Effect of hydrogel drug delivery system for treating ulcerative colitis: A preclinical meta-analysis.

Hydrogel drug delivery systems (DDSs) for treating ulcerative colitis (UC) have garnered attention. However, there is a lack of meta-analysis summarizing their effectiveness. Therefore, this study aimed to conduct a meta-analysis of pre-clinical evidence comparing hydrogel DDSs with free drug administration. Subgroup analyses were performed based on hydrogel materials (polysaccharide versus non-polysaccharide) and administration routes of the hydrogel DDSs (rectal versus oral). The outcome indicators included colon length, histological scores, tumor necrosis factor-α (TNF-α), zonula occludens protein 1(ZO-1), and area under the curve (AUC). The results confirmed the therapeutic enhancement of the hydrogel DDSs for UC compared with the free drug group. Notably, no significant differences were found between polysaccharide and non-polysaccharide materials, however, oral administration was found superior regarding TNF-α and AUC. In conclusion, oral hydrogel DDSs can serve as potential excellent dosage forms in oral colon -targeting DDSs, and in the design of colon hydrogel delivery systems, polysaccharides do not show advantages compared with other materials.

Association of Radiotherapy for Rectal Cancer and Second Gynecological Malignant Neoplasms.

Importance: Radiotherapy is a common treatment for rectal cancer, yet the risk of second gynecological malignant neoplasms (SGMNs) in patients with rectal cancer undergoing radiotherapy have not been adequately studied. Objective: To investigate the association between radiotherapy and the risk of individual types of SGMN in patients with rectal cancer and assess survival outcomes. Design, Setting, and Participants: A large population-based cohort study was designed to identify the risk of SGMNs in patients with rectal cancer diagnosed from January 1973 to December 2015. The statistical analysis was conducted from September 2019 to April 2020. The study was based on the 9 cancer registries of Surveillance, Epidemiology, and End Results database. A total of 20 142 female patients with rectal cancer in localized and regional stage were included. Exposure: Receipt of neoadjuvant radiotherapy for rectal cancer. Main Outcomes and Measures: The development of an SGMN defined as any type of GMN occurring more than 5 years after the diagnosis of rectal cancer. The cumulative incidence of SGMNs was estimated by Fine-Gray competing risk regression. Poisson regression was used to evaluate the radiotherapy-associated risk for SGMNs in patients undergoing radiotherapy vs patients not undergoing radiotherapy. The Kaplan-Meier method was used to assess the survival outcomes of patients with SGMNs. Results: Of 20 142 patients, 16 802 patients (83.4%) were White and the median age was 65 years (interquartile range, 54-74 years). A total of 5310 (34.3%) patients were treated with surgery and radiotherapy, and 14 832 (65.7%) patients were treated with surgery alone. The cumulative incidence of SGMNs during 30 years of follow-up was 4.53% among patients who received radiotherapy and 1.53% among patients who did not. In competing risk regression analysis, undergoing radiotherapy was associated with a higher risk of developing cancer of the uterine corpus (adjusted hazard ratio, 3.06; 95% CI, 2.14-4.37; P < .001) and ovarian cancer (adjusted hazard ratio, 2.08; 95% CI, 1.22-3.56; P = .007) compared with those who did not receive radiotherapy. The dynamic radiotherapy-associated risks (RR) for cancer of the uterine corpus significantly increased with increasing age at rectal cancer diagnosis (aged 20-49 years: adjusted RR, 0.79; 95% CI, 0.35-1.79; P = .57; aged 50-69 years: adjusted RR, 3.74; 95% CI, 2.63-5.32; P < .001; aged ≥70 years: adjusted RR, 5.13; 95% CI, 2.64-9.97; P < .001) and decreased with increasing latency since rectal cancer diagnosis (60-119 months: adjusted RR, 3.22; 95% CI, 2.12-4.87; P < .001; 120-239 months: adjusted RR, 2.72; 95% CI, 1.75-4.24; P < .001; 240-360 months: adjusted RR, 1.95; 95% CI, 0.67-5.66; P = .22), but the dynamic RR for ovarian cancer increased with increasing latency since rectal cancer diagnosis (60-119 months: adjusted RR, 0.70; 95% CI, 0.26-1.89; P = .48; 120-239 months: adjusted RR, 2.26; 95% CI, 1.09-4.70; P = .03; 240-360 months: adjusted RR, 11.84; 95% CI, 2.18-64.33; P = .004). The 10-year overall survival among patients with radiotherapy-associated cancer of the uterine corpus was significantly lower than that among matched patients with primary cancer of the uterine corpus (21.5% vs 33.6%; P = .01). Conclusions and Relevance: Radiotherapy for rectal cancer was associated with an increased risk of cancer of the uterine corpus and ovarian cancer. Special attention should be paid to reduce radiotherapy-associated SGMNs and improve their prognosis.

