UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer.

UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 in oxaliplatin resistance in colorectal cancer (CRC) remains unknown. In our study, UPF1 is upregulated in CRC in mRNA and protein levels and overexpression of UPF1 predicts a poor overall survival (OS) and recurrence-free survival (RFS) in CRC patients and is an independent risk factor for recurrence. UPF1 promotes chemoresistance to oxaliplatin in vitro and in vivo. UPF1-induced oxaliplatin resistance can be associated with interaction between zinc finger of UPF1 and Toprim of TOP2A and increasing phosphorylated TOP2A in a SMG1-dependent manner. Moreover, UPF1 maintains stemness in a TOP2A-dependent manner in CRC. Taken together, UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced chemoresistance to oxaliplatin in CRC, which may result from regulation of TOP2A activity and maintenance of stemness. Our findings could provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

HIF1α promotes tumor chemoresistance via recruiting GDF15-producing TAMs in colorectal cancer.

Chemoresistance is a tremendous challenge to efficacy of systemic chemotherapy which is the preferred treatment for the advanced CRC patients. More tumor-associated macrophages (TAMs) are recruited into the CRC tumor under chemotherapy, which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we present that activated HIF1α signaling in CRC cells under chemotherapy drives the expression of HMGB1to promotes macrophage infiltration and in turn chemoresistance development. Chemotherapeutic treatment with 5-FU leads to increased recruitment of macrophages into tumors, which display tumor-protective alternative activation. Mechanistically, tumor HIF1α signaling activated by chemo-induced ROS drives the transcription of HMGB1 to promote more macrophage infiltration into CRC tumor. Furthermore, high levels of GDF15 produced by TAMs impair the chemosensitity of tumor cells via enhancing fatty acids ß-oxidation. Together, our current study reveals a new insight into the cross-talking between tumor cells and immune cells, and provides novel drug targets for clinic treatments for CRC.

Hypoxia Induces Growth Differentiation Factor 15 to Promote the Metastasis of Colorectal Cancer via PERK-eIF2α Signaling.

Hypoxia plays an essential role in orchestrating Epithelial-mesenchymal transition and promoting metastasis of colorectal cancer. However, the underlying mechanisms are still not well elucidated. Here, we present that hypoxic exposure causes endoplasmic reticulum stress and activates the unfolded protein response pathways, which drives GDF15 expression in colorectal cancer cells. Mechanistically, upregulated CHOP led by activated PERK-eIF2α signaling promotes GDF15 transcription via directly binding to its promoter. Further study implicates that hypoxia-induced GDF15 is required for the EMT and invasion of colorectal cancer cells; enforced expression of GDF15 promotes the mitochondrial oxidation of fatty acids in colorectal cancer cells. Moreover, the abrogation of GDF15 results in smaller xenograft tumors in size and impaired metastasis. GDF15 is expressed much more in tumor tissues of CRC patients and displays positive correlations with CHOP and HIF1α in mRNA levels. Our study demonstrates a novel molecular mechanism underlying hypoxia-promoted metastasis of CRC and provides PERK signaling-regulated GDF15 as a new and promising therapeutic target for clinical treatment and drug discovery.

Prognosis of three histological subtypes of colorectal adenocarcinoma: A retrospective analysis of 8005 Chinese patients.

BACKGROUND AND OBJECTIVES: To evaluate the effect of the varied histological subtypes on clinical outcomes and to determine the prognostic implications of mucinous adenocarcinomas (MAC) and signet ring cell carcinomas (SRCC) compared with classic adenocarcinomas (AC). METHODS: A total of 8005 patients, including 7502 AC, 428 MAC and 75 SRCC, who underwent definitive surgery between 2007 and 2015 at Fudan University Shanghai Cancer Center were remained for analysis in this study. RESULTS: MAC and SRCC were more common in right-sided colon cancer, in males and in young patients, compared to AC; moreover, MAC and SRCC led to a higher probability to develop lymph node metastasis, lymphovascular invasion and perineural invasion. For survival outcomes, we found that the 5-year overall survival (OS) of SRCC was significantly lower than that of MAC and AC, while the 5-year OS of MAC is much lower than that of AC. However, in multivariable analysis, the difference in survival between SRCC, MAC and AC was no longer significant, especially when stratified by N stage. CONCLUSIONS: MAC and SRCC are rare subtypes of colorectal cancer with a higher T stage, N stage as well as higher incidence of lymphovascular and nerve invasion. However, neither MAC nor SRCC was an independent predictor of decreased survival in multivariate analysis.

Laparoscopic surgery may decrease the risk of clinical anastomotic leakage and a nomogram to predict anastomotic leakage after anterior resection for rectal cancer.

INTRODUCTION: Anastomotic leakage is still one of the most dreaded complications after anterior resection for rectal cancer. This study aimed to identify risk factors for anastomotic leakage and to create a nomogram for precise prediction of anastomotic leakage after anterior resection for rectal cancer. METHODS: Two thousand six hundred eighteen consecutive patients who underwent anterior resection for rectal cancer with primary anastomosis, with or without diverting stoma, were retrospectively analyzed as a training dataset. Univariate and multivariable Cox regression analyses were used to determine independent risk factors associated with anastomotic leakage. A nomogram was constructed to predict anastomotic leakage. Data containing 611 patients were prospectively collected as a test dataset. The performance of the nomogram was evaluated by using a bootstrapped-concordance index and calibration plots. RESULTS: The rate of clinical anastomotic leakage was 9.3% in the training dataset. Multivariate analysis identifies the following variables as independent risk factors for anastomotic leakage: gender (male) (odds ratio (OR) = 2.286), distance of tumor to anal verge (OR = 0.791), tumor size (OR = 1.175), operating time (OR = 1.009), diabetes mellitus (OR = 1.704), laparoscopic surgery (OR = 0.445), anastomotic bleeding (OR = 13.46), and diverting stoma (OR = 0.386). We created a nomogram with high discriminative ability (concordance index, 0.722). The area under the curve value, which evaluated the predictive performance of external validation, was 0.723. CONCLUSIONS: A protective diverting stoma and laparoscopic surgery significantly decrease the risk of anastomotic leakage. Our nomogram was a useful tool for precise prediction of anastomotic leakage after anterior resection for rectal cancer.

A negative-doughnut distal resection margin less than 5 mm does not affect prognosis in rectal cancer.

AIM: Many issues relating to the distal margin of anterior resection of the rectum still exist. We aimed to investigate whether negative distal resection margin (DRM) and positive DRM in the main specimen with negative doughnut has equivalent prognosis in patients with rectal cancer. METHODS: We included 287 patients with rectal cancer, including 69 cases with positive margins and 218 cases with negative margins, all of whom underwent regular follow-up. Survival rate was calculated using Kaplan-Meier survival analysis, while the log-rank test was used to determine statistical difference. Prognostic factors were found using the Cox regression model. RESULTS: There was no significant difference in clinicopathological features between the two groups with the exception of tumor location. Positive findings in the DRM with negative findings in the doughnut resection do not affect the overall survival, local recurrence, or distant metastasis. Factors relating to resection margin, such as the length of resection, negative, or positive findings, were not found to be prognostic. CONCLUSION: Given postoperative pathology results with positive DRM but negative findings in the doughnut resection, a second surgery was not necessary. Instead, adjuvant radiochemotherapy and close follow-up will suffice.

Temporary Diverting Stoma Improves Recovery of Anastomotic Leakage after Anterior Resection for Rectal Cancer.

Temporary diverting stoma might be a protective factor for the prevention of anastomotic leakage (AL) after anterior resection. Its role in leakage recovery is unknown. This study aimed to evaluate the effect of temporary diverting stoma on anastomotic leakage severity and recovery. We analyzed 323 patients who underwent anterior resection for rectal cancer and developed anastomotic leakage, in which 44 had temporary diverting stoma. Association between diverting stoma and occurrence of anastomotic leakage, recovery time, length of hospital stay, overall costs, local and distant relapse-free survival were further studied. In non-severe AL group, temporary diverting stoma improved leakage recovery by 4 days (mean: 20.7 days vs. 16.1 days, p = 0.031), especially in patients who did not receive neoadjuvant treatment (mean time: 20.9 days vs. 14.4 days, p = 0.016). However, it did not delay the occurrence of anastomotic leakage. Moreover, no significant difference was found in the overall length of hospital stay and costs among patients with versus without a diverting stoma. In severe AL group, however, no difference was detected. The advantage of shortened leakage recovery did not reduce the local and distant relapse-free survival. In conclusion, our findings indicated the recovery benefit from diverting stoma in patients with anterior resection.

Rectovaginal fistula after low anterior resection in Chinese patients with colorectal cancer.

