Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

BACKGROUND: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. METHODS: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. RESULTS: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. CONCLUSIONS: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

Circ_0000591 served as endogenous RNA for miR-326 to promote progression of cholangiocarcinoma via the TLR4/MyD88/IL6 axis.

BACKGROUND: Cholangiocarcinoma (CCA) is the second most common liver malignancy with poor prognosis after hepatocellular carcinoma (HCC). Emerging evidences have proved that circular RNAs (circRNAs) are involved in the progression of multiple cancers, while their roles in tumorigenesis of CCA remains largely unclear. In the present study, we found circ_0000591 was upregulated in CCA cells and tissues. The highly expressed circ_0000591 could promote the proliferation, migration, invasion and carcinogenesis of CCA cells in vitro and in vivo. Functionally, circ_0000591 induced the proliferation, migration and invasion of CCA cells through sponging miR-326. Moreover, silencing of circ_0000591 attenuated LPS-induced anti-apoptosis of CCA cells through the TLR4/MyD88/IL6 pathway. In conclusion, this study revealed a novel regulatory mechanism that circ_0000591 contributed to the progression of CCA via miR-326/TLR4/MyD88/IL6 axis. These findings enhanced our knowledge of potential molecular mechanism involved in the malignant progression of CCA.

Safety and feasibility of prolonged versus early laparoscopic cholecystectomy for acute cholecystitis: a single-center retrospective study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard treatment for acute cholecystitis (AC), and it should be performed within 72 h of symptoms onset if possible. In many undesired situations, LC was performed beyond the golden 72 h. However, the safety and feasibility of prolonged LC (i.e., performed more than 72 h after symptoms onset) are largely unknown, and therefore were investigated in this study. METHODS: We retrospectively enrolled the adult patients who were diagnosed as AC and were treated with LC at the same admission between January 2015 and October 2018 in an emergency department of a tertiary academic medical center in China. The primary outcome was the rate and severity of adverse events, while the secondary outcomes were length of hospital stay and costs. RESULTS: Among the 104 qualified patients, 70 (67.3%) underwent prolonged LC and 34 (32.7%) underwent early LC (< 72 h of symptom onset). There were no differences between the two groups in mortality rate (none for both), conversion rates (prolonged LC 5.4%, and early LC 8.8%, P = 0.68), intraoperative and postoperative complications (prolonged LC 5.7% and early LC 2.9%, P ≥ 0.99), operation time (prolonged LC 193.5 min and early LC 198.0 min, P = 0.81), and operation costs (prolonged LC 8,700 Yuan, and early LC 8,500 Yuan, P = 0.86). However, the prolonged LC was associated with longer postoperative hospitalization (7.0 days versus 6.0 days, P = 0.03), longer total hospital stay (11.0 days versus 8.0 days, P < 0.01), and subsequently higher total costs (40,400 Yuan versus 31,100 Yuan, P < 0.01). CONCLUSIONS: Prolonged LC is safe and feasible for patients with AC for having similar rates and severity of adverse events as early LC, but it is also associated with longer hospital stay and subsequently higher total cost.

Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 cooperates with enhancer of zeste homolog 2 to promote hepatocellular carcinoma development by modulating the microRNA-22/Snail family transcriptional repressor 1 axis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.

Primary Gastrointestinal Stromal Tumor Mimicking as Gynecologic Mass: Characteristics, Management, and Prognosis.

BACKGROUND: Primary gastrointestinal stromal tumor (GIST)-mimicking gynecologic masses are easily misdiagnosed. This study aimed to investigate the clinicopathological features, management, and prognosis of primary GIST mimicking as gynecologic mass. METHODS: Clinicopathological and survival data of GIST mimicking as gynecologic mass admitted to our center from January 2005 to December 2017 were retrospectively analyzed. RESULTS: Thirty-eight patients were included. The most common primary tumor site was the jejunoileum (n = 33, 86.9%), and 33 patients (86.9%) were classified as high recurrence risk. The short-term outcomes of operative incision length (P = 0.004), time to gas passage (P = 0.002), and hospital stay (P = 0.012) with laparoscopy-assisted resection were significantly shorter than those with open resection, showing no significant differences of long-term outcomes. With a median follow-up of 56 mo for 31 patients (81.6%), 18 (58.1%) received adjuvant therapy with imatinib. The 5-year disease-free survival and disease-specific survival of pelvic high-risk GIST was 37.0% and 48.3%, respectively; both were significantly lower than those of the other female high-risk group (both P < 0.05). CONCLUSIONS: GIST mimicking as gynecologic mass is not uncommon, most originate from the jejunoileum and have a high risk of recurrence. Laparoscopy-assisted resection may be preferable for more favorable short-term outcomes. Compared with the other female high-risk GIST, pelvic high-risk GIST has a significantly worse prognosis; a longer duration of adjuvant therapy with imatinib than recommended may be beneficial.