Automated assessment of DNA ploidy, chromatin organization, and stroma fraction to predict prognosis and adjuvant therapy response in patients with stage II colorectal carcinoma.

DNA ploidy, tumor stroma, and chromatin organization have important implications in tumorigenesis and patient outcome. Automated image cytometry tools were developed to quantitatively measure DNA ploidy (P), stroma fraction (S), and chromatin organization or Nucleotyping (N). This study aimed to discover their clinical value in different stages of colorectal cancer (CRC) in a Chinese patient population. A total of 496 CRC patients of stages I, II, and LMCRC (liver metastatic CRC) were enrolled in this study. Stage II CRC patients with diploidy, low-stroma, or chromatin homogenous status predicted significantly higher 5-year OS and DFS. We constructed a PSN-panel enabled the stage II patients to be further stratified into low-, middle-, high-risk groups, the 5-year OS (89.5% vs 67.9% vs 60.9%, P<0.001) and DFS (86.0% vs 62.3% vs 53.6%, P<0.001) were stratified significantly. In addition, when combined the PSN-panel with T stage or MSS status in stage II patients, the PSN-low risk patients showed significant longer 5-year OS and DFS than the PSN-high risk patients in T3 (OS: 86.3% vs 65.3%, P=0.015; DFS: 83.5 vs 59.8%, P=0.013) or MSS (OS: 86.4% vs 63.9%, P=0.005; DFS: 85.5 vs 57.8%, P=0.003) patients. Finally, in the group of stage II patients with at least one high-risk factor (non-diploidy, high-stroma, chromatin heterogenous), patients who received adjuvant therapy showed significantly longer OS (72.1% vs 48.3%, P=0.007) and DFS (64.5% vs 43.9%, P=0.015) than those who did not receive adjuvant therapy. In contrast, P, S, N couldn't predict the prognosis of stage I and LMCRC patients. Overall, our data demonstrate that the PSN panel is an accurate prognostic tool that can guide treatment decisions for Chinese stage II CRC patients.

Risk and Prognosis of Secondary Rectal Cancer After Radiation Therapy for Pelvic Cancer.

BACKGROUND: The relationship between pelvic radiation therapy (RT) and second primary rectal cancer (SPRC) is unclear. The aim of this study was to assess the risk and prognosis of SPRC after pelvic RT. MATERIALS AND METHODS: Data for patients who had primary pelvic cancer (PPC) between 1973 and 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Multiple primary standardized incidence ratios (SIRs) were used to assess the risk of SPRC. Five-year overall survival (OS) and rectal cancer-specific survival (RCSS) were calculated using Kaplan-Meier curves. RESULTS: A total of 573,306 PPC patients were included, 141,225 of whom had been treated with RT. Primary cancers were located in the prostate (50.83%), bladder (24.18%), corpus uterus (16.26%), cervix (5.83%), and ovary (2.91%). A total of 1,491 patients developed SPRC. Overall, the patients who received RT were at increased risk of developing SPRC (SIR = 1.39, 95% confidence interval [CI]: 1.27-1.52). The risk of SPRC decreased in patients who did not undergo RT (SIR = 0.85, 95% CI: 0.80-0.91). The SIR for SPRC in patients who underwent external beam radiation therapy (EBRT) was 1.22 (95% CI: 1.09-1.36). The SIR for SPRC in patients who underwent a combination of EBRT and brachytherapy (EBRT-BRT) was 1.85 (95% CI: 1.60-2.14). For patients who received RT, the SIR for SPRC increased with time after a 5-year latency period from PPC diagnosis. The survival of RT-treated SPRC patients was significantly worse than that of patients with primary rectal cancer only (PRCO). CONCLUSIONS: Patients receiving pelvic RT were at an increased risk of developing SPRC. Different pelvic RT treatment modalities had different effects on the risk of SPRC. We suggest that long-term surveillance of SPRC risk is required for patients who have undergone pelvic RT, especially young patients.

Risk and Prognosis of Secondary Bladder Cancer After Radiation Therapy for Rectal Cancer: A Large Population-Based Cohort Study.