Rectovaginal fistula is a postoperative complication of low anterior resection. We investigated the incidence of rectovaginal fistula (RVF) after low anterior resection, its risk factors and its optimal treatment. We analyzed data from 1,493 female patients who underwent low anterior resection for colorectal cancer between January 2006 and March 2016. We calculated the incidence of RVF and performed univariate and multivariate logistic regression analyses to identify risk factors. Twenty-four patients experienced RVF, giving an incidence of 1.61%. Univariate analysis revealed a short distance between the tumor and the anal verge (p < 0.001), longer surgery duration (p = 0.009), unsatisfactory anastomosis (p < 0.001), and greater intraoperative blood loss (p = 0.002) to be risk factors for RVF. Multivariate analysis showed that only distance between the tumor and the anal verge and unsatisfactory anastomosis were risk factors for RVF. Sixteen patients (66.7%) healed within a range of 30-1,225 days (median, 210 days). Twenty-one patients underwent surgery for diverting stoma; of those, 15 of them (71.4%) recovering after ostomy. These results indicate the primary risk factors for RVF are unsatisfactory anastomosis and short distance between the tumor and the anal verge. Most cases of RVF can be healed using a diverting stoma alone, without the need for additional surgery.

A study of peritoneal metastatic xenograft model of colorectal cancer in the treatment of hyperthermic intraperitoneal chemotherapy with Raltitrexed.

Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes. Tumor sites in the treatment groups were reduced significantly. The administration dose of Raltitrexed influenced concentration in systemic blood and peritoneal tissues. Temperature promoted the intracellular absorption of Raltitrexed significantly. Our findings reveal that hyperthermic intraperitoneal chemotherapy is an efficient therapy in treating peritoneal metastatic carcinoma in nude mice. It can effectively reduce the extension of carcinoma cells from macro and micro examination. The combination of hyperthermia and Raltitrexed resulted in an improved therapeutic effect on animal models.

Comparative study of single-center patients with thyroid metastases from colorectal cancer and previously reported cases in the literature.

BACKGROUND: Thyroid metastases from colorectal cancer (CRC) are rare, both in clinical practice and in the literature; hence, their diagnosis, appropriate treatment, and prognostic factors require further investigations. METHODS: A retrospective analysis was performed for four cases of thyroid metastases from CRC, treated in our center between January 2005 and December 2015, and the relevant literature was searched using PubMed, resulting in the identification of 17 patients with detailed information available. The clinical data and follow-up information of our patients and the previously reported cases were collected and compared. RESULTS: The median age of the 21 patients was 59 years (44.5 and 66 years for our patients and the previously reported cases, respectively). Fifteen (71.4%) primary tumors were distributed throughout the distal colon or rectum (75% [3/4] in our center and 70.5% [12/17] in the previously reported cases). According to our analysis, we found that 81.0% of patients (17/21) showed concomitant lung metastasis. Among them, all four patients in our center showed lung metastasis, and 75% (3/4) developed thyroid metastases after the lung metastasis. In the previously reported cases, the corresponding proportions were 76.5 and 76.5% (13/17) of patients, respectively. The median time after primary tumor diagnosis to thyroid metastasis development was 28 months (26 months in our center and 35 months in the previously reported cases). One patient with advanced CRC in our center died 5 months after the thyroid metastasis was identified, while the remaining three patients are currently alive (longest follow-up time, 27 months). The median survival time after thyroid metastasis during 3 years of follow-up of the previously reported 17 patients was 12 months. There was no difference in the overall survival between patients treated non-surgically (8/21) and patients undergoing thyroidectomy alone or thyroidectomy with adjuvant therapy (13/21) (p = 0.388). In addition, we found that the overall survival of the patients whose other metastases were treated with radical treatment was superior to that in those treated with palliative treatment (p = 0.022). CONCLUSIONS: Thyroid metastases from CRC are rare in clinical practice and are a manifestation of advanced CRC. The prognosis of patients with thyroid metastases from CRC is related to various factors, including the grade of malignancy of the primary lesion, the presence of other metastases, and whether the metastases are timely diagnosed and a radical treatment strategy is employed.

Very Early Colorectal Anastomotic Leakage within 5 Post-operative Days: a More Severe Subtype Needs Relaparatomy.

