.65%, a minor complication rate of 8.03% and a mortality rate of 0%. Fever and pain were the most common side effects after MWA. CONCLUSIONS: US-guided percutaneous MWA of CRLM is a safe and effective method that is expected to become a routine treatment for local tumor control of CRLM.

Robotic Versus Laparoscopic Rectal Surgery for Rectal Cancer: A Meta-Analysis of 7 Randomized Controlled Trials.

Background. Robotic surgery has been recently used as a novel tool for rectal surgery. This study assessed the current evidence regarding the efficiency, safety, and potential advantages of robotic rectal surgery (RRS) compared with laparoscopic rectal surgery (LRS). Methods. We comprehensively searched PubMed, Embase, and the Cochrane Library databases and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) assessing the 2 approaches. Results. Seven RCTs including a total of 1022 cases were identified. The conversion rate is significantly lower for RRS (odds ratio: 0.29; 95% confidence interval: 0.09 to 0.96; P = .04). The length of the distal margin was significantly shorter in the LRS group than in the RRS group (weighted mean difference: 0.60; 95% confidence interval: 0.09 to 1.10; P = .02). Perioperative complication rates, harvested lymph nodes, positive circumferential resection margins, complete total mesorectal excision, first flatus, and length of stay did not differ significantly between approaches (P > .05). Conclusions. This meta-analysis indicates that RRS is a safe and effective approach. It is not inferior to LRS in terms of oncologic outcomes and postoperative complications. Future large-volume, well-designed RCTs with extensive follow-up are awaited to confirm and update the findings of this analysis.

Epigenetic silencing of TPM2 contributes to colorectal cancer progression upon RhoA activation.

Beta-tropomyosin (ß-tropomyosin, TPM2) has been found to be downregulated in colorectal cancer (CRC) in previous studies. In this study, we aimed to investigate the mechanisms and potential biological consequences of the downregulation of TPM2 in colorectal cancer. TPM2 expression in colorectal cancer was assessed by qRT-PCR and immunostaining. The biological functions of TPM2 were assessed in cell lines either overexpressing or underexpressingTPM2. Aberrant DNA methylation in the promoter region is associated with suppression of TPM2 expression in primary colorectal cancer tissue samples. Treatment with the demethylation agent 5-AZA can induceTPM2 expression in colorectal cancer cell lines. Reconstitution of TPM2 suppresses cell proliferation and migration in colorectal cancer cell lines, whereas the loss of TPM2 expression is associated with increased tumor proliferation and migration in vitro, which was accompanied by RhoA activation. In summary, our findings indicate that TPM2 appears to be commonly silenced by aberrant DNA methylation in colon cancer. TPM2 loss is associated with RhoA activation and tumor proliferation.

Erectile and urinary function in men with rectal cancer treated by neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy alone: a randomized trial report.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 < 0.05). And score difference was statistically higher in RCS group compared with CS group at t2 and t3, especially t3 (9.3 ± 5.5 vs. 6.1 ± 5.1, P < 0.01). Univariate analysis of the RCS group's IIEF-5 scores associated age, stoma, location, and tumor size to erectile dysfunction. However, mean IPSS scores did not differ between the two groups at any point. CONCLUSIONS: Compared with the CS group, erectile and urinary functions were significantly affected by NA CRT. Age, stoma, tumor location, and tumor size were also correlated with erectile dysfunction in the RCS group.

Transanal total mesorectal excision for rectal cancer: a preliminary report.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer.

NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. NTRK3 is methylated in 60% of colon adenomas and 67% of colon adenocarcinomas. NTRK3 methylation suppresses NTRK3 expression. Reconstitution of NTRK3 induces apoptosis in colorectal cancers, if NT-3 is absent. Furthermore, the loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo. We also found that a naturally occurring mutant NTRK3 found in human colorectal cancer inhibits the tumor suppressor activity of NTRK3. In summary, our findings suggest NTRK3 is a conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3.

[The effect of patterns of recurrence after radical resection of rectal cancer on long-term survival after recurrence].

OBJECTIVE: To establish the classification of colorectal cancer recurrence patterns based on their relations to prognosis and recurrence. METHODS: A total of 463 patients with recurrent rectal cancer (Stage I-III) following curative resection in our hospital from June 2002 to June 2012 were included consecutively. Recurrence status, time, location, survival time after relapse, curability, symptoms and CEA level were recorded. The correlation between each recurrent pattern and recurrent survival (RS) rate were analyzed retrospectively. The survival curve was drawn by Kaplan-Meier method. The Log-rank test was used to test the significance. Univariate analysis was performed by using Cox proportional hazard model. RESULTS: Patients with recurrence within one year, multiple metastases, symptomatic disease, elevated CEA level and unresectable recurrence had significantly lower RS rate than patients with recurrence after one year, solitary metastasis, asymptomatic manifestation, normal CEA level and resectable recurrence respectively. The hazard ratio were 1.34 (95%CI 1.02-1.76, P= 0.033), 1.41 (95%CI 1.04-1.91, P= 0.026), 1.74 (95%CI 1.05-2.88, P= 0.032), 4.06 (95%CI 2.11-7.85, P<0.001) and 1.99 (95%CI 1.34-2.97, P= 0.001) respectively. CONCLUSION: Early recurrence (<12 months), multiple metastases, symptomatic, unresectable recurrence and elevated CEA indicate poor prognosis after relapse. This study provides a systematic basis for the classification of recurrence in colorectal cancer after radical resection.

Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.

BACKGROUND & AIMS: Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. METHODS: We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. RESULTS: We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. CONCLUSIONS: Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.