BACKGROUND: Although radiation therapy (RT) improves local control for rectal cancer (RC), the long-term risks from RT, including development of a secondary malignancy, are controversial. The risk and prognosis of secondary bladder cancer (SBC) in RC patients undergoing RT have not been adequately studied. Our goal is to investigate the impact of RT on the risk of developing SBC and assess their survival outcomes. METHODS: This large population-based study included RC patients as their initial primary cancer from nine registries of the Surveillance, Epidemiology and End Results (SEER) database between 1973 and 2015. The cumulative incidence of SBC was assessed by using Fine and Gray's competing risk regression. The standardized incidence ratio (SIR) was used to compare the incidence of SBC in RC survivors to the US general population. The Kaplan-Meier method was used to evaluate the 10-year overall survival (OS) and 10-year cancer specific survival (CSS) for patients with SBC. RESULTS: Of 74,646 RC patients, 24,522 patients were treated with surgery and RT and 50,124 patients were treated with surgery alone. The incidence of SBC was 1.85% among patients who received RT and 1.24% among patients who did not. The incidence of SBC in RC patients who received RT was higher than the US general population (SIR, 1.35; 95% CI, 1.19-1.53, P<0.05), and decreased with increasing age at diagnosis, and increased with time since diagnosis. In competing risk regression analysis, undergoing RT was associated with a higher risk of SBC (hazard ratio [HR], 1.443, 95% confidence interval [CI], 1.209-1.720; P<0.001). The results of the dynamic SIR for SBC revealed that a slightly increased risk of SBC was observed after RT in the early latency, and was significantly related to the variations of age at RC diagnosis and decreased with time progress. The 10-year OS and CSS among SBC patients after RT were comparable to SBC patients after NRT. CONCLUSION: Radiation was associated with an increased risk of developing SBC in RC patients, and special attention should be paid to the surveillance of these patients.

GGN Promotes Tumorigenesis by Regulating Proliferation and Apoptosis in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. GGN is a germ cell-specific gene, but its function in CRC has been rarely reported to date. The aim of this study was to investigate the potential role of GGN in CRC tumorigenesis. Therefore, in this study, we examined the expression of GGN in CRC cell lines and tissues and its effects on cellular proliferation and apoptosis. We then explored the underlying mechanism. Our results showed that GGN was significantly overexpressed in both CRC cell lines and tissues. Silencing GGN robustly inhibited proliferation of CRC cells, and it also promoted apoptosis of CRC cells. Moreover, knockdown of GGN inhibited the expression of p-Akt in CRC cells. Taken together, these results showed that knockdown of GGN inhibits proliferation and promotes apoptosis of CRC cells through the PI3K/Akt signaling pathway. Our findings revealed for the first time a potential oncogenic role for GGN in CRC progress. This finding may provide a unique perspective on how a germ cell-specific gene might serve as a biomarker, or even as a therapeutic target, for CRC.

Long non-coding RNA H19 confers 5-Fu resistance in colorectal cancer by promoting SIRT1-mediated autophagy.

Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. The role of the differentially expressed lncRNAs in 5-Fluorouracil chemoresistance has not fully explained. Here, we observed lncRNA H19 was associated with the 5-Fu resistance in CRC. Quantitative analysis indicated that H19 was significantly increased in recurrent CRC patient samples. Kaplan-Meier survival analysis indicated that high H19 expression in CRC tissues was significantly associated with poor recurrent free survival. Our functional studies demonstrated that H19 promoted colorectal cells 5-Fu resistance. Mechanistically, H19 triggered autophagy via SIRT1 to induce cancer chemoresistance. Furthermore, bioinformatics analysis showed that miR-194-5p could directly bind to H19, suggesting H19 might work as a ceRNA to sponge miR-194-5p, which was confirmed by Dual-luciferase reporter assay and Immunoprecipitation assay. Extensively, our study also showed that SIRT1 is the novel direct target of miR-194-5p in CRC cells. Taken together, our study suggests that H19 mediates 5-Fu resistance in CRC via SIRT1 mediated autophagy. Our finding provides a novel mechanistic role of H19 in CRC chemoresistance, suggesting that H19 may function as a marker for prediction of chemotherapeutic response to 5-Fu.

GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer.

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305⁻0.753] and PFS:HR 0.490, [95% CI 0.336⁻0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.

Current practice patterns of preoperative bowel preparation in colorectal surgery: a nation-wide survey by the Chinese Society of Colorectal Cancer.

BACKGROUND: The optimal preoperative bowel preparation for colorectal surgery remains controversial. However, recent studies have established that bowel preparation varies significantly among countries and even surgeons at the same institution. This survey aimed to obtain information on the current practice patterns of bowel preparation for colorectal surgery in China. METHODS: A paper-based survey was circulated to the members of the Chinese Society of Colorectal Cancer (CSCC). The survey responses were collected and analyzed. Statistical analysis was performed for all the categorical variables according to the responses to individual questions. RESULTS: Three hundred forty-one members completed the questionnaire. Regarding surgical practice, 203 (59.5%) performed > 50% of the colorectal operations laparoscopically or robotically; the use of mechanical bowel preparation (MBP) alone was significantly higher (63.5 vs 31.9%; P < 0.001). The respondents who performed > 200 colonic or rectal resections provided significantly more MBP alone (79.6 vs 39.1%, P < 0.001; 76.6 vs 43.2%, P < 0.001; respectively). Among hospitals with fewer than 500 beds, 52.4% of the respondents used MBP + oral antibiotics preparation (OAP) + enema, a significantly higher percentage than the respondents of hospitals with more than 500 beds (P < 0.001). Nearly 40% of the respondents prescribed OAP in regimens; meanwhile, 74.8% prescribed preoperative intravenous antibiotics. CONCLUSIONS: The study demonstrates considerable variation among members from the CSCC. These findings should be considered when developing multicenter trials and to provide more definitive answers.

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFß/SMAD Signaling Pathway in Colorectal Cancer Metastasis.

BACKGROUND/AIMS: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGFß)/SMAD signaling pathway. METHODS: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGFß/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. RESULTS: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGFß/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. CONCLUSIONS: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGFß/SMAD signaling-mediated EMT.

Apolipoprotein E Overexpression Is Associated With Tumor Progression and Poor Survival in Colorectal Cancer.

Apolipoprotein E (ApoE) plays a key role in tumorigenesis and progression, such as cell proliferation, angiogenesis and metastasis. ApoE overexpression was associated with aggressive biological behaviors and poor prognosis in a variety of tumor according to previous studies. This study aimed to assess the prognostic value and explore the potential relationship with tumor progression in colorectal cancer (CRC). We collected the expression profiling microarray data from the Gene Expression Omnibus (GEO), investigated the ApoE expression pattern between the primary CRC and liver metastasis of CRC, and then explored the gene with prognostic significance based on the TCGA database. ApoE high expression was associated with poor overall survival (OS, p = 0.015) and progression-free survival (PFS, p = 0.004) based on the public databases. Next, ApoE expression was evaluated in two CRC cohorts by immunohistochemistry, of whom 306 cases were stage II and 201 cases were metastatic liver CRC. In the cohort of the liver metastasis, the ApoE expression was increasing in normal mucosa tissue, primary colorectal cancer (PC), and colorectal liver metastases (CLM) in order. Meanwhile, the level of ApoE expression in stage II tumor sample which had no progression evidence in 5 years was lower than that in PC of synchronous liver metastases. The high ApoE expression in PC was an independent risk factor in both stage II (HR = 2.023, [95% CI 1.297-3.154], p = 0.002; HR = 1.883, [95% CI 1.295-2.737], p = 0.001; OS and PFS respectively) and simultaneous liver metastasis (HR = 1.559, [95% CI 1.096-2.216], p = 0.013; HR = 1.541, [95% CI 1.129-2.104], p = 0.006; OS and PFS respectively). However, the overexpression of ApoE could not predict the benefit from the chemotherapy in stage II. The study revealed that the relevance of the ApoE overexpression in CRC progression, conferring a poor prognosis in CRC patients especially for stage II and simultaneous liver metastasis. These finding may improve the prognostic stratification of patients for clinical strategy selection and promote CRC clinic outcomes.

Exploration of the Optimal Minimum Lymph Node Count after Colon Cancer Resection for Patients Aged 80 Years and Older.

The elderly colon cancer (CC) patients are increasing and represent a heterogeneous patient group. The objectives of this study were to identify the features of lymph node examination and to explore the optimal minimum lymph node count after CC resection for patients aged ≥80. Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 65719 CC patients in stage I-III between 2004 and 2012, 26.0% of patients were aged ≥80. The median node count decreased with increasing age, which were 25.5, 20.2, 17.8 and 16.9 for patients aged 20-39, 40-59, 60-79, and ≥80. The rate of ≥12 nodes and the rate of node positivity for patients aged ≥80 were obviously lower than younger patients. Using X-tile analysis, we determined 9 nodes as the optimal node count for patients aged ≥80. Then, we compared the 5-year cancer specific survival (CSS) between patients with ≥9 nodes and <9 nodes. The results showed the 5-year CSSs were improved for patients with ≥9 nodes. Furthermore, the rate of node positivity and survival under the 9-node measure were equal to 12-node measure. Therefore, the lymph node examination should be discriminately evaluated for elder patients, and 9-node measure was available for patients aged ≥80.