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List of tumor and plasma variants and their ctDNA detection thresholds

Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker; however, ctDNA as a marker for mCRC patients is not well established, and there is still no consensus about how to utilize it most cost-effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients. We performed next-generation sequencing (NGS) by using a 12-gene panel to identify genetic variants in 136 tumor tissue and ctDNA samples from 32 mCRC patients. Genetic variants were detected in approximately 70% of samples, and there was a high concordance (85%) between tumor tissue and plasma ctDNA. We observed ctDNA changes in 18 follow-up patients, including the emergence of new variants. Changes in ctDNA levels significantly correlated with tumor shrinkage (P = 0.041), and patients with a ctDNA decrease >80% after treatment had a longer progression-free survival compared with patients with a ctDNA decrease of P = 0.015). The objective response rate among patients with a ctDNA decrease of >80% was better than those with a ctDNA decrease P = 0.007). In conclusion, this study demonstrates that monitoring of genetic ctDNA variants can serve as a valuable biomarker for therapeutic efficacy in mCRC patients, and that using a moderate-sized 12-gene NGS panel may be suitable for such clinical monitoring. Mol Cancer Ther; 17(10); 2238–47. ©2018 AACR.

It is controversial whether patients who achieve clinical complete remission (cCR) of rectal cancer should be treated with the “watch and wait” (W&W) or radical resection (RR) strategy. Our study aimed to compare the survival outcomes and ostomy rate of the W&W and RR strategies. Between January 2008 and December 2015, we investigated 26 patients who achieved pathologic complete remission after undergoing RR and 36 patients who adopted the W&W strategy because of cCR. The tumor regrowth, salvage surgery, recurrence, disease-free, and overall survival (OS) rates were assessed. In our study, recurrences occurred in nine and two patients from the W&W and RR groups, respectively. Each patient in the RR group had a temporary or permanent ostomy, but only three (8.3%) had an ostomy in the W&W group. The 5-year recurrence rate was 25.0% in the W&W group and 7.7% in the RR group. Six patients (16.7%) had tumor regrowth in the W&W group, and all were resectable when regrowth. The 5-year OS rates between the two groups were nonsignificant. There is no specific risk factor for recurrence and OS. Under close surveillance, the W&W group achieved similar OS to the RR group and benefited from a lower ostomy rate.

Here, we describe a novel interaction between the RNA helicase DDX3 and the deubiquitinase ubiquitin-specific peptidase 9 X-linked (USP9X) in human cells. Domain mapping studies reveal that the C-terminal region of DDX3 interacted with the N terminus of USP9X. USP9X was predominantly localized in the cytoplasm where the interaction between DDX3 and USP9X occurred. USP9X was not visibly enriched in cytoplasmic stress granules (SGs) under oxidative stress conditions, whereas overexpression of GFP-DDX3 induced SG formation and recruited USP9X to SGs in HeLa cells. Luciferase reporter assays showed that depletion of USP9X had no significant effect on DDX3-mediated translation. Given that DDX3 is not ubiquitinated upon ubiquitin overexpression, it is unlikely that DDX3 serves as a substrate of USP9X. Importantly, we found that ubiquitinated MCL1 was accumulated upon depletion of USP9X and/or DDX3 in MG132-treated cells, suggesting that USP9X and DDX3 play a role in regulating MCL1 protein stability and anti-apoptotic function. This study indicates that DDX3 exerts anti-apoptotic effects probably by coordinating with USP9X in promoting MCL1 deubiquitination.

AIM Laparoscopic anterior resection with natural orifice specimen extraction (NOSE) has favourable short-term outcomes. However, NOSE is rarely adopted for left hemicolectomy procedures. This study aimed to review the feasibility, safety and short-term outcomes of transrectal NOSE in patients undergoing laparoscopic left hemicolectomy. METHOD All consecutive patients who underwent laparoscopic left hemicolectomy surgery with transrectal NOSE in a single institution between January 2018 and December 2020 were reviewed. Transrectal NOSE was performed with an enterotomy at the upper rectum. The specimen was brought out via a transanal endoscopic microsurgery scope inserted through the anus. A supplementary video demonstrates this technique. Surgical outcomes, including complications, postoperative short-term recovery and the level of pain intensity, are presented. RESULTS Twenty patients were reviewed. There were no immediate postoperative complications and no wound infections in these patients. The average time to tolerate a soft diet was 3.6 days, and the average postoperative hospital stay was 4.5 days. The average score on the numerical rating scale of postoperative pain was 3.0 on postoperative day 1. The median follow-up time was 23.5 months. CONCLUSION Laparoscopic left hemicolectomy with transrectal NOSE is a safe and feasible procedure that leads to early postoperative recovery and a short hospital stay.

Purpose: The optimal timing of stoma closure during or after adjuvant chemotherapy for rectal cancer patients undergoing sphincter-preserving surgery remains unknown. This study aimed to investigate the influence of clinical and oncological outcomes depending on the timing of stoma closure. Methods: Between January 2006 and December 2015, we enrolled 244 consecutive rectal cancer patients who underwent curative-intent sphincter-preserving surgery with diverting colostomy and adjuvant chemotherapy. Patients with stoma closure during (During group) adjuvant chemotherapy were compared to those who had stoma closure after adjuvant chemotherapy (After group). Results: Parastomal hernia occurred more frequently in the after group than in the during group. (10% vs. 2.9%, p = 0.028). Overall, no significant difference was observed in overall survival (OS) or disease-free survival (DFS) between the two groups (p = 0.911 for OS, p = 0.505 for DFS). However, an inferior OS occurred if reopen surgery was performed within 30 days of stoma closure in the during group, as compared with the after group (p = 0.004). In addition, a marginally poor DFS was observed in the group of patients who received further operations due to 30-day stoma closure complications compared to the other patients (p = 0.07). Conclusions: For rectal cancer patients who underwent sphincter-preserving surgery, attention should be given to avoid 30-day major complications after stoma reversal because patients who require reoperation during adjuvant chemotherapy may have poor long-term survival.