Early anastomotic leakage (AL), usually defined as leakage within 30 post-operative days, represents a severe entity. However, mounting evidence has indicated that majorities of leakage occur within one week after surgery, making late AL rarity. Here we analyzed 101 consecutive colorectal AL, all of which occurred within 30 post-operative days, during Jan 2013 and Dec 2015 in cancer hospital of Fudan University. AL occurring within 5 post-operative days was defined as very early AL (vE-AL). We evaluated risk factors of vE-AL compared with non-vEAL and correlated with post-leakage peritonitis and need of relaparatomy. We found that AL occurred at median time of 7 days after surgery. 23 cases were vE-AL. Reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with non-vE-AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). Besides, patients with vE-AL trended to correlate with increased re-operation rate after leakage (p = 0.088). In concludsion, vE-AL occurring within 5 post-operative days represents a severe subtype associated with general peritonitis and need of relaparatomy.

High preoperative peripheral blood neutrophil predicts poor outcome in rectal cancer treated with neoadjunctive chemoradiation therapy.

Distant metastasis impaired the value of neoadjunctive chemoradiation therapy (NCRT) for patients who were not pathological completed response. The objective of this study was to evaluate whether the absolute counts of preoperative neutrophils (pN) could predict survival outcomes of patients treated with NCRT. In this study, 289 locally advanced rectal cancer patients receiving NCRT and radical surgery were recruited between January 2006 and December 2012 at the Fudan University Shanghai Cancer Center. The absolute counts of pN were gathered and analyzed. Survival analysis was used to evaluate the prognostic value of pN. As results, a pN 3.00 was elected as the optimal cutoff points in term of survival by X-tile program. There were 112 patients (38.8%) in high-pN group and 177 patients (61.2%) in low pN group. The 4-year rectal cancer-specific survival (RCSS) and disease free survival (DFS) rate was 48.5% and 80.6%, 50.9% and 76.7% in high and low pN group, respectively. Univariate and multivariate analysis revealed that high-pN predicted poor RCSS and DFS. In conclusion, an elevated pN level was a significantly risk factor for locally advanced rectal cancer patient treated with NCRT, which may serve as a valuable marker to predict the outcomes of those patients.

Silencing of long non-coding RNA SBDSP1 suppresses tumor growth and invasion in colorectal cancer.

Long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. This study was undertaken to examine the expression and biological functions of a novel lncRNA SBDSP1 in colorectal cancer (CRC). Quantitative real-time PCR analysis was used to measure the expression of SBDSP1 in CRC tissues and cell lines. Knockdown of SBDSP1 via short hairpin RNA technology was performed to determine the roles of SBDSP1 in CRC cell growth, colony formation, cell cycle progression, migration, and invasion. The effect of SBDSP1 knockdown on tumorigenesis of CRC cells was investigated in a subcutaneous tumor mouse model. Western blot analysis was done to examine the involvement of signaling pathways in the action of SBDSP1. Notably, SBDSP1 was overexpressed in CRC tissues and cells relative to corresponding normal controls. Moreover, SBDSP1 expression was significantly greater in CRCs with nodal metastasis than in primary tumors (P=0.0259). Downregulation of SBDSP1 significantly inhibited cell proliferation, colony formation, migration, and invasion in SW480 and HCT116 cells, which was accompanied by suppression of Akt, ERK1/2, and STAT3 phosphorylation. SBDSP1-depleted cells showed a G0/G1 cell cycle arrest and deregulation of p21 and cyclin D1. In vivo studies confirmed that SBDSP1 downregulation retarded the growth of HCT116 xenogaft tumors. Altogether, SBDSP1 plays an essential role in CRC cell growth, invasion, and tumorigenesis, largely through inactivation of multiple signaling pathways. Therefore, targeting SBDSP1 may have therapeutic benefits in the treatment of CRC.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict chemotherapy outcomes and prognosis in patients with colorectal cancer and synchronous liver metastasis.

BACKGROUND: Recent evidence indicates that inflammatory parameters could be useful to predict metastasis from colorectal cancer. However, their roles in predicting chemotherapy response and prognosis in patients with synchronous colorectal liver metastasis (CLM) are unknown. METHODS: The clinical data and baseline laboratory parameters of 55 patients with synchronous CLM were retrospectively reviewed. All patients underwent palliative resection of the primary tumor and oxaliplatin-based chemotherapy. Two indices of systemic inflammation were reviewed-neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)-preoperatively and before the second cycle of chemotherapy. Associations between prognostic variables and tumor response, progression, and survival were investigated. RESULTS: NLR < 4 and PLR < 150 were correlated with better disease control (p = 0.024 and 0.026, respectively). In univariate analysis, elevated NLR and PLR were significant prognostic factors for poor overall survival (OS) and progression-free survival (PFS). In multivariate analysis, PLR (p = 0.027), age (p = 0.018), resection of liver metastases (p = 0.017), and lactate dehydrogenase level (p = 0.011) were independent predictors of PFS, while resection of liver metastases was the only independent predictor of OS (p = 0.002). In addition, when patients were divided into groups according to changes in NLR and/or PLR, reduced NLR and PLR were associated with improved disease control (p = 0.038 and 0.025, respectively). Normalization of NLR also was associated with improved PFS. CONCLUSIONS: NLR and PLR are potentially useful clinical biomarkers to predict chemotherapy response in patients with synchronous CLM. PLR also may be useful to predict PFS in these patients.

