Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

circRNADisease v2.0: an updated resource for high-quality experimentally supported circRNA-disease associations.

circRNADisease v2.0 is an enhanced and reliable database that offers experimentally verified relationships between circular RNAs (circRNAs) and various diseases. It is accessible at http://cgga.org.cn/circRNADisease/ or http://cgga.org.cn:9091/circRNADisease/. The database currently includes 6998 circRNA-disease entries across multiple species, representing a remarkable 19.77-fold increase compared to the previous version. This expansion consists of a substantial rise in the number of circRNAs (from 330 to 4246), types of diseases (from 48 to 330) and covered species (from human only to 12 species). Furthermore, a new section has been introduced in the database, which collects information on circRNA-associated factors (genes, proteins and microRNAs), molecular mechanisms (molecular pathways), biological functions (proliferation, migration, invasion, etc.), tumor and/or cell line and/or patient-derived xenograft (PDX) details, and prognostic evidence in diseases. In addition, we identified 7 159 865 relationships between mutations and circRNAs among 30 TCGA cancer types. Due to notable enhancements and extensive data expansions, the circRNADisease 2.0 database has become an invaluable asset for both clinical practice and fundamental research. It enables researchers to develop a more comprehensive understanding of how circRNAs impact complex diseases.

Immunological profiles of human oligodendrogliomas define two distinct molecular subtypes.

BACKGROUND: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome. METHODS: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation. FINDINGS: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts. INTERPRETATION: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas. FUNDING: The funders are listed in the Acknowledgement.

Primary tumor resection with or without metastasectomy for left- and right-sided stage IV colorectal cancer: an instrumental variable analysis.

BACKGROUND: Whether primary tumor location (PTL) is predictive of survival benefits following primary tumor resection plus metastasectomy (PMTR) and primary tumor resection (PTR) alone in stage IV colorectal cancer patients is not known. We sought to address this issue by employing instrumental variable analysis to evaluate the efficacy of PMTR and PTR with stratification for primary tumor location in stage IV colorectal cancer patients. PATIENTS AND METHODS: Stage IV colorectal cancer patients diagnosed between January 1, 2005 and December 31, 2015 were identified from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. To account for both measured and unmeasured confounders, the efficacy of PMTR and PTR in the left- and right-sided subgroups was evaluated using instrumental variable analysis, with the health service area as the instrument variable. Overall survival (OS) was the primary outcome of interest. RESULTS: A total of 50,333 eligible patients were analyzed (left-sided, n = 29,402 and right-sided, n = 20,931). OS was significantly better with PMTR than with other treatments (PTR, metastasectomy only, or no surgery) in patients with left-sided tumors (hazard ratio [HR] = 0.37 [95% CI 0.24-0.58], P < 0.001), but not in patients with right-sided tumors (HR = 0.98 [95% CI 0.65-1.47], P = 0.910; interaction test P < 0.001). OS was comparable in patients treated with PTR and those treated with no surgery in both the left-sided (HR = 1.11 [95% CI 0.68-1.81], P = 0.690) and right-sided (HR = 0.85 [95% CI 0.50-1.43], P = 0.530; interaction test P = 0.466) subgroups. CONCLUSIONS: PMTR appears to only benefit patients with left-sided stage IV colorectal cancer but not those with right-sided tumors. PTR does not improve OS, regardless of primary tumor location. When selecting patients for PMTR, primary tumor location should be considered. Overuse of PTR should be avoided.

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer.

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: a randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC).

PURPOSE: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. METHODS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative chemotherapy, which consist of portal vein chemotherapy, intraluminal chemotherapy and intraperitoneal chemotherapy, plus surgery group, whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. RESULTS: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2 vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group. Intraoperative chemotherapy did not decrease the rate of patients who received postoperative chemotherapy between the intraoperative group and control group (29.3 vs. 30.2%, P = 0.795). CONCLUSIONS: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. ClinicalTrial.gov Register Number: NCT01465451.

Patterns of recurrence in patients achieving pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer.

PURPOSE: The aim of this study was to characterize the patterns of recurrence in patients achieving pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: Patients with locally advanced rectal cancer treated with neoadjuvant CRT and who achieved pCR from January 2004 to December 2012 were collected. The primary outcome measurement was the patterns of recurrence. RESULTS: Among 195 patients who achieved pCR, 18 developed recurrence. Furthermore, local recurrence occurred in 1.5% of patients (3/195), while distant metastases occurred in 7.7% of patients (15/195), which included 7 lung metastases, 1 liver metastasis, and 8 metastases in other locations. CONCLUSIONS: Our study indicated that patients achieving pCR following neoadjuvant CRT have a favorable prognosis, with distant metastases predominating in all recurrences. Among patients with distant metastases, non-liver metastases were the predominant pattern.

Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum.

BACKGROUND: Schistosomiasis is one of the world's major public health problems. Besides praziquantel (PZQ), there is currently no other effective treatment against schistosomiasis. The development of new antischistosomal agents to curb the emergence of PZQ resistance should be a high priority. Oxadiazole-2-oxides have been identified as potential antischistosomal reagents, with thioredoxin glutathione reductase (TGR) being one of their molecular targets. METHODS: To develop novel treatment reagents against Schistosoma japonicum, 30 novel oxadiazole-2-oxides were synthesised and their antischistosomal activities on juvenile and adult S. japonicum were evaluated in vitro and in vivo. Their inhibitory activities against S. japonicum thioredoxin glutathione reductase (SjTGR) were also analysed. RESULTS: Most of the oxadiazole-2-oxides showed good juvenile and adult S. japonica killing activities in vitro. However, the antischistosomal effects of these compounds were not positively correlated with either their inhibition of SjTGR, or with nitric oxide (NO) release. Compounds 4a, 4b, 7c, 13, 16 and 20 resulted in 87.7%, 83.1%, 87.1%, 84.6%, 90.8% and 69.5%, respectively, mortality in the adult worms, when used to treat infected mice at schistosomula stage. These mortality rates were similar to or higher than that of artemisinin. Furthermore, compounds 4a and 16 resulted in 66.7% and 69.4% reductions in the worm burdens, respectively, when infected mice were treated at the adult worm stage. These treatment effects were similar to PZQ. No differences in activity of the oxadiazole-2-oxides against female and male adult worms were observed. The toxicity of the oxadiazole-2-oxides on mammalian cells appeared to be similar to, or less than, that of PZQ. CONCLUSIONS: The antischistosomal activity of the oxadiazole-2-oxides does not depend on NO production or the inhibition of SjTGR activity. There may be other functional targets of the oxadiazole-2-oxides in S. japonicum. Several of the novel oxadiazole-2-oxides synthesised in this study could be used to develop novel antischistosomal drugs and explore potential molecular targets.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial.

INTRODUCTION: Multimodality therapy, including preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy (CCRT) involving XELOX regimen (oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma. METHODS: We randomly assigned patients to the TME group (TME without preoperative CCRT) or CCRT + TME group (TME with preoperative CCRT). The primary endpoint was disease-free survival (DFS); the secondary endpoints were overall survival (OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months. RESULTS: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 % (P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 % (P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT + TME groups were 71.3 % and 70.0 % (P = 0.849), respectively. In the TME group, 16 (17.0 %) patients were proven to have pTNM stage I disease after surgery. In the CCRT + TME group, 32 (35.6 %) patients achieved a pathologic complete response (pCR). CONCLUSIONS: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high pCR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted. CLINICAL TRIAL REGISTRATION NUMBER: Chi CTR-TRC-08000122.

1H-2,3-dihydroperimidine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.10-fold respectively) over T-cell protein tyrosine phosphatases (TCPTP). These results have provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Intraoperative blood loss independently predicts survival and recurrence after resection of colorectal cancer liver metastasis.

BACKGROUND: Although numerous prognostic factors have been reported for colorectal cancer liver metastasis (CRLM), few studies have reported intraoperative blood loss (IBL) effects on clinical outcome after CRLM resection. METHODS: We retrospectively evaluated the clinical and histopathological characteristics of 139 patients who underwent liver resection for CRLM. The IBL cutoff volume was calculated using receiver operating characteristic curves. Overall survival (OS) and recurrence free survival (RFS) were assessed using the Kaplan-Meier and Cox regression methods. RESULTS: All patients underwent curative resection. The median follow up period was 25.0 months (range, 2.1-88.8). Body mass index (BMI) and CRLM number and tumor size were associated with increased IBL. BMI (P=0.01; 95% CI = 1.3-8.5) and IBL (P<0.01; 95% CI = 1.6-12.5) were independent OSOs predictors. Five factors, including IBL (P=0.02; 95% CI = 1.1-4.1), were significantly related to RFS via multivariate Cox regression analysis. In addition, OSOs and RFS significantly decreased with increasing IBL volumes. The 5-year OSOs of patients with IBL≤250, 250-500, and >500mL were 71%, 33%, and 0%, respectively (P<0.01). RFS of patients within three IBL volumes at the end of the first year were 67%, 38%, and 18%, respectively (P<0.01). CONCLUSIONS: IBL during CRLM resection is an independent predictor of long term survival and tumor recurrence, and its prognostic value was confirmed by a dose-response relationship.

