Mucinous histology is a negative predictor of neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

Mucinous histology is associated with poor prognosis in locally advanced colorectal adenocarcinoma treated with postoperative first-line adjuvant chemotherapy: A systematic review and meta-analysis.

PURPOSE: Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy. METHODS: Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963-August 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI). RESULTS: This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07-1.41, p < 0.01, I2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22-7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups. CONCLUSION: MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.

Characteristics of colorectal carcinoma patients with PMS2 defects detected by immunohistochemistry.

Lynch syndrome is the most prevalent form of familial colorectal cancer (CRC) and is caused by pathogenic germline mismatch repair (MMR) gene mutations. MLH1, MSH2 and MSH6 mutations have been well studied, but the rate and characteristics of PMS2 mutations are rare, especially in China. This study enrolled 1706 unselected patients with CRC who underwent colorectal resection from June 2016 to November 2018, the MMR status and clinicopathological features were analysed. A total of 11.8% of patients with CRC had defects in at least one MMR-related protein. Among them, 8.3% were identified with PMS2 defects, and 3.1% of patients had isolated PMS2 defects. Compared with MMR-proficient CRC, PMS2-defect CRC occurred more frequently in the right colon and less frequently in the rectum, had more poorly differentiated and mucinous carcinoma cases, and had fewer perineural invasions and a lower pN stage but a more advanced pT stage and a larger tumour size. In the cases with PMS2 defect, there were fewer tumours in the right colon, fewer poorly differentiated cases and smaller tumour sizes than in the cases with both MLH1 and PMS2 defects. In addition, in cases with isolated PMS2 defects, there were more tumours in the right colon and, more mucinous carcinoma cases than in cases with MMR-proficient CRCs, but had a similar cancer onset age. This study identified the rate, clinicopathological and age characteristics of PMS2 defects in CRCs in China and highlighted the importance of universal screening and germline detection of PMS2 in CRC.

Endoscopy biopsy is not efficiency enough for diagnosis of mucinous colorectal adenocarcinoma.

BACKGROUND: Endoscopy biopsy (EB) is the standard diagnostic method for colorectal cancer (CRC), whereas its accuracy and efficiency in mucinous adenocarcinoma (MAC) initial diagnosis is unclear. METHODS: The initial EB and postoperative specimen (PS) pathological diagnosis of MAC from two centers were retrospectively collected and analyzed. The accuracy and efficiency of initial EB compared with PS pathological diagnosis were analyzed. The potential factors which would affect the initial EB diagnosis of MAC were analyzed. RESULTS: 280 and 78 eligible cases were enrolled in this study from two centers respectively. The initial EB diagnosis accuracy for MAC were 84.62% and 83.33%. However, among the cases of PS diagnosis with MAC, the diagnostic efficiency of initial EB was only 36.49% and 32.50% respectively. Lower tumor differentiation and more EB number were associated with an increased probability for the EB diagnosis of MAC, but only tumor differentiation was an independent diagnositic factor for EB in the two cohorts. CONCLUSIONS: The accuracy of initial EB with MAC is high, but the diagnostic efficiency was extremely low. Tumor differentiation and EB number were associated with the diagnosis efficiency of MAC before surgery.

Surgery improves the prognosis of colon mucinous adenocarcinoma with liver metastases: a SEER-based study.

BACKGROUND: Mucinous adenocarcinoma (MC) is the second most common pathological type of colon carcinoma (CC). Colon cancer liver metastases (CLMs) are common and lethal, and complete resection of the primary tumour and metastases for CLM patients would be beneficial. However, there is still no consensus on the role of surgery for MC with liver metastases (M-CLM). METHODS: Patients diagnosed with M-CLM or classical adenocarcinoma with CLM (A-CLM) from 2010 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. The clinicopathological features and overall survival (OS) and cancer-specific survival (CSS) data were compared and analysed. RESULTS: The results showed that the M-CLM group had a larger tumour size, more right colon localizations, higher pT and pN stages, more female patients, and more retrieved and positive lymph nodes and accounted for a higher proportion of surgeries than the A-CLM group. The OS and CSS of M-CLM patients who underwent any type of surgery were significantly better than those of patients who did not undergo any surgery, but poorer than those of A-CLM patients who underwent surgery. Meanwhile, the OS and CSS of M-CLM and A-CLM patients who did not undergo any surgery were comparable. Compared with hemicolectomy, partial colectomy led to similar or better OS and CSS for M-CLM, and surgery was an independent protective factor for long-term survival in M-CLM. CONCLUSIONS: M-CLM had distinct clinicopathological characteristics from A-CLM, and surgery could improve the survival and is an independent favourable prognostic factor for M-CLM. In addition, partial colectomy might be a non-inferiority choice as hemicolectomy for M-CLM according to the results from this study.

Clinical Value of Serum LHPP-associated miR-765 in the Prognosis of Laparoscopic or Open Hepatectomy for Hepatocellular Carcinoma.

PURPOSE: The current study aims to investigate the effect of tumor suppressor LHPP-associated microRNA (miR)-765 on the prognosis of laparoscopic hepatectomy (LH) or open hepatectomy (OH) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 160 patients with HCC were enrolled and randomly divided into the LH or OH group. According to the operation time, these patients were followed up for 12 months, and the number of deaths and the corresponding death time during the follow-up period were counted. RESULTS: The authors found that the LHPP gene levels in HCC tissues were lower than that in adjacent normal tissues, whereas miR-765 was overexpressed in HCC tissue. Overexpression of miR-765 promoted the epithelial-mesenchymal transition and proliferation and inhibited apoptosis of HCC through directly downregulating LHPP expression. Serum miR-765 expression level was significantly associated with lymph node metastasis and histologic grading. Survival analysis showed that the overall survival rate in 12 months after the operation was significantly lower in the OH-high miR-765 group (P<0.05). CONCLUSION: For patients with a low miR-765 level, both LH and OH are available, otherwise, LH is more recommended.

Hemicolectomy Does Not Provide Survival Benefit for Right-Sided Mucinous Colon Adenocarcinoma.

BACKGROUND: The extent of bowel resection is widely debated in colon cancer surgery. Right hemicolectomy (RHC) and partial colectomy (PC) are the most common operation options for right-sided colon cancer (RCC). However, there are still no treatment guidelines or published studies to guide surgical options for mucinous adenocarcinoma (MAC) of RCC. METHODS: Patients with MAC and non-specific adenocarcinoma (AC) of RCC who underwent RHC and PC from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. The general characteristics and survival were compared and analyzed. RESULTS: A total of 27,910 RCC patients were enrolled in this study, among them 3,413 were MAC. The results showed that race, carcinoembryonic antigen (CEA) level, perineural invasion (PNI), tumor size, tumor location, TNM stage, liver metastasis, chemotherapy were significantly different between MAC and AC groups. The MAC group had similar dissected lymph nodes, but more positive lymph nodes than the AC group. The overall survival (OS) of the MAC group was poorer than that of the AC group, but cancer-specific survival (CSS) was similar between the two groups. The RHC subgroup of the MAC group had more patients of age ≤60 years, larger tumor size, cecum/ascending colon location and dissected lymph nodes than the PC subgroup, but similar positive lymph nodes, perioperative mortality, OS and CSS as the PC subgroup. Moreover, the univariate and multivariable analyses for the survival of RCC patients with MAC showed that RHC might not be a superior predictor for OS and CSS compared with PC. CONCLUSIONS: RHC could not dissect more positive lymph nodes or provide long-term survival benefits for RCC patients with MAC compared with PC. This study could provide some evidence for surgery treatment selection for MAC of RCC, which has important clinical value in individual management of colon cancer patients.

Knockdown of ZBTB7A inhibits cell proliferation of breast cancer through regulating the ubiquitination of estrogen receptor alpha.

AIMS: ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. MAIN METHODS: In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α's level via targeting ER-α's expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. KEY FINDINGS: We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α's downstream genes, and promote the growth of estrogen receptor alpha (ER-α)-positive breast cancer cells. SIGNIFICANCE: Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer.

Pokemon Inhibits Transforming Growth Factor ß-Smad4-Related Cell Proliferation Arrest in Breast Cancer through Specificity Protein 1.

PURPOSE: Pokemon, also known as ZBTB7A, belongs to the POZ and Krüppel (POK) family of transcription repressors and is implicated in tumor progression as a key proto-oncogene. This present study aimed at determining the mechanism by which Pokemon inhibits transforming growth factor ß (TGFß)-Smad4 pathway-dependent proliferation arrest of breast cancer cells via specificity protein 1 (SP1). METHODS: Over-expressing plasmid or small interfering RNA (siRNA) transfection was used to regulate Pokemon levels. The EdU incorporation assay, MTS assay, and clone formation were used to identify the inhibitory effect of Pokemon siRNA on cell proliferation. Quantitative real-time polymerase chain reaction assay confirmed that Pokemon deletion inhibited the expression of proliferation-associated genes. The dual-luciferase reporter assay, electrophoretic mobility shift assay, and co-immunoprecipitation assay were used to analyze binding between Pokemon, Smad4, and SP1. RESULTS: Pokemon deletion induced proliferation arrest of breast cancer cells and inhibited the expression of proliferation-associated genes, especially Smad4. Pokemon bound with SP1 to interdict Smad4 promoter activity. Information on clinical samples was obtained from The Cancer Genome Atlas data, in which the Pokemon mRNA levels showed a negative correlation with Smad4 levels in different subtypes of breast cancer in two independent datasets. CONCLUSION: We demonstrated that Pokemon binds to SP1 to down-regulate Smad4 expression, thereby promoting proliferation of breast cancer cells. This suggests that Pokemon is a potential TGFß-signaling participant in breast cancer progression.