Prognostic risk factors in patients with bone metastasis from colorectal cancer.

The morbidity of bone metastasis (BM) from colorectal cancer (CRC) is increasing more than ever; however, insufficient research on BM from CRC leads to reduced awareness of the issue. Therefore, the aim of this study was to evaluate the clinical features and prognostic risk factors of CRC patients with BM. Clinical data were retrospectively analyzed for a total of 242 CRC patients with BM. Of the 242 CRC patients with BM, 52 (21.5 %) had bone metastasis alone (BMA) and 190 (78.5 %) had both bone and visceral metastasis (BM&VM). The median survival time (MST) after the diagnosis of BM in all 242 patients was 15.6 months (95 % confidence interval [CI] 12.74-18.46 months). The MST of the BMA group was significantly longer than that of the BM&VM group (29.1 vs. 12.8 months, p = 0.003). Using a Cox proportional hazard model, we identified a high carcinoembryonic antigen (CEA) level and BMA as independent prognostic factors for CRC patients with BM. For the BMA group, the independent prognostic factors were elevated alkaline phosphatase (ALP) and perineural invasion of the primary cancer, which were distinct from the factors for the entire group of BM patients. Furthermore, we found that the BMA patients with multiple sites of BM had similar prognosis to the BM&VM patients. These findings together provide us with a further understanding of BM from CRC and reveal that BMA may be a distinct subset of BM from CRC that has unique independent prognostic factors and a good prognosis.

CapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase II trial.

OBJECTIVE: The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy (NAC) using oxaliplatin plus capecitabine (CapOX) for patients with operable locally advanced colon cancer (CC). METHODS: Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1, plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade (TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in ClinicalTrials.gov (No: NCT02415829). RESULTS: Forty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments. The total radiological response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation (1/47, 2%). There was no treatment-related death. CONCLUSIONS: Our results suggest that NAC with CapOX is an effective and safe treatment option for patients with locally advanced CCs.

Lymph node count after preoperative radiotherapy is an independently prognostic factor for pathologically lymph node-negative patients with rectal cancer.

Recent studies indicated that preoperative radiotherapy significantly reduces the lymph nodes (LNs) harvest from patients with rectal cancer. This may weaken the prognostic value of current standard of LNs retrieval (≥12 LNs). This study investigates the prognostic impact of the LN counts on pathologically LN-negative (ypN0) after preoperative radiotherapy for patients with rectal cancer.Surveillance, Epidemiology and End Results (SEER) registered nonmetastatic rectal cancer patients diagnosed between 1998 and 2005 were included in this study. Optimal cutoff value for number of LNs retrieved was determined by X-tile program. Log-rank tests were adopted to compare the rectal cause specific survival (RCSS) for ypN0 patients using separated cutoff value of LN counting from 2 to 20. Correlation between LN count and tumor regression was investigated in an additional 221 patients from Fudan University Shanghai Cancer Center (FUSCC).The results showed that there were fewer number of LNs examined in patients with preoperative radiotherapy than those without (8.9 vs 10.9, P < 0.001). X-tile program identified the difference in survival was most significant (maximum of χ log-rank values) for the number 4. And 5-year RCSS increased accordingly with the cutoff values ranging from 4 to 15, which were confirmed as optimal cutoff and validated as independent prognostic factors in multivariate regression analysis (χ = 50.65, P < 0.001). Patients in FUSCC set were found to have fewer LNs retrieval in group of good tumor regression than in that of poor one (P = 0.01).These results confirmed the reduced number of LN retrieval in patients with rectal cancer treated with preop-RT. LN count is still an independently prognostic factor for ypN0 rectal cancer.

Unfavorable effect of small tumor size on cause-specific survival in stage IIA colon cancer, a SEER-based study.