Oncological consequence of emergent resection of perforated colon cancer with complete obstruction after stent insertion as a bridge to surgery.

PURPOSE: Colonic perforation is a life-threatening complication after colonic stent insertion as a bridge to surgery for acute obstruction caused by colorectal cancer. The oncological consequence of colonic perforation after emergent surgical intervention was unknown. The aim of this short communication was to investigate whether or not the perforation and emergent surgery had obviously impact on the peritoneal recurrence and long-term survival of patients. METHODS: Data of the patients who underwent colorectal stenting as a bridge to surgery in 5 years from 2012 to 2017 was collected by the Endoscopical Surgery Group of Hubei. The perforated cases treated by emergent operation were retrospectively analyzed. RESULTS: During 5 years from 2012 to 2017, 116 cases of colorectal stenting as a bridge to surgery had been performed, and 7 patients had perforation after stent placement and treated by emergent surgery, including 1 case of synchronic liver metastasis treated by one-stage metastasectomy. One of the 7 patients died of septic shock after operation, and the remaining patients were followed up for 6-60 months. There was no evidence of abdominal implantation or extra-abdominal metastasis. CONCLUSION: This small case series implicated that colonic perforation after stent insertion for malignant colorectal obstruction treated by emergent surgery might not obviously increase the peritoneal implantation and metastasis.

Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling.

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/ß-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.

Comparative efficacy and tolerability of antiemetic prophylaxis for adult highly emetogenic chemotherapy: A network meta-analysis of 143 randomized controlled trials.

Chemotherapy-induced nausea and vomiting (CINV) is one of the commonest side-effects among cancer patients. However, there is lacking of hierarchical evidences comparing different antiemetics against highly emetogenic chemotherapy. Therefore, we conducted a network meta-analysis to investigate their comparative efficacy and tolerability. Randomized controlled trials that compared different antiemetic categories for adult highly emetogenic chemotherapy were included after searching PubMed, Web of Science, Embase and Cochrane Central. Acute-phase no emesis and no nausea were identified as primary endpoints. We made pairwise and hierarchical calculations by random-effects model. Effect sizes were presented by odds ratio and 95% confidential interval. Subgroup analysis was additionally performed. 143 randomized trials were included into pooled analysis, containing 22,776 patients and 18 antiemetic categories. 5-HT3 RA plus corticosteroid plus NK-1 RA plus other (5CNO) displayed best protection against both acute emesis (SUCRA: 99.7%) and nausea (95.6%). 5CNO (99.7%) and 5-HT3 RA plus corticosteroid plus other (5CO, 85.3%) topped subgroup hierarchies for no-naivety and anthracycline plus cyclophosphamide (AC)-based studies. On the other hand, 5-HT3 RA plus dopamine RA plus other (5DO) may be best fit for delayed emesis (92.0%) and nausea (92.7%). Subgroups featuring no-naivety and AC-based trials preferred 5DO (91.9%) and 5CN (88.6%), respectively. In addition, dopamine RA plus other (DO) had the lowest incidence of TRAE in most circumstances, except for AC-based subgroup where corticosteroid plus dopamine RA plus other (CDO) preponderated (69.2%). 5CNO and 5DO should be considered as first-line regimens against highly emetogenic chemotherapy induced acute and delayed CINV, respectively.

Technical Standardization of Laparoscopic Left Hemicolectomy - Video Vignette.

Large multicentre trials have shown good safety profiles and low complication rates for laparoscopic management of left-sided colon cancer [1-3]. However, there are a wide range of options and variations in technique, which extend the learning curve of trainee surgeons. Here we provide a video to demonstrate a standardized operative technique simplified into 'one plane, two points and three lines' when applied to laparoscopic left hemicolectomy. This article is protected by copyright. All rights reserved.

Clinicopathologic features and prognosis of primary gastrointestinal stromal tumor patients under 35 years of age: A 10-year retrospective study.