Supplemental Digital Content is available in the text., Background: Because methods of performing laparoscopic left hemicolectomy differ between surgeons, standardizing the procedure is crucial to reduce complications and secure good oncologic outcomes. Materials and Methods: This is a retrospective hospital-based cohort study using a propensity score–weighted method. This study was conducted at the department of colorectal surgery in a tertiary teaching hospital between October 2007 and December 2017. The short-term and long-term outcomes of open and laparoscopic left hemicolectomy from 10 years of experience using a standardized 4-step laparoscopic procedure at one institution were compared. Short-term outcomes were postoperative morbidity and mortality. Long-term outcomes were disease-free survival and overall survival. Results: We enrolled 564 patients who underwent open or laparoscopic left hemicolectomy for primary colon adenocarcinoma. The open surgery and laparoscopy groups had 357 and 207 patients, respectively. Compared with the open surgery group, the laparoscopy group had significantly shorter hospital stays (open vs. laparoscopy, 10 vs. 7 d, P

BACKGROUND Physical activity might be directly or indirectly linked to the risk of colorectal cancer and the prognosis of patients with colorectal cancer. OBJECTIVE This study aimed to elucidate whether preoperative physical activity plays a role in reducing short-term postoperative complications and improving long-term survival of patients with colorectal cancer. DESIGN This was a retrospective analysis of prospectively collected data. SETTINGS This study was conducted at a department of colorectal surgery in a tertiary teaching hospital between January 1995 and December 2016. PATIENTS Patients who underwent curative resection for stage I to III primary colorectal cancer were enrolled. According to the preoperative leisure-time weekly metabolic equivalent of task values, patients were divided into 2 groups: the metabolic equivalent of task

A lack of physical activity is a generally accepted risk factor for colorectal cancer. However, research on the effect of preoperative physical activity on postoperative and long-term outcomes is limited, especially in patients with stage IV colorectal cancer who underwent palliative surgery. Patients who underwent bowel resection for stage IV primary colorectal cancer between January 1995 and December 2016 were retrospectively enrolled. A total of 2185 patients were divided into two groups according to preoperative leisure-time weekly physical activity as assessed by metabolic equivalent of task (MET) values: MET < 12 (n = 1845) and MET ≥ 12 (n = 340). Inverse probability of treatment weighting (IPTW) was used to reduce imbalance and selection biases between the two groups. After the IPTW process, the MET < 12 group showed a higher postoperative morbidity rate (18.7% vs. 10.6%; p < 0.001) and mortality rate (2.4% vs. 0.6%; p < 0.001) than the MET ≥ 12 group. No significant difference was found in overall survival. Weekly preoperative leisure-time physical activity with MET ≥ 12 was associated with reduced short-term postoperative morbidity and mortality in patients undergoing palliative resection for metastatic colorectal cancer. However, no difference was detected in long-term survival.

The association of habitual behaviors with the prevalence of synchronous colorectal cancer (sCRC) is unknown. Here, we investigated whether these behaviors, which are known risk factors for colorectal polyps, may be related to sCRC risk. We enrolled 17,093 patients who underwent cancer treatment between January 1995 and December 2016 and examined the association of age, sex, familial history of hereditary colorectal cancer (CRC), and status of three common habitual behaviors (smoking and alcohol and coffee consumption) with the prevalence of sCRC. Of the enrolled patients, 960 (5.6%) patients had sCRC. The independent risk factors for sCRC prevalence included advanced age, male sex, hereditary CRC, smoking, and daily alcohol consumption of more than one bottle (> 600 mL). Contrary to these factors, daily coffee consumption of more than one cup seemed to provide a protection from sCRC. In the Kaplan-Meier test, the significantly worse 5-year overall survival (OS) was noted in smokers with stage 0–III CRC. The effect of alcohol consumption on 5-year OS was significant in stages II and III. Compared with those without daily coffee consumption, patients with daily coffee consumption had significantly higher 5-year OS in stages I (93.0% vs. 86.4%), II (87.1% vs. 77.2%), III (71.5% vs. 61.9%), and IV (18.0% vs. 13.0%). sCRC prevalence was significantly associated with habitual behaviors. Patients with smoking or with daily alcohol consumption of one bottle had higher sCRC prevalence than did those without these habits. Coffee consumption could be a protective factor for lowering sCRC risk.