Inhibition of hsa_circ_0001313 (circCCDC66) induction enhances the radio-sensitivity of colon cancer cells via tumor suppressor miR-338-3p: Effects of cicr_0001313 on colon cancer radio-sensitivity.

Circular RNA_0001313 (circ_0001313), also known as circCCDC66, is a novel circRNA that recently found to be upregulated in colon cancer tissues and promote colon cancer progression. However, the role of circ_0001313 in regulating radio-sensitivity of colon cancer and its molecular mechanism remain undetermined. Here we found circ_0001313 was significantly upregulated and miR-338-3p was downregulated in radio-resistant colon cancer tissues compared to radio-sensitive tissues. Radiation treatment in colon cells triggered a remarkable upregulation of circ_0001313 and a downregulation of miR-338-3p. Knockdown of circ_0001313 reduced cell viability, colony formation rate and increased caspase-3 activity in colon cancer cells under irradiation. Moreover, circ_0001313 act as a sponge for miR-338-3p in colon cancer cells. Furthermore, miR-338-3p could reverse the effects of circ_0001313 knockdown on cell viability, colony formation, and caspase-3 activity. These findings revealed that knockdown of circ_0001313 could induce radio-sensitivity of colon cancer cells by negatively regulating miR-338-3p.

Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET.

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFκB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.

Safety and efficacy of enhanced recovery after surgery (ERAS) programs in patients undergoing hepatectomy: A prospective randomized controlled trial.

BACKGROUND AND AIM: Enhanced recovery after surgery (ERAS) programs, following a variety of perioperative treatments with evidence-based medical evidence, has indicated its validity to accelerate rehabilitation in a wide variety of surgical procedures. This randomized controlled trial (RCT) study was implemented to verify the safety and efficacy of the perioperative effects in patients undergoing hepatectomy with ERAS or with conventional surgery (CS). METHODS: From August 2016 to November 2017, according to the inclusion criteria, 160 patients with liver diseases were suitable for participating in this experiment. Patients before liver resection were randomized into ERAS group (n = 80) and CS group (n = 80), and then the outcome measures were compared between the two groups. RESULTS: Enhanced recovery after surgery group had significantly less complications than CS group (P = .009). Compared with CS group, patients in ERAS group had low peak of WBCs in postoperative day (POD1), ALT in POD1 and POD3 (P < .05), high value of ALB in POD3 and POD5 (P < .05), less pain and higher patient satisfaction (P < .001), earlier exhaust, oral feeding, ambulation and extubation time (P < .05),and also had less hospital stay and cost (P < .001). There were no significant differences in readmission rate (<30 days) between two groups (P = .772). CONCLUSIONS: Enhanced recovery after surgery programs applied to patients undergoing hepatectomy can safely and effectively relieve stress response, reduce the incidence of complications, improve patient satisfaction, accelerate patient recovery, reduce financial burden, and bring economic benefits.

BPTF Associated with EMT Indicates Negative Prognosis in Patients with Hepatocellular Carcinoma.

BACKGROUND/AIMS: Epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC) dissemination. Bromodomain PHD-finger transcription factor (BPTF) could regulate embrogenesis and stem cell differentiation, and it may be involved in tumor progression and EMT. In this study, we aimed to determine BPTF, E-cadherin and vimentin expression in tumor tissues and the clinical significance in relation to HCC. METHODS: The BPTF, vimentin and E-cadherin expression of 106 HCC tissue samples was examined by immunohistochemical staining. RESULTS: BPTF and vimentin showed high expression and E-cadherin showed low expression in HCC. BPTF is associated with the tumor number, vascular invasion, Edmondson-Steiner grade, TNM stage and recurrence (P < 0.05). Vimentin is positively correlated with tumor size, tumor number, vascular invasion, Edmondson-Steiner grade, TNM stage and recurrence (P < 0.05). E-cadherin is negatively correlated with tumor number, Edmondson-Steiner grade, TNM stage and recurrence (P < 0.05). Survival analysis has shown that high expression of BPTF and vimentin indicates poorer overall and disease-free survival (P < 0.05). Multivariate analysis shows that BPTF is an independent marker for survival prediction (P = 0.015). Additionally, high BPTF expression is correlated with high vimentin expression and low E-cadherin expression (P < 0.05). CONCLUSION: High BPTF expression may be an independent marker for survival prediction in HCC patients and is probably involved in EMT.