BACKGROUND: We sought to determine the prognostic role of tumor size on cause-specific survival (CSS) of patients with stage IIA colon cancer. METHODS: Surveillance, Epidemiology and End Results (SEER) database was utilized to identify patients with stage IIA colorectal cancer (examined lymph nodes ≥12) diagnosed from 1988 to 2003. The prognostic effect of tumor size on CSS was evaluated by univariate and multivariate analyses. RESULTS: A total of 8775 patients were enrolled in the analysis. The median follow-up time was 109 months. As determined by minimal P value method, tumor sizes of 2.5 and 6.0 cm were used as optimal cutoff value to divide the cohort. The 8-year CSS of colon cancer with tumor sizes ≤2.5, 2.6-6.0, and >6.0 cm was 81.6, 86.2, and 86.7% respectively (P = 0.003). In the multivariate analysis of colon cancer, using ≤2.5-cm tumors as reference, decreased hazard ratio (HR) of CSS was observed in 2.6-6.0 cm (HR, 0.736; 95% confidence interval (CI), 0.599-0.905; P = 0.004) and >6.0 cm (HR, 0.770; 95% CI, 0.619-0.958; P = 0.019) tumors. CONCLUSIONS: In stage IIA colon cancer, small tumor size represented a subset with decreased CSS. Further studies are merited to validate the unfavorable prognostic role of small tumor size in stage IIA colon cancer.

Risk factors of synchronous inguinal lymph nodes metastasis for lower rectal cancer involving the anal canal.

PURPOSE: The aim of the study is to identify the risk factors of synchronous ILN metastasis for lower rectal cancer involving the anal canal. METHODS: Patients with lower rectal cancer who underwent radical resection at the Fudan University Shanghai Cancer Center were retrospectively analyzed. The synchronous ILN metastasis was defined as the metastasis occurring within 6 months after the diagnosis of rectal cancer. Patients' gender, age, tumor diameter, dentate line invasion, differentiation level, histological type, depth of invasion, perirectal LN metastasis, lymphovascular invasion or perineural invasion were analyzed in the study. The correlation between synchronous ILN involvement and clinicopathological features were analyzed with Chi-square test/fisher's exact test. Variables with p<0.05 in univariate analysis were then analyzed in a multivariate logistic model. Odds ratio (OR) along with 95% confidence intervals (95% CI) were calculated. RESULTS: A total of 325 patients (182 men and 143 women) with lower rectal cancer met the criteria and were enrolled in the study. Among them, 20 patients (6.2%) had synchronous ILN metastasis. Both univariate and multivariate analysis showed the invasion of the dentate line had a strong correlation with synchronous ILN metastasis with the odds ratio (OR) of 23.558 [95% confidence interval (CI) 6.380-86.982] (p<0.001). The presence of lymphovascular invasion also showed a significant correlation synchronous ILN metastasis with odds ratio (OR) of 5.260 [95% confidence interval (CI) 1.818-15.212] (p = 0.002). CONCLUSIONS: The invasion of dentate line and lymphovascular invasion are two independent risk factors of inguinal lymph node metastasis for lower rectal cancer involving the anal canal.

RNA-seq identifies determinants of oxaliplatin sensitivity in colorectal cancer cell lines.

Oxaliplatin-based chemotherapy, such as FOLFOX, is the first-line therapy for advanced colorectal cancer (CRC) or metastatic CRC patients. However, the partial response of patients to these regimes and the severe peripheral neuropathy toxicity induced by oxaliplatin makes it urgent to figure out biomarkers for oxaliplatin sensitivity to select suitable patients who benefit from these treatments. In present work, 21 CRC cell lines with different sensitivities to oxaliplatin were applied to RNA-seq. The basal expression profiles of these cell lines were correlated to their response to oxaliplatin. Bioinformatics analysis suggested that expression of 58 genes was correlated, negatively or positively, to oxaliplatin response across the 21 CRC cell lines. These 58 genes were mainly enriched in small molecules biochemistry, Wnt/ß-catenin signaling and EMT pathways. The latter two pathways were predicted to be activated in oxaliplatin-resistant CRC cell lines. Moreover, 15 genes were validated by qPCR that their expression levels were actually closely correlated to their response to oxaliplatin, in line with the biocomputation prediction. Taken together, our work might provide potential biomarkers for oxaliplatin sensitivity in CRC cell lines and therapeutic targets for combinational therapy with oxaliplatin.