Simple Summary Information describing circulating tumor cells (CTCs) holds promise for clinical applications. However, conventional CTCs enumeration could ignore the CTCs more relevant to cancer metastasis. Thus, negative selection CTC enumeration was proposed, by which information on the numbers of CTCs and CD45neg EpCAMneg cells can be obtained. By combining this approach with the conventional biomarker carcinoembryonic antigen (CEA), this study aimed to explore whether any combination of these biomarkers could improve the predictive performance for colorectal cancer (CRC) or its status. Results revealed that a combination of the two cell populations showed improved performance (AUROC: 0.893) for CRC prediction over the use of only one population. Compared with CEA alone, the combination of the three biomarkers increased the performance (AUROC) for advanced CRC prediction from 0.643 to 0.727. Compared with that of CEA alone for metastatic CRC prediction, the AUROC was increased from 0.780 to 0.837 when the CTC count was included. Abstract Conventional circulating tumor cell (CTC) enumeration could ignore the CTCs more relevant to cancer metastasis. Thus, negative selection CTC enumeration was proposed, by which information on two cellular biomarkers (numbers of CTCs and CD45neg EpCAMneg cells) can be obtained. By combining this approach with the conventional biomarker carcinoembryonic antigen (CEA), this study aimed to explore whether any combination of these biomarkers could improve the predictive performance for colorectal cancer (CRC) or its status. In this work, these two cell populations in healthy donors and CRC patients were quantified. Results revealed that enumeration of these two cell populations was able to discriminate healthy donors from CRC patients, even patients with non-advanced CRC. Moreover, the combination of the two cell populations showed improved performance (AUROC: 0.893) for CRC prediction over the use of only one population. Compared with CEA alone, the combination of the three biomarkers increased the performance (AUROC) for advanced CRC prediction from 0.643 to 0.727. Compared with that of CEA alone for metastatic CRC prediction, the AUROC was increased from 0.780 to 0.837 when the CTC count was included. Overall, this study demonstrated that the combination of these two cellular biomarkers with CEA improved the predictive performance for CRC and its status.

Background Radical resection is associated with good prognosis among patients with cT1/T2Nx rectal cancer. However, still some of the patients experienced cancer recurrence following radical resection. This study tried to identify the postoperative risk factors of local recurrence and distant metastasis separately. Methods This retrospective, single-center study comprised of 279 consecutive patients from Linkou branch of Chang Gung Memorial Hospital in 2005–2016 with rectal adenocarcinoma, pT1/T2N0M0 at distance from anal verge ≤ 8cm, who received curative radical resection. Results The study included 279 patients with pT1/pT2N0 mid-low rectal cancer with median follow-up of 73.5 months. Nineteen (6.8%) patients had disease recurrence in total. Nine (3.2%) of them had local recurrence, and fourteen (5.0%) of them had distant metastasis. Distal resection margin < 0.9 (cm) (hazard ratio = 4.9, p = 0.050) was the risk factor of local recurrence. Preoperative carcinoembryonic antigen (CEA) ≥ 5 ng/mL (hazard ratio = 9.3, p = 0.0003), lymph node yield (LNY) < 14 (hazard ratio = 5.0, p = 0.006), and distal resection margin < 1.4cm (hazard ratio = 4.0, p = 0.035) were the risk factors of distant metastasis. Conclusion For patients with pT1/pT2N0 mid-low rectal cancer, current multidisciplinary treatment brings acceptable survival outcome. Insufficient distal resection margin attracted the awareness of risk factors for local recurrence and distant metastasis as a foundation for future research.

Additional file 1: Supplementary table 1 Patient characteristics

BackgroundsThough better short-term outcomes were frequently reported, differences in specimen parameters and the rate of subsequent peritoneal recurrence between intracorporeal anastomosis (IA) and extracorporeal anastomoses (EA) for laparoscopic right hemicolectomy have not been analyzed. We aimed to compare the pathologic differences and oncological outcomes between these two approaches.MethodsWe retrospectively analyzed 217 consecutive patients who underwent laparoscopic right hemicolectomies from September 2016 to April 2018 and classified them into IA and EA groups, based on the approach used. Propensity score matching analysis was performed, after which 101 patients were included in each group with the patients matched for demographics, tumor stage, and localization.ResultsThe IA group had a longer operative time, shorter length of stay, shorter time to first flatus and tolerating a soft diet, and better pain scale scores at postoperative day 3. No inter-group differences in conversion, postoperative complication, mortality, or readmission rates were found. The IA group had a longer resected colon length (23.67 vs. 19.75 cm,p= 0.010) and nearest resected margin (7.51 vs. 5.40 cm,p= 0.010) for cancer near the hepatic flexure. There are comparable 3-year overall survival (87.7% vs. 89.6%,p= 0.604) and disease-free survival (75.0% vs. 75.7%,p= 0.842) between the IA and EA groups. The rate of peritoneal recurrence was similar between the two groups (5.9% vs. 7.9%,p= 0.580).ConclusionsThe overall survival, disease-free survival, and the rate of peritoneal recurrence were comparable between the IA and EA procedures. IA ensures better recovery and comparable complications to EA and achieved a more precise tumor excision; thus, IA can be considered a safe procedure for patients with right-sided colon lesions.

Additional file 2: Supplementary table 2 Patient characteristics for non-RT vs. RT

BackgroundThe purpose was to examine the effect of nonmetastatic lymph nodes number (NLN) on survival in stage III colon cancer. To reduce the interference of acute inflammation, we included patients with stage III colon cancer who had undergone elective surgery and excluded those who had tumor perforation, obstruction, ischemia, or massive tumor bleeding.MethodsThis retrospective cohort study included 2244 patients with stage III colon cancer between 1995 and 2016 at a single center. The effect of NLN on 5-year relapse-free survival (RFS), 5-year overall survival (OS), and comparison of multivariate factors was assessed according to tumor locations.ResultsThe two optimal cutoff values of NLN for proximal and distal colon, namely 27 and 12, were determined by plotting the time-dependent receiver operating characteristic curve. Overall, 499 of 891 and 1020 of 1353 patients with right-side and left-side colon cancer, respectively, had high NLN. In right-side colon cancer, patients with high NLN (≥ 27) had superior OS (74.9% vs. 62.7%, P< 0.001) and RFS (75.0% vs. 61.9%, P< 0.001) than did those with low NLN. Moreover, in left-side colon cancer, patients with high NLN (≥12) experienced significantly superior OS (80.8% vs. 68.6%, P< 0.001) and RFS (77.3% vs. 66.2%, P< 0.001) than did those with low NLN. Among the different subgroups of stage III colon cancer, the high NLN group showed significantly superior RFS and OS in stage IIIB (RFS: 77.0% vs. 68.0%, P= 0.001; OS: 78.6% vs. 67.9%, P< 0.001) and IIIC (RFS: 58.2% vs. 44.1%, P= 0.001; OS: 65.7% vs. 51.1%, P< 0.001) colon cancer. However, in stage IIIA colon cancer, high NLN only showed survival benefit in OS (91.5% vs. 89.8%, P= 0.041). Multivariate analyses confirmed that high NLN, high carcinoembryonic antigen (≥ 5ng/mL) level, and stage IIIC status are three independent prognostic factors in both the proximal and distal colon.ConclusionsNLN is a crucial prognostic factor for stage III colon cancer in various tumor locations or in the subgroups of stage III disease. In advanced stage III colon cancer, the importance of NLN and its role in anti-cancer immune response could be highlighted.

Background Laparoscopic surgery has achieved significant results in elderly patients with colorectal cancer (CRC). In this study, we compared the short-term and long-term outcomes of open surgery and laparoscopic surgery in patients with CRC aged above 75 years at a single tertiary medical center. Methods We analyzed 967 patients who underwent curative resection for primary colorectal adenocarcinoma without distant metastasis between January 2009 and December 2015, in a single institution. Of the enrolled patients, 305 underwent laparoscopic surgery, and 662 received open laparotomy surgery. Results Compared to the patients who underwent open surgery, those who received laparoscopic surgery had significantly shorter postoperative stay (10.3 vs. 13.5 days p p = 0.354) and mortality (p = 0.082). In the laparoscopy cohort, six of 305 patients were converted to open surgery and one died. The long-term overall survival, cancer-specific survival, and recurrence rate were similar between both cohorts in each stage. Conclusions Laparoscopic surgery is suitable for elderly patients owing to shorter postoperative stay, similar long-term outcomes with open surgery, and acceptable low conversion rates. For long-term overall and oncological outcomes, the results of laparoscopic surgery were similar to that of open surgery in each TNM stage.

Background: The neutrophil-to-lymphocyte ratio is a significant prognostic marker in resectable colorectal cancer; however, there are no equivalent findings for perforated colon cancer. Using our colorectal cancer database, we retrospectively analyzed the data from 1995 to 2015 to determine whether the preoperative neutrophil-to-lymphocyte ratio is associated with survival outcomes in patients with perforated colon cancer.Methods: One-to-one propensity score matching was applied to minimize the difference between the high (>5) and low (≤5) neutrophil-to-lymphocyte ratio groups. Clinicopathological factors, long-term overall survival, and disease-free survival were analyzed and compared between the two groups. The primary outcomes were overall survival and disease-free survival.Results: Before propensity score matching, the high neutrophil-to-lymphocyte ratio group had a significantly higher prevalence of leukocytosis (low vs. high neutrophil-to-lymphocyte ratio groups: 12 [12.9%] vs. 46 [59.7%], pvs. high neutrophil-to-lymphocyte ratio groups: 30 [32.3%] vs. 42 [54.5%], p=0.003), and a higher emergent operation rate (low vs. high neutrophil-to-lymphocyte ratio groups: 5 [5.4%] vs. 20 [26.0%], pConclusions: The neutrophil-to-lymphocyte ratio has limited predictive value for determining outcomes in patients with perforated colon cancer.

Background: The neutrophil-to-lymphocyte ratio is a significant prognostic marker in resectable colorectal cancer; however, there are no equivalent findings for perforated colon cancer. Using our colorectal cancer database, we retrospectively analyzed the data from 1995 to 2015 to determine whether the preoperative neutrophil-to-lymphocyte ratio is associated with survival outcomes in patients with perforated colon cancer.Methods: One-to-one propensity score matching was applied to minimize the difference between the high (>5) and low (≤5) neutrophil-to-lymphocyte ratio groups. Clinicopathological factors, long-term overall survival, and disease-free survival were analyzed and compared between the two groups. The primary outcomes were overall survival and disease-free survival.Results: Before propensity score matching, the high neutrophil-to-lymphocyte ratio group had a significantly higher prevalence of leukocytosis (low vs. high neutrophil-to-lymphocyte ratio groups: 12 [12.9%] vs. 46 [59.7%], pvs. high neutrophil-to-lymphocyte ratio groups: 30 [32.3%] vs. 42 [54.5%], p=0.003), and a higher emergent operation rate (low vs. high neutrophil-to-lymphocyte ratio groups: 5 [5.4%] vs. 20 [26.0%], pConclusions: The neutrophil-to-lymphocyte ratio has limited predictive value for determining outcomes in patients with perforated colon cancer.

Background Colorectal cancer (CRC) is a major health concern globally, but exhibits regional and/or environmental distinctions in terms of outcome especially for patients with stage III CRC. Methods From 2014 to 2016, matched pairs of tumor and adjacent normal tissue samples from 60 patients with stage I–IV CRC Chang Gung Memorial Hospital in Taiwan were analyzed using next-generation sequencing. The DNA, mRNA, and miRNA sequences of paired tumor tissues were profiled. An observational study with survival analysis was done. Online datasets of The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) were also integrated and compared. Results The gene that exhibited the highest mutation rate was adenomatous polyposis coli (APC) (75.0%), followed by TP53 (70.0%), KRAS (56.6%), and TTN (48.3%). APC was also the most frequently mutated gene in TCGA and ICGC datasets. Surprisingly, for non-metastatic cases (stages I-III), CRC patients with mutated APC had better outcome in terms of overall survival (p = 0.041) and recurrence free survival (p = 0.0048). Particularly for stage III CRC, the overall survival rate was 94.4% and 67.7%, respectively (p = 0.018), and the recurrence free survival rate was 94.4% and 16.7%, respectively (p = 0.00044). Further clinical and gene expression analyses revealed that the APC wt specimens to a greater extent exhibit poor differentiation state as well as EGFR upregulation, providing molecular basis for the poor prognosis of these patients. Finally, based on integrated transcriptome analysis, we constructed the mRNA-miRNA networks underlying disease recurrence of the stage III CRC and uncovered potential therapeutic targets for this clinical condition. Conclusion For stage III CRC, patients with mutated APC had better overall and recurrence free survival.

The purpose of this study was to report the clinicopathological characteristics and treatment outcomes of 45 rectal cancer patients who have a history of cervical cancer with or without remote radiotherapy. Twenty-nine patients (64.4%) with a history of cervical cancer treated with pelvic radiotherapy were classified as group A, 16 (35.6%) patients with a history of cervical cancer not treated with radiotherapy were classified as group B. The median duration between radiotherapy for cervical cancer and rectal adenocarcinoma diagnosis was 18 years. At the time of rectal cancer diagnosis, 5 (17.2%) patients presented stage I disease, 15 (51.7%) had stage II, 1 (3.4%) had stage III, and 8 (27.6%) had stage IV. The patients in group A had older age, higher rates of gross ulcerative lesions, low hemoglobin levels, and a lower rate of lymph node metastases. The patients with secondary rectal cancer developed after radiotherapy for cervical cancer usually presented with abnormal abdominal symptoms, such as proctitis, cystitis, or rectal fistula. Higher colostomy rate was found in this group of patients due to severe pelvic fibrosis or proctitis.

Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker; however, ctDNA as a marker for mCRC patients is not well established, and there is still no consensus about how to utilize it most cost-effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients. We performed next-generation sequencing (NGS) by using a 12-gene panel to identify genetic variants in 136 tumor tissue and ctDNA samples from 32 mCRC patients. Genetic variants were detected in approximately 70% of samples, and there was a high concordance (85%) between tumor tissue and plasma ctDNA. We observed ctDNA changes in 18 follow-up patients, including the emergence of new variants. Changes in ctDNA levels significantly correlated with tumor shrinkage (P = 0.041), and patients with a ctDNA decrease >80% after treatment had a longer progression-free survival compared with patients with a ctDNA decrease of 80% was better than those with a ctDNA decrease

Background Local excision (LE) is a feasible treatment approach for rectal cancers in stage pT1 and presents low pathological risk, whereas total mesorectal excision (TME) is a reasonable treatment for more advanced cancers. On the basis of the pathology findings, surgeons may suggest TME for patients receiving LE. This study compared the survival outcomes between LE with/without chemoradiation and TME in mid and low rectal cancer patients in stage pT1/pT2, with highly selective intermediate pathological risk. Methods This retrospective study included 134 patients who received TME and 39 patients who underwent LE for the treatment of intermediate risk (pT1 with poor differentiation, lymphovascular invasion, perineural invasion, relatively large tumor, or small-sized pT2 tumor) rectal cancer between 1998 and 2016. Results Overall survival (OS), disease-free survival (DFS), and cumulative recurrence rate (CRR) were similar between the LE (3-year DFS 92%) and TME (3-year DFS 91%) groups. Following subgrouping into an LE with adjuvant therapy group and a TME without adjuvant therapy group, the compared survival outcomes (OS, DFS, and CRR) were found not to be statistically different. The temporary and permanent ostomy rates were higher in the TME group than in the LE group (p < 0.001). Rates of early and late morbidity following surgery were higher in the TME group (p = 0.005), and LE had similar survival compared with TME. Conclusion For patients who had mid and low rectal cancer in stage pT1/pT2 and intermediate pathological risk, LE with chemoradiation presents an alternative treatment option for selected patients.

The prediction of tumor in the TNM staging (tumor, node, and metastasis) stage of colon cancer using the most influential histopathology parameters and to predict the five years disease-free survival (DFS) period using machine learning (ML) in clinical research have been studied here. From the colorectal cancer (CRC) registry of Chang Gung Memorial Hospital, Linkou, Taiwan, 4021 patients were selected for the analysis. Various ML algorithms were applied for the tumor stage prediction of the colon cancer by considering the Tumor Aggression Score (TAS) as a prognostic factor. Performances of different ML algorithms were evaluated using five-fold cross-validation, which is an effective way of the model validation. The accuracy achieved by the algorithms taking both cases of standard TNM staging and TNM staging with the Tumor Aggression Score was determined. It was observed that the Random Forest model achieved an F-measure of 0.89, when the Tumor Aggression Score was considered as an attribute along with the standard attributes normally used for the TNM stage prediction. We also found that the Random Forest algorithm outperformed all other algorithms, with an accuracy of approximately 84% and an area under the curve (AUC) of 0.82 &plusmn, 0.10 for predicting the five years DFS.

(1) Background: The aim of this study was to develop a prediction model for assessing individual mPC risk in patients with pT4 colon cancer. Methods: A total of 2003 patients with pT4 colon cancer undergoing R0 resection were categorized into the training or testing set. Based on the training set, 2044 Cox prediction models were developed. Next, models with the maximal C-index and minimal prediction error were selected. The final model was then validated based on the testing set using a time-dependent area under the curve and Brier score, and a scoring system was developed. Patients were stratified into the high- or low-risk group by their risk score, with the cut-off points determined by a classification and regression tree (CART). (2) Results: The five candidate predictors were tumor location, preoperative carcinoembryonic antigen value, histologic type, T stage and nodal stage. Based on the CART, patients were categorized into the low-risk or high-risk groups. The model has high predictive accuracy (prediction error ≤5%) and good discrimination ability (area under the curve &gt, 0.7). (3) Conclusions: The prediction model quantifies individual risk and is feasible for selecting patients with pT4 colon cancer who are at high risk of developing mPC.

Purpose To assess preoperative serum alkaline phosphatase (ALP) levels in colon adenocarcinomapatients with various clinical features and determine its prognostic value. Between 2000 and 2013, 10,800 stage I-IV colon cancer patients who underwent surgery wereretrospectively enrolled. The relationship between ALP level and variables, including age, gender,carcinoembryonic Antigen (CEA) levels, aspartate aminotransferase (AST) level, bilirubin level, tumor size,liver cirrhosis, hepatitis, albumin level, histological type, and TNM-stage, were evaluated. The impact of ALP level elevation on survival was evaluated. Significant elevations in ALP level were found in patients with CEA ≥5 ng/ml (p

Objective Our purpose was to evaluate the effects of a health education and telephone counseling program on knowledge and attitudes about colorectal cancer and screening and the psychological impact of positive screening results. Methods A randomized controlled trial was conducted with 2 groups using a pretest and posttest measures design. Patients with positive colorectal cancer screening results were selected and randomly assigned to an experimental (n = 51) or control (n = 51) group. Subjects in the experimental group received a health education and telephone counseling program, while the control group received routine care only. Patients were assessed pretest before intervention (first visit to the outpatient) and posttest at 4 weeks after intervention (4 weeks after first visit to the outpatient). Results Patients in the experimental group had a significantly better level of knowledge about colorectal cancer and the psychological impact of a positive screening result than did the control group. Analysis of covariance revealed that the health education and telephone counseling program had a significant main effect on colorectal cancer knowledge. Conclusions A health education and telephone counseling program can improve knowledge about colorectal cancer and about the psychological impact in patients with positive colorectal cancer screening results. The health education and telephone counseling program is an easy, simple, and convenient method of improving knowledge, improving attitudes, and alleviating psychological distress in patients with positive colorectal cancer screening results, and this program can be expanded to other types of cancer screening.

// Hung-Chih Hsu 1, 2 , Tan Kien Thiam 3 , Yen-Jung Lu 3 , Chien Yuh Yeh 2, 4 , Wen-Sy Tsai 2, 4 , Jeng Fu You 2, 4 , Hsin Yuan Hung 2, 4 , Chi-Neu Tsai 5 , An Hsu 3 , Hua-Chien Chen 3 , Shu-Jen Chen 3 , Tsai-Sheng Yang 1, 2 1 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan 2 College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan 3 ACT Genomics, Neihu Dist., Taipei 114, Taiwan 4 Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan 5 Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan Correspondence to: Shu-Jen Chen, e-mail: sjchen@actgenomics.com Tsai-Sheng Yang, e-mail: a481124@cgmh.org.tw Keywords: BRAF, metastatic colorectal cancer, RAS, mutation, cetuximab resistance Received: July 17, 2015 Accepted: February 18, 2016 Published: March 12, 2016 ABSTRACT Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF , PIK3CA , KRAS (exons 3 and 4), NRAS , PTEN , and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS , NRAS , or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS , and BRAF mutations predict response to cetuximab treatment in mCRC patients.

Routine postoperative surveillance is recommended for the patients with colorectal cancer (CRC). This study aimed to clarify the conditions indicate initial suspicion of CRC recurrence in different preoperative serum carcinoembryonic antigen (CEA) level groups, including positive physical signs/symptoms, elevated CEA level, positive radiologic studies results, and other elevated tumor markers.A total of 2268 patients with recurrence after curative surgery for CRC were enrolled in this study. The patients were classified into 3 groups according to preoperative serum CEA level (low

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGF&beta, pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25, 95% CI, 1.83&ndash, 5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33, 95% CI, 1.47&ndash, 7.54, p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.