OBJECTIVES: To investigate gastrointestinal stromal tumor (GIST) clinicopathologic characteristics in young adults. METHODS: Clinicopathologic data from GIST patients under 35 years diagnosed at our hospital from January 2005 to December 2014 were retrospectively collected. RESULTS: Thirty-one (5.3%, 31/585) patients were included; 17 (54.8%) were female. The most common presentation and primary tumor site were gastrointestinal bleeding (n = 18, 58.1%) and the small intestine (n = 13, 41.9%), respectively. Fifteen (48.4%) GISTs were classified as having a high relapse risk; two (6.4%), intermediate; nine (29.0%), low; and five (16.1%), very low. All patients underwent tumor resection. With a median follow-up of 51 months for 20 (64.5%) patients, 12 (60%) were given imatinib methylate as adjuvant therapy. One (5%) patient died of peritoneal GIST dissemination, four (20%) developed abdominal recurrences, two (10%) had hepatic metastasis, and thirteen (65%) were disease free. The 5-year disease-free survival rate was 51.2%. CONCLUSIONS: GISTs rarely occur in young adults. The most common location is the small intestine. A slight female predominance was observed in the current study. Adjuvant therapy longer than the recommended duration may be beneficial for GISTs with a high relapse risk. Combined targeted therapy and surgery is appropriate for recurrent and metastatic GISTs in select patients. J. Surg. Oncol. 2016;114:977-981. © 2016 Wiley Periodicals, Inc.

Sodium phosphate versus polyethylene glycol for colonoscopy bowel preparation: an updated meta-analysis of randomized controlled trials.

BACKGROUND: Adequate bowel cleansing is of great importance for a high-quality colonoscopy examination. Nevertheless, whether sodium phosphate or polyethylene glycol is a gold standard agent for bowel preparation is still under debate. In consideration of the clinical needs, we thus performed an updated meta-analysis of randomized controlled trials concerning the comparison between both regimens. The efficacy, safety and acceptability of each regimen are major indicators to measure and appraise. METHODS: By searching PubMed, EMBASE, Web of Science and Cochrane Library databases, 15 original trials published from 2000 to 2014 were included as eligible studies. We carried out data extraction and subsequent pooling analysis for each indicator in a standard manner. Sensitivity analysis was performed by elimination of low-quality trials, while a funnel plot and Egger's test were employed to analyze the publication bias across studies. RESULTS: Our pooling analysis revealed that patients undergoing sodium phosphate as a cleansing agent displayed better acceptability, compliance, cleansing scores, preparation taste, polyp detection rate and less adverse effects including nausea, vomiting and abdominal pain (P < 0.05). In terms of procedure time, adequate preparation rate and electrolyte concentration, there was no significant difference between both regimens (P > 0.05). The pooling analysis offered stable conclusions which were verified by our sensitivity analysis. There was no publication bias across studies as a symmetric funnel plot was demonstrated and the result of Egger's test was P = 0.56. CONCLUSIONS: Regarding preparation efficacy, safety and acceptability, sodium phosphate was a better agent than polyethylene glycol for colonoscopy bowel cleansing, with its advantages of higher efficacy, better tolerability and acceptability as well as comparable safety.

Role of IL-17 and TGF-ß in peritoneal adhesion formation after surgical trauma.

Peritoneal adhesions are fibrous tissues formed after surgery. Both cytokines and transforming growth factors (TGFs) are involved in this process. The objective of this study was to investigate the cross talk between these entities. Peritoneal drainage fluid after surgery from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter. Data showed that the concentrations of interferon (IFN)-γ and interleukin (IL)-17 reached their peaks 6-12 hours after surgery, whereas TGF-ß1 concentrations showed two postoperative peak time points at 2 and 72-96 hours. By neutralizing IFN-γ, IL-17 6-12 hours, and TGF-ß1 72-96 hours after surgery, the degree of adhesion reduced significantly. However, neutralizing TGF-ß1 2 hours after surgery did not affect adhesion formation. Furthermore, in vitro studies showed that compared with the fibroblasts that were directly stimulated with TGF-ß1, the prestimulation of IL-17 promoted plasminogen activator inhibitor-1 production while inhibiting tissue-type plasminogen activator production. Moreover, additional stimulation with IFN-γ enhanced this effect. Together, these data indicate that IL-17 may promote adhesion formation by increasing the reaction of fibroblasts against TGF-ß1. Blocking IL-17 might have a therapeutic potential in preventing adhesion formation after surgery.

Machine learning based peri-surgical risk calculator for abdominal related emergency general surgery: a multicenter retrospective study.

BACKGROUND: Currently, there is a lack of ideal risk prediction tools in the field of emergency general surgery (EGS). The American Association for the Surgery of Trauma recommends developing risk assessment tools specifically for EGS-related diseases. In this study, we sought to utilize machine learning (ML) algorithms to explore and develop a web-based calculator for predicting five perioperative risk events of eight common operations in EGS. METHOD: This study focused on patients with EGS and utilized electronic medical record systems to obtain data retrospectively from five centers in China. Five ML algorithms, including Random Forest (RF), Support Vector Machine, Naive Bayes, XGBoost, and Logistic Regression, were employed to construct predictive models for postoperative mortality, pneumonia, surgical site infection, thrombosis, and mechanical ventilation >48 h. The optimal models for each outcome event were determined based on metrics, including the value of the Area Under the Curve, F1 score, and sensitivity. A comparative analysis was conducted between the optimal models and Emergency Surgery Score (ESS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and American Society of Anesthesiologists (ASA) classification. A web-based calculator was developed to determine corresponding risk probabilities. RESULT: Based on 10 993 patients with EGS, we determined the optimal RF model. The RF model also exhibited strong predictive performance compared with the ESS, APACHE II score, and ASA classification. Using this optimal model, the authors developed an online calculator with a questionnaire-guided interactive interface, catering to both the preoperative and postoperative application scenarios. CONCLUSIONS: The authors successfully developed an ML-based calculator for predicting the risk of postoperative adverse events in patients with EGS. This calculator accurately predicted the occurrence risk of five outcome events, providing quantified risk probabilities for clinical diagnosis and treatment.

HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection.

Peritoneal metastasis of colorectal cancer is a major clinical issue and results in poor prognosis for patients after surgical resection. Here, we found that abdominal surgery trauma induced high release of high-mobility group box 1 (HMGB1) in the peritoneal cavity of mice. Recombinant HMGB1 injected in the peritoneal cavity recruited abundant myeloid derived suppressor cells (MDSCs) after the surgical trauma. HMGB1 Box-A and gemcitabine reduced the recruitment of MDSCs in the peritoneal cavity after the operation and ameliorated the peritoneal metastasis burden of colon cancer in mouse model. These results showed that abdominal surgery trauma leads to a large amount of HMGB1 released in the peritoneal cavity which recruits numerous MDSCs to promote peritoneal metastasis of colon cancer after curative surgery.

Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial.

Background: Recently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients. Methods: We performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy-chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392. Results: Thirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III-IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823-0.884). Discussion: Our study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].

Duodenal gastrointestinal stromal tumors: A retrospective study based on a 13 years experience of a single center in China.

AIM: Duodenal gastrointestinal stromal tumors (GISTs) constitute a small rare subset. This study aims to analyze the prognostic differences between duodenal and jejunoileal GISTs and evaluate the clinical treatment and prognostic characteristics of patients with duodenal GISTs. METHODS: Data of patients with primary duodenal or jejunoileal GISTs were collected. Patients were matched through propensity score matching (PSM). Perioperative and long-term outcomes of patients with duodenal GISTs were compared based on surgical approach. RESULTS: Altogether, 101 duodenal and 219 jejunoileal GISTs were identified. In patients with duodenal GISTs, 79 (78%) underwent local resection (LR) and 22 (22%) underwent pancreaticoduodenectomy (PD). Patients undergoing PD had a longer postoperation stay (18.5 vs 13 days, P = 0.001) and more complications (Clavien-Dindo I-II complications for PD vs LR, 31.8 vs 15.2%; Clavien-Dindo III-V complications for PD vs LR, 22.7 vs. 2.5%; P < 0.001). There was no difference in recurrence-free survival (RFS) (P = 0.8) or overall survival (OS) (P = 0.9) when comparing patients who underwent LR versus PD. Multivariable analysis showed that tumor size >5 cm was the only independent predictor of shorter RFS (P = 0.004) and OS (P = 0.012). After matching, there was no significant difference in RFS and OS between patients with duodenal versus jejunoileal GISTs (both P > 0.05). CONCLUSION: The prognosis of duodenal and jejunoileal GISTs are similar. Recurrence and OS of duodenal GISTs primarily depend on tumor size. For duodenal GISTs, LR is associated with comparable long-term survival when compared to PD, but with superior short-term outcomes.

Comparative efficacy and tolerability of adjuvant systemic treatments against resectable colon cancer: a network meta-analysis.

BACKGROUND: Currently, 6-month oxaliplatin-based chemotherapy has been recommended as the preferred adjuvant treatment against high-risk stage 2 and stage 3 colon cancer patients. METHODS: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology and European Society for Medical Oncology meeting libraries from inception to November 2019. Regarding survival and tolerability, randomized controlled trials comparing different adjuvant systemic regimens against high-risk stage 2 and stage 3 colon cancer were eligible. Disease-free survival was primary endpoint. Network calculation was based on a random-effects model, and relative ranking of each node was numerically indicated by p score. RESULTS: A total of 30 trials were included, corresponding to 54,109 patients. Regarding disease-free survival, none of the analyzed regimens displayed significant superiority against common comparator 6-month capecitabine plus oxaliplatin (XELOX), while 12-month [network hazard ratio (HR) 0.81 (0.60-1.10); 0.79 (0.57-1.10)] and 3-month XELOX [0.95 (0.86-1.04); 0.93 (0.83-1.05)] were top-ranking regimens showing non-inferiority among overall and stage 3 patients. Moreover, by pairwise meta-analysis, 3-month XELOX demonstrated significant superiority against 6-month XELOX among low-risk stage 3 patients [pairwise HR 0.78 (0.63-0.97)]. Concerning adverse events, 3-month oxaliplatin-based chemotherapy was significantly better than the 6-month counterpart with respect to peripheral sensory neuropathy, thrombocytopenia and fatigue. The 12-month capecitabine monotherapy failed to display non-inferiority among other major adverse events. CONCLUSIONS: The 3-month XELOX treatment could be an alternative option of the 6-month regimen among low-risk stage 3 patients. Among high-risk stage 3 patients, 6-month oxaliplatin-based regimens still seem more competitive. In addition, clinical application of 12-month capecitabine monotherapy should be cautious, despite its top rankings, especially among non-Asian countries.

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer.

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

Multimodal treatments for resectable gastric cancer: A systematic review and network meta-analysis.

Different countries prefer particular types of multimodal treatments against resectable gastric cancer. Due to lacking of unified conclusions, we therefore conducted a network meta-analysis to rank all recommended strategies simultaneously and hierarchically. Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting libraries from inception to September 2018. Randomized controlled trials featuring comparisons between different preferred multimodal treatments against resectable gastric cancer were eligible. The Cochrane Risk of Bias Tool was applied to assess methodological quality of included trials. Overall survival was primary endpoint. Network calculation was based on random-effects model and the relative ranking of each node was numerically indicated by P-score. All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis (CRD42018109147). As a result, a total of 11 studies were included into our systematic review, corresponding to 7235 patients. Regarding overall survival, "PeriCT (FLOT)" (perioperative 5-FU plus leucovorin plus oxaliplatin plus docetaxel chemotherapy) topped the hierarchy (HR 1.00, P-score = 0.918), followed by "PostCT (XP)" (postoperative capecitabine plus platinum chemotherapy; HR 1.14, P-score = 0.759) and "PostCT (S-1)" (postoperative S-1 monotherapy; HR 1.16, P-score = 0.732). In subgroup analyses, "PostCT (XP)" became the top regimen for eastern population while "PeriCT (FLOT)" was the optimal node for western population. In conclusion, perioperative FLOT chemotherapy could potentially be the best multimodal treatment against resectable gastric cancer than other recommended strategies. Therefore, a global D2-lymphadenectomy randomized controlled trial comparing perioperative FLOT chemotherapy with postoperative XELOX chemotherapy should be carried out.

Multimodal treatments for resectable esophagogastric junction cancer: a systematic review and network meta-analysis.

BACKGROUND: Currently, preoperative chemoradiotherapy, perioperative chemotherapy and preoperative chemotherapy are recommended by NCCN, ESMO and Japanese guidelines respectively for resectable esophageal and junctional cancer. However, these recommendations are mainly based on esophageal cancer research. Therefore, specific for esophagogastric junction cancer, we conducted the first systematic review and network meta-analysis to rank all potential treatments simultaneously and hierarchically. METHODS: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO Meeting Library from inception to September 2018. Regarding time-to-event survival data, randomized controlled trials featuring comparisons between different multimodal treatments against resectable esophagogastric junction cancer were eligible. Overall survival was the endpoint. Network calculation was based on a random-effects model and the relative ranking of each node was numerically indicated by P-score (CRD42018110369, registration identifier of the meta-analysis in PROSPERO.). RESULTS: Eight studies were included in our systematic review, corresponding to 1218 patients. Regarding overall survival, 'PreCRT' (preoperative chemoradiotherapy) topped the hierarchy (HR 1.00, P-score = 0.823), better than 'PeriCT' (perioperative chemotherapy; HR 1.32, P-score = 0.591) and 'PreCT' (preoperative chemotherapy; HR 1.54, P-score = 0.428). In sensitivity analyses, irrespective of interchanging to fixed-effects model or removing potentially heterogeneous studies, relative rankings remained stable and 'PreCRT' was still the optimal node. CONCLUSION: Preoperative chemoradiotherapy could potentially be the optimal multimodal treatment, which displayed more overall survival benefits than perioperative chemotherapy and preoperative chemotherapy among resectable esophagogastric junction cancer patients. To further verify our pooled results, more randomized trials will be needed to compare preoperative chemoradiotherapy with perioperative chemotherapy (especially FLOT-based regimens).