Synthesis and SAR studies of praziquantel derivatives with activity against Schistosoma japonicum.

The synthesis and structure-activity relationship (SAR) studies of praziquantel derivatives with activity against adult Schistosoma japonicum are described. Several of them showed better worm killing activity than praziquantel and could serve as leads for further optimization.

Hybridization kinetics on microarray surfaces.

Kinetic hybridization data are compared to a number of different models. A first-order Langmuir model provides the best fit to the data.

High-density lipoproteins enhance progenitor-mediated endothelium repair in mice.

OBJECTIVE: We quantified endothelial progenitor cell (EPC) engraftment into the endothelial layer as an index of progenitor-mediated endothelial repair. Studies were conducted in C57BL/6J and in apolipoprotein E-deficient (apoE(-/-)) mice. We also investigated the possibility that high-density lipoproteins (HDL) may promote progenitor-mediated endothelial repair. METHODS AND RESULTS: Thoracic aortic sections from C57BL/6J and apoE(-/-) mice were analyzed for evidence of progenitor-derived endothelium as determined by the number of stem cell antigen-1-positive (Sca-1+) cells in the endothelial layer. EPCs (Sca-1+ cells) were significantly increased after endothelial damage induced by lipopolysaccharide (LPS) administration in C57BL/6J mice. The number of EPCs was greater in the aortic endothelium of untreated apoE(-/-) than in untreated C57BL/6J mice and was similar to the number observed in LPS-treated C57BL/6J mice. The number of EPCs in the aortic endothelium of apoE(-/-) mice more than doubled after intravenous infusion of reconstituted HDL. CONCLUSIONS: EPCs are recruited into the aortic endothelial layer of mice in response to an inflammatory insult. EPCs are also increased in the aortic endothelium of untreated apoE(-/-) mice. The observation that number is further increased in apoE(-/-) mice after injection of HDL suggests a role for HDL in promoting progenitor-mediated endothelial repair.

Microarray gene expression analysis free of reverse transcription and dye labeling.

A new microarray system has been developed for gene expression analysis using cationic gold nanoparticles with diameters of 250 nm as a target detection reagent. The approach utilizes nonlabeled target molecules hybridizing with complementary probes on the array, followed by incubation in a colloidal gold solution. The hybridization signal results from the precipitation of nanogold particles on the hybridized spots due to the electrostatic attraction of the cationic gold particles and the anionic phosphate groups in the target DNA backbone. In contrast to conventional fluorescent detection, this nanoparticle-based detection system eliminates the target labeling procedure. The visualization of hybridization signals can be accomplished with a flatbed scanner instead of a confocal laser scanner, which greatly simplifies the process and reduces the cost. The sensitivity is estimated to be less than 2 pg of DNA molecules captured on the array surface. The signal from hybridized spots quantitatively represents the amount of captured target DNA and therefore permits quantitative gene expression analysis. Cross-array reproducibility is adequate for detecting twofold or less signal changes across two microarray experiments.

Increased MMP-2 expression in connective tissue growth factor over-expression vascular smooth muscle cells.

Connective tissue growth factor (CTGF) is abundantly expressed in the vascular smooth muscle cells (VSMC) of atherosclerotic lesions but not in normal vessels. CTGF is able to promote VSMC proliferation and migration and influences the composition of extracellular matrix. The mechanisms for controlling these events remain unclear. We studied the effects of CTGF on matrix metalloproteinases (MMPs) by introducing a CTGF over-expression construct into VSMC. We found that the over-expression of CTGF significantly increased the activity of MMP-2 in VSMC conditioned medium. MMP-2 activity was similarly increased by exogenous CTGF treatment, and this effect could be blocked by an anti-CTGF antibody. We also showed that the increased MMP-2 activity was due to an increase in MMP-2 mRNA levels in VSMC. We further studied the mechanisms involved in the regulation of MMP-2 mRNA levels and found that the AP-2 transcription factor is responsible for most of the CTGF-induced MMP-2 transcription. Because MMP-2 is an important factor directly involved in controlling cell movement and the turnover of extracellular matrix, our study may provide a mechanism for CTGF-promoted VSMC migration.