BACKGROUND AND OBJECTIVES We aim to investigate whether a difference exists between right-sided and left-sided colon cancer at the same disease stage and subsequent liver metastasis and identify whether tumor location can independently influence survival. METHODS Right-sided colon cancer was defined as malignancy arising from the cecum to the transverse colon; left-sided colon cancer was defined as malignancy arising from the splenic flexure to the sigmoid colon. Clinicopathological features and survival data were collected for analysis. RESULTS Overall, 1442 patients were included for analysis. The median follow-up time was 58.2 months. Patients with left-sided colon cancer had better 5-year overall survival (75.2% vs 61.7%, P = 0.005), 5-year cancer-specific survival (81.6% vs 73.4%, P = 0.001), and 5-year recurrence-free survival (70.9% vs 66.5%, P = 0.033) compared with patients having right-sided colon cancer. After the presentation of subsequent liver metastasis, patients with primary left-sided colon cancer had better 3-year cancer-specific survival ( P

The rate of postoperative morbidity and mortality is reportedly high in patients aged ≥ 75 years with colorectal cancer (CRC). In such patients, a comparison of the short-term outcome between open method and laparoscopy has not been clearly defined in Taiwan. We aimed to compare postoperative morbidity and mortality parameters after open method and laparoscopy in CRC patients aged ≥ 75 years. We retrospectively analyzed patients who underwent surgery for CRC from February 2009 to September 2015 at the Linkou Chang Gung Memorial Hospital in Taiwan and analyzed their clinicopathological factors. Postoperative morbidity and mortality were analyzed for evaluating if laparoscopic surgery offers more favorable outcomes than open surgery in the elderly. A total of 1133 patients were enrolled and analyzed in this study; they were divided into two groups (open method vs. laparoscopy = 797 vs. 336). The anastomotic leakage rate was significantly higher in the laparoscopy group than in the open method group (3.3 vs. 0.9%, p = 0.003). Overall postoperative morbidity and mortality rates showed no significant difference between these two groups. Postoperative hospital stay was significantly shorter in the laparoscopy group than in the open method group (10.4 ± 8.7 vs. 13.8 ± 13.5 days, p

Background The preoperative carcinoembryonic antigen (CEA) level as a prognostic factor of colorectal cancer (CRC) has been in debate. Methods A consecutive case series were collected from our database of CRC from 1995 to 2010. Clinicopathological factors were matched by propensity score methods with calliper width of 0.05 and a 1:4 ratio. Long-term overall survival (OS) and disease-specific survival (DSS) were analysed and compared between 3 different serum CEA levels. Results A total number of 9634 patients were included initially. After exclusion and matching, a number of 6099 cases were matched by propensity score matching methods with median follow-up period 86 months. The survival analysis showed poor OS in elevated serum CEA groups than normal CEA level (5 year survival rate: 75% vs. 66% vs. 61%) and was also presented in both subgroups divided by lymph node (LN) stage (LN positive: 69% vs. 56% vs. 50%, LN negative: 83% vs. 77% vs. 72%) but not between elevated groups. In contrast, DSS showed significantly poor outcome between each group and was proportional to serum CEA elevation (5 year survival rate: 83% vs. 76% vs. 69%, p In multivariate Cox regression model after adjusted with TNM stage, smoking, DM, renal insufficiency, liver cirrhosis and other factors, elevated CEA showed higher risk in DSS (5 to 10 ng/ml HR=1.540,>10 ng/ml HR=1.910, both p Conclusions Elevated preoperative serum CEA can be an independent prognostic factor for stage I to III CRC patients after curative resection with poor long-term overall and oncological outcome.

Lysine-specific demethylase 1 (LSD1) was highly expressed in several malignancies and had been implicated in pathological processes of cancer cells. However, the role of LSD1 in colorectal cancer (CRC) carcinogenesis, prognosis and treatment remains uncharacterized. In this study, we examined LSD1 expression in paraffin-embedded CRC specimens from 295 patients, including 65 patients with paired samples of colorectal carcinoma, adjacent adenoma and normal colorectal tissues. Using an LSD1 inhibitor, CBB1003, as a probe, we studied the association between LSD1 and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a CRC stem cell marker involved in carcinogenesis. The anti-tumor effects of CBB1003 on CRC cells were also examined. LSD1 expression was significantly elevated in colorectal tumor tissues compared with adjacent adenoma and normal colorectal tissues (P

Liver resection (LR) is the standard procedure for treating colorectal cancer (CRC) hepatic metastasis; however, LR associated with a high recurrence incidence. This study aimed to determine an optimal post-LR adjuvant chemotherapeutic strategy to improve overall long-term patient outcomes. A retrospective study of 490 patients who had undergone curative LR for CRC hepatic metastasis was performed. Patients who underwent post-LR adjuvant chemotherapy demonstrated high overall survival (OS) rates (hazard ratio [HR] = 0.58, P = .002) but not high recurrence-free survival (RFS) rates (HR = 1.02, P = .885). Moreover, OS was significantly longer in patients who underwent 5-fluorouracil + leucovorin (5-FU/LV; HR = 0.63, P = .039), oxaliplatin-based chemotherapy (HR = 0.45, P

