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Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Hutchison MediPharma.

Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1–16·7) in the surufatinib group and 16·6 months (9·2–not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4–11·1) in the surufatinib group versus 3·8 months (3·7–5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22–0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. Hutchison MediPharma.

To better design treatments for cancer, it is important to understand the heterogeneity in tumors and how this contributes to metastasis. To examine this process, Bian et al. used a single-cell triple omics sequencing (scTