The prognostic and predictive significance of perineural invasion in stage I to III colon cancer: a propensity score matching-based analysis.

BACKGROUND: Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain. METHODS: We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures. RESULTS: PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease. CONCLUSIONS: Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present.

Smoking cessation for less than 10 years remains a risk factor of anastomotic leakage in mid-to-low rectal cancer patients undergoing sphincter-preserving surgery.

PURPOSE: Although cigarette smoking is a well-known risk factor for anastomotic leakage during rectal surgery, the proper duration of smoking cessation that can decrease anastomotic leakage in patients undergoing sphincter-preserving surgery is unclear. This study aimed to investigate the optimal duration of smoking cessation that can reduce this complication. METHODS: Between January 1, 2000, and December 31, 2012, we enrolled 1246 consecutive patients who underwent curative-intent sphincter-preserving surgery without preventive stoma at the Division of Colorectal Surgery of a tertiary referral center in Taiwan. Questionnaires were used to record their pre-surgical smoking status. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off duration of smoking cessation. Multivariate analysis was used to verify the effect of cigarette cessation on anastomotic leakage. RESULTS: The ROC curve showed a cut-off value of 10.5 years of cessation duration. Therefore, the former-smoker group was further divided using a cessation duration of 10 years. The overall anastomotic leakage rate was 5.29%. However, the anastomotic leakage rate in current smokers (9.3%) and in those who quit for < 10 years (12.9%) was significantly higher than that in non-smokers (3.3%) and those who quit for ≥ 10 years (4.5%). On multivariate analysis, current smokers (p = 0.022), former smokers with < 10 years of smoking cessation (OR 2.725; p = 0.029), male sex (p = 0.015), and low rectal cancer (p < 0.001) were all independently related to the development of anastomotic leakage. CONCLUSION: Smoking cessation for < 10 years remains a risk factor for anastomotic leakage in patients with mid-to-low rectal cancer undergoing sphincter-preserving surgery.

Prognostic value of regional lymph node involvement in patients with metastatic colorectal cancer: palliative versus curative resection.

BACKGROUND: Approximately 20% of patients with colorectal cancer are initially diagnosed with stage IV disease. This study aims to examine the role of regional lymph node (LN) status in metastatic colorectal cancer (mCRC) with respect to clinicopathologic features and survival outcomes. METHODS: We investigated 1147 patients diagnosed with mCRC and had undergone surgical resection of the primary CRC. A total of 167 patients were placed in the LN-negative (LN-) group and another 980 in the LN-positive (LN+) group. RESULTS: LN+ patients exhibited a significantly higher rate of T4 tumors (p = 0.008), poorly differentiated adenocarcinoma (p < 0.001), lymphovascular invasion (p < 0.001), and perineural invasion (p < 0.001) than those in the LN- group. LN- patients had a significantly higher rate of lung metastasis (p < 0.001), whereas the rate of peritoneal seeding (p < 0.001) and systemic node metastasis (p < 0.001) was both significantly higher in the LN+ group. The 5-year overall survival (OS) in the LN+ group was significantly poorer than that in the LN- group (LN- vs. LN+ 23.2% vs. 18.1%; p = 0.040). In patients with curative resection, the 5-year OS rate has no significant difference between the two groups (LN- vs. LN+ 19.5% vs. 24.3%; p = 0.890). CONCLUSIONS: Metastatic CRC patients with LN+ who underwent primary tumor resection may present with more high-risk pathological features, more peritoneal seeding, and systemic node metastasis, but less lung metastasis than LN- patients. LN+ patients had poorer long-term outcomes compared with that in LN- patients. Nevertheless, with curative resection, LN+ patients could have similar survival outcomes as LN- patients.

Preoperative Carcinoembryonic Antigen as a Poor Prognostic Factor in Stage I-III Colorectal Cancer After Curative-Intent Resection: A Propensity Score Matching Analysis.

BACKGROUND: Preoperative carcinoembryonic antigen (CEA) has yet to be used as a prognostic or adjuvant chemotherapy factor for colorectal cancer (CRC). METHODS: This retrospective cohort study included all stage I-III CRC patients with different preoperative serum CEA levels (≤ 5, 5-10, and > 10 ng/ml) at a single center between 1995 and 2010. Propensity score matching was performed in a 1:1 ratio between the two elevated CEA groups (5-10 ng/ml and > 10 ng/ml) and in a 1:2 ratio between the elevated and non-elevated groups (≤ 5 ng/ml), with a caliper of 0.05. RESULTS: After exclusion and matching, 3857 patients had preoperative CEA levels ≤ 5 ng/ml, 1121 patients had CEA levels between 5 and 10 ng/ml, and 1121 patients had CEA levels > 10 ng/ml. Elevated preoperative CEA showed an increased risk of overall survival (5-10 ng/ml: hazard ratio [HR] 1.376; > 10 ng/ml: HR 1.523; both p < 0.001), cancer-specific survival (5-10 ng/ml: HR 1.404; > 10 ng/ml: HR 1.712; both p < 0.001), and recurrence free interval (5-10 ng/ml: HR 1.190; > 10 ng/ml: HR 1.468; both p < 0.05). Patients with negative lymph node staging (LNs) and CEA > 10 ng/ml, as well as those with positive LNs and CEA ≤ 5 ng/ml, showed similar overall survival (5-year survival: 72% vs. 69%; p = 0.542) and recurrence free intervals (19.9 vs. 21.72 months; p = 0.662). CONCLUSIONS: A preoperative CEA level can be an independent prognostic factor for stage I-III CRC after curative resection. Patients with negative LNs and preoperative CEA level > 10 ng/ml should be considered for intensive follow-up or adjuvant chemotherapy.

Survival analysis of local excision vs total mesorectal excision for middle and low rectal cancer in pT1/pT2 stage and intermediate pathological risk.

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.

Various clinicopathological features of patients with metachronous colorectal cancer in relation to different diagnostic intervals.

BACKGROUNDS: Clinicopathologic factors relating to developing metachronous colorectal cancer (CRC) have been reported. However, the effects of different diagnostic intervals on these risk factors required further analysis. PATIENTS AND METHODS: This retrospective study comprised 14,481 patients diagnosed from January 1995 to December 2012. Metachronous CRC was defined as the occurrence of a second colorectal cancer at least 1 year post-operatively. RESULTS: A total of 153 (1.06%) patients developed metachronous CRCs during the follow-up. Significantly higher rates of developing metachronous cancer occurred in male patients (1.2 vs 0.9%), patients with synchronous CRC (2.0 vs 1.0%), and patients with a positive family history of CRC (1.4 vs 0.9%). Pertaining to diagnostic intervals related to clinicopathological features, more severe staging was significant in the diagnostic interval between 2 and 3 years (35 vs 7.7%, 20.6%, 17.5%, P = .01) compared with other intervals. Male patients were more frequently detected to have CRC within 3 years compared with females (53.1 vs 29.1%, P = .005). For a diagnostic interval ≧ 5 years, a significantly higher rate of metachronous CRC located at the right colon was observed than that located at the left colon (36.6 vs 19.7%, p = 0.03). CONCLUSIONS: We evinced that a diagnostic interval between 2 and 3 years was a key time for metachronous CRC diagnosis with worse staging distribution. Based on current findings, we recommend the stratification of metachronous CRCs into diagnostic intervals of 1-2, 2-3, and ≧ 3 years, as they exhibit significantly different characteristics.

The dark side of laparoscopic surgery for colorectal cancer patients aged 75 years or older.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). CONCLUSIONS: Our results suggest that laparoscopy in patients aged ≥ 75 years with CRC had higher anastomosis leakage rate compared with open surgery but is acceptable and offers the benefit of a shorter hospital stay over open surgery.

Anorectal melanoma: review of 22 consecutive cases.