OBJECTIVES: There is a significant unmet need for a blood test with adequate sensitivity to detect colorectal cancer (CRC) and adenomas. We describe a novel circulating tumor cell (CTC) platform to capture colorectal epithelial cells associated with CRC and adenomas. METHODS: Blood was collected from 667 Taiwanese adults from 2012 to 2018 before a colonoscopy. The study population included healthy control subjects, patients with adenomas, and those with stage I–IV CRC. CTCs were isolated from the blood using the CellMax platform. The isolated cells were enumerated, and an algorithm was used to determine the likelihood of detecting adenoma or CRC. Nominal and ordinal logistic regression demonstrated that CTC counts could identify adenomas and CRC, including CRC stage. RESULTS: The CellMax test demonstrated a significant association between CTC counts and worsening disease status (Cuzick's P value < 0.0001) with respect to the adenoma-carcinoma sequence. The test showed high specificity (86%) and sensitivity across all CRC stages (95%) and adenomatous lesions (79%). The area under the curve was 0.940 and 0.868 for the detection of CRC and adenomas, respectively. DISCUSSION: The blood-based CTC platform demonstrated high sensitivity in detecting adenomas and CRC, as well as reasonable specificity in an enriched symptomatic patient population. TRANSLATIONAL IMPACT: If these results are reproduced in an average risk population, this test has the potential to prevent CRC by improving patient compliance and detecting precancerous adenomas, eventually reducing CRC mortality.

(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13−0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.

Impaired kidney function is associated with different diseases. However, its impact on colorectal cancer has not been clarified. In order to understand the effect of preoperative kidney function on the outcome of patients with cancer, we analyzed colorectal cancer patients with localized or regional diseases.In total, 3731 stage I to III colorectal cancer (CRC) patients were analyzed in Chang Gung Memorial Hospital. Modification of Diet in Renal Disease (MDRD) formula was used for estimated glomerular filtration rate (eGFR). Receiver operating characteristic (ROC) analysis for kidney function cut-off value; Chi-square method, independent t test, or analysis of variance (ANOVA) method for clinicopathological factors; Kaplan-Meier method for disease-free survival (DFS); Cox proportional hazard model for multivariate analysis.Among colon cancer patients, low eGFR (MDRD70) was associated with more male patients, T2 stage, patients without adjuvant chemotherapy, and patients with elevated creatinine level. Low eGFR is a significant risk factor only for stage III colon cancer (hazard ratio 1.70, 95% CI: 1.28-2.26; P0.001). Furthermore, postoperative adjuvant chemotherapy did not significantly increase 5-year DFS for both high and low eGFR groups in stage II patients (5 yrs DFS, 94.8% vs. 84.1%, P = 0.098 for high eGFR subgroup; and 75.0% vs. 75.8%, P = 0.379 for low eGFR subgroup). However, significant improvement of 5-yrs DFS after chemotherapy was found in low eGFR stage III colon cancer patients (64.7% vs. 39.4%, P0.001 for low eGFR subgroup). In contrast, no significant DFS difference was caused by chemotherapy for high eGFR stage III subgroup (70.5% vs. 63.9%, P = 0.110).Although low eGFR is an independent risk factor for stage III colon cancer. However, the adjuvant chemotherapy impacts on stage III colon cancer patients differently according to eGFR status.

Our purpose was to evaluate the effects of a health education and telephone counseling program on knowledge and attitudes about colorectal cancer and screening and the psychological impact of positive screening results.A randomized controlled trial was conducted with 2 groups using a pretest and posttest measures design. Patients with positive colorectal cancer screening results were selected and randomly assigned to an experimental (n = 51) or control (n = 51) group. Subjects in the experimental group received a health education and telephone counseling program, while the control group received routine care only. Patients were assessed pretest before intervention (first visit to the outpatient) and posttest at 4 weeks after intervention (4 weeks after first visit to the outpatient).Patients in the experimental group had a significantly better level of knowledge about colorectal cancer and the psychological impact of a positive screening result than did the control group. Analysis of covariance revealed that the health education and telephone counseling program had a significant main effect on colorectal cancer knowledge.A health education and telephone counseling program can improve knowledge about colorectal cancer and about the psychological impact in patients with positive colorectal cancer screening results. The health education and telephone counseling program is an easy, simple, and convenient method of improving knowledge, improving attitudes, and alleviating psychological distress in patients with positive colorectal cancer screening results, and this program can be expanded to other types of cancer screening.

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had

We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) on disease-free survival in patients with stages I to III colorectal cancer (CRC).There were 3857 patients identified from our database. We used receiver operating characteristic (ROC) analysis to identify the best cutoff value of NLR. A 5-year disease-free survival was used as end point. Survival analysis was used to assess the NLR effect, after stratification by several clinopathologic factors.In the ROC analysis, NLR = 3 had the highest sensitivity and specificity. Elevated NLR (3) in colon cancer seemed to accompany larger tumor size (~5 cm) and more advanced T stage. By multivariate analysis, elevated NLR in colon cancer was associated with an increased risk of disease progression or cancer death [hazard ratio (HR) 1.377, 95 % confidence interval 1.104-1.717, P = 0.014]. However, elevated NLR in rectal cancer lost its significance in multivariate analysis (HR 1.121, 95 % confidence interval 0.941-1.336, P = 0.200). Patients with elevated NLR had worse outcome, especially for colon cancer.Preoperative NLR influenced the disease-free survival in patients with stages I to III CRC. Elevated NLR (3) was associated with worse outcome (5-year disease-free survival 66.3 % vs. 78.9 % in colon cancer, P 0.001; 60. 5 % vs. 66.2 % in rectal cancer, P = 0.008). The difference was larger in colon cancer than in rectal cancer. NLR should be considered as a prognostic factor for stages I to III CRC patients after curative surgery.