BACKGROUND/AIMS: To evaluate outcome and prognostic factors of patients with anorectal melanoma. METHODOLOGY: Twenty-two consecutive patients with anorectal melanoma received operation from 1993 through 2011 were reviewed. The definitions of stage I, II and III are local disease, locoregional lymphadenopathy and metastatic disease, respectively. RESULTS: The patients included 8 men and 14 women, aged from 36 to 83 years (mean, 58.4 years). At the end of the follow-up period, 19 patients died of disease and only 3 patients were alive with disease. Only two patients were alive longer than 5 years after operation. For stage I and II tumors that underwent clinical curative resection (n=17), stage II (p=0.04), tumor size >3 cm (p=0.008) and invasion depth to muscle (p=0.021) all showed poorer prognosis in overall survival. Though wide local excision (WLE) were performed in the patients with earlier tumors, there was no statistical difference in overall (p=0.063) and disease-free survival (p=0.333) between WLE and radical surgery. Furthermore, patients with WLE had more chance of local recurrence than radical surgery (6/7 vs. 3/10, p=0.050). Four salvage radical operations could be performed after local recurrence in WLE group. CONCLUSIONS: WLE increases the chance of local recurrence more than radical surgery. Care should be taken to avoid microseeding during performed WLE.

Concurrent chemoradiotherapy in the treatment of locally recurrent rectal cancer.

BACKGROUND/AIMS: Long course concurrent chemoradiotherapy provides potential tumor downstaging. When local recurrent rectal cancer without distant metastases is diagnosed, a potentially curative resection can be performed. The aim of this study was to assess the outcome of concurrent chemoradiotherapy in treating isolated local recurrent rectal cancer. METHODOLOGY: Patients (n=102) with isolated local recurrent rectal cancer within the pelvis were scheduled for concurrent chemoradiotherapy, consisting of pelvic irradiation with a total dose of 50.4 Gy in 28 fractions. Chemotherapy was administered concurrently and included 85 mg/m2 oxaliplatin by venous infusion over 2 h on day 1, followed by 1,200 mg*m-2*day-1 of continuous venous infusion for 2 days. This regimen was repeated every 2 weeks for 6 cycles. The overall survival rate, responses, disease-free interval and toxicities were assessed. RESULTS: A total of 96 patients completed planned concurrent chemoradiation. Complete clinical responses were found in 13 of the 96 patients (14%), partial responses in 59 (61%), stable disease in 21 (22%) and disease progression in 3 (3%). The overall survival and disease-free survival rates in all the 96 patients were 45% and 14%, respectively. CONCLUSIONS: The treatment of locally recurrent rectal cancer is complicated. Concurrent chemoradiation can increase disease-free survival and overall survival by increasing complete resection rate of locally recurrent tumors and even complete response of the tumors. Ongoing treatment strategies aim to enhance response rates and to accurately assess the extent of local recurrent tumor response to concurrent chemoradiation.

Localization of Colorectal Cancer Lesions in Contrast-Computed Tomography Images via a Deep Learning Approach.

Abdominal computed tomography (CT) is a frequently used imaging modality for evaluating gastrointestinal diseases. The detection of colorectal cancer is often realized using CT before a more invasive colonoscopy. When a CT exam is performed for indications other than colorectal evaluation, the tortuous structure of the long, tubular colon makes it difficult to analyze the colon carefully and thoroughly. In addition, the sensitivity of CT in detecting colorectal cancer is greatly dependent on the size of the tumor. Missed incidental colon cancers using CT are an emerging problem for clinicians and radiologists; consequently, the automatic localization of lesions in the CT images of unprepared bowels is needed. Therefore, this study used artificial intelligence (AI) to localize colorectal cancer in CT images. We enrolled 190 colorectal cancer patients to obtain 1558 tumor slices annotated by radiologists and colorectal surgeons. The tumor sites were double-confirmed via colonoscopy or other related examinations, including physical examination or image study, and the final tumor sites were obtained from the operation records if available. The localization and training models used were RetinaNet, YOLOv3, and YOLOv8. We achieved an F1 score of 0.97 (±0.002), a mAP of 0.984 when performing slice-wise testing, 0.83 (±0.29) sensitivity, 0.97 (±0.01) specificity, and 0.96 (±0.01) accuracy when performing patient-wise testing using our derived model YOLOv8 with hyperparameter tuning.

Can neutrophil-to-lymphocyte ratio predict the survival of colorectal cancer patients who have received curative surgery electively?

PURPOSE: We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) on disease-free survival in patients with stages I to III colorectal cancer (CRC). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A high density of PD-L1-expressing immune cells is significantly correlated with favorable disease free survival in nonmetastatic colorectal cancer.

ABSTRACT: The impact of immune cells (ICs) expressing various markers remains poorly understood in nonmetastatic colorectal cancer patients who have undergone colectomy. Here, we aimed to clarify the correlation between IC density and clinical parameters and survival.Programmed death protein-1 (PD-1), programmed cell death protein ligand-1 (PD-L1), clusters of differentiation (CD)-3, CD-8, and CD45RO immunostaining was performed for 421 patients using tissue microarray and automatic counting. Tumor stroma area immune density was assessed in comparison to clinical histological factors and surgical outcomes.High-density CD-8 expression was significantly associated with current smoking habits or a smoking history (P = .006). High-density of PD-1 expression was correlated with Lynch syndrome patients (P < .001) and with patients who did not consume alcohol (P = .034). A significant decrease in CR45RO expression density was associated with aging (P = .002 and r = -0.014), and high-density CD-3, CD-8, and PD-1 expression was significantly associated with right colon tumor location (P < .001). High CD-3 and PD-L1 expression was significantly associated with early tumor T-staging (P = .018 and P = .002). High-density PD-1 expression was significantly correlated with mucinous type adenocarcinoma (P = .027) and poor differentiation (P < .001). For treatment outcomes, multivariate analysis confirmed that patients exhibiting high-density PD-L1 expression possessed significantly longer disease free survival (adjusted hazard ratio: 0.752, 95% confidence interval [CI]: 0.61-0.92, P = .006) and overall survival (adjusted hazard ratio: 0.872, 95% CI: 0.75-1.91, P = .064)Significantly varied density in IC subsets was related to distinct demographic or clinic-histological factors. The presence of high-density PD-L1-expressing ICs is an independent favorable prognostic factor for disease free survival and overall survival among stage I to III colorectal cancer patients.

Association of Preoperative Physical Activity with Short- and Long-Term Outcomes in Patients Undergoing Palliative Resection for Metastatic Colorectal Cancer: An Inverse Probability of Treatment Weighting Analysis.

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.

Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer.

Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.

Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy.

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.

Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients.

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 from 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.

Real-World Effectiveness of Adjuvant Oxaliplatin Chemotherapy in Stage III Colon Cancer: A Controlled Interrupted Time Series Analysis.

Background: The real-world effectiveness of oxaliplatin in stage III colon cancer has not been determined in a large-scale population. We aimed to assess the real-world impact of adjuvant oxaliplatin treatment on the survival of these patients. Methods: Based on Taiwan cancer registry, we evaluated 17,801 patients with resected stage III colon cancer, including 14,168 patients receiving adjuvant chemotherapy and 3,633 not receiving adjuvant chemotherapy as the control group between 2004 and 2014. We used the controlled interrupted time-series analysis to assess the three-year disease-free survival and five-year overall survival rates before (2004-2008) and after (2009-2014) the addition of oxaliplatin. Results: The introduction of oxaliplatin was associated with no significant improvement in the slopes (per half-year) of the three-year disease-free survival rate (0.2%, 95% CI: -1.7∼2.2%) and five-year overall survival rate (0.6%, 95% CI: -1.8∼3%). The patients receiving oxaliplatin-based chemotherapy also showed no significant increase in the slopes (per half-year) of the three-year disease-free survival rate (0.6%, 95% CI: -1.4∼2.6%) and five-year overall survival rate (1%, 95% CI: -1.5∼3.5%). The nonsignificant results were consistent across subgroup analyses of age (<70 vs. ≥70 years), recurrence risk (T1-3 or N1 vs. T4 or N2), and cycle of oxaliplatin use (≤6 vs. >6). However, oxaliplatin-based chemotherapy significantly increased the slope (per half-year) of the five-year OS (2%, 95% CI: 0.2∼3.8%) for patients in the high-risk group (T4 or N2). The present results were robust in several sensitivity analyses. Conclusion: Among real-world patients with stage III colon cancer, the introduction of oxaliplatin does not yield a significant improvement in survival. Future work should identify the subpopulation(s) of patients who benefit significantly from the addition of oxaliplatin.

Colon Tissues Classification and Localization in Whole Slide Images Using Deep Learning.

Colorectal cancer is one of the leading causes of cancer-related death worldwide. The early diagnosis of colon cancer not only reduces mortality but also reduces the burden related to the treatment strategies such as chemotherapy and/or radiotherapy. However, when the microscopic examination of the suspected colon tissue sample is carried out, it becomes a tedious and time-consuming job for the pathologists to find the abnormality in the tissue. In addition, there may be interobserver variability that might lead to conflict in the final diagnosis. As a result, there is a crucial need of developing an intelligent automated method that can learn from the patterns themselves and assist the pathologist in making a faster, accurate, and consistent decision for determining the normal and abnormal region in the colorectal tissues. Moreover, the intelligent method should be able to localize the abnormal region in the whole slide image (WSI), which will make it easier for the pathologists to focus on only the region of interest making the task of tissue examination faster and lesser time-consuming. As a result, artificial intelligence (AI)-based classification and localization models are proposed for determining and localizing the abnormal regions in WSI. The proposed models achieved F-score of 0.97, area under curve (AUC) 0.97 with pretrained Inception-v3 model, and F-score of 0.99 and AUC 0.99 with customized Inception-ResNet-v2 Type 5 (IR-v2 Type 5) model.

A Prediction Model for Metachronous Peritoneal Carcinomatosis in Patients with Stage T4 Colon Cancer after Curative Resection.

(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 >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.

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While both genetic and environmental factors have been linked to the incidence and mortality associated with CRC, an ethnic aspect of its etiology has also emerged. Since previous large-scale cancer genomics studies are mostly based on samples of European ancestry, the patterns of clinical events and associated mechanisms in other minority ethnic patients suffering from CRC are largely unexplored. We collected 104 paired and adjacent normal tissue and CRC tumor samples from Taiwanese patients and employed an integrated approach - paired expression profiles of mRNAs and microRNAs (miRNAs) combined with transcriptome-wide network analyses - to catalog the molecular signatures of this regional cohort. On the basis of this dataset, which is the largest ever reported for this type of systems analysis, we made the following key discoveries: (1) In comparison to the The Cancer Genome Atlas (TCGA) data, the Taiwanese CRC tumors show similar perturbations in expressed genes but a distinct enrichment in metastasis-associated pathways. (2) Recurrent as well as novel CRC-associated gene fusions were identified based on the sequencing data. (3) Cancer subtype classification using existing tools reveals a comparable distribution of tumor subtypes between Taiwanese cohort and TCGA datasets; however, this similarity in molecular attributes did not translate into the predicted subtype-related clinical outcomes (i.e., death event). (4) To further elucidate the molecular basis of CRC prognosis, we developed a new stratification strategy based on miRNA-mRNA-associated subtyping (MMAS) and consequently showed that repressed WNT signaling activity is associated with poor prognosis in Taiwanese CRC. In summary, our findings of distinct, hitherto unreported biosignatures underscore the heterogeneity of CRC tumorigenesis, support our hypothesis of an ethnic basis of disease, and provide prospects for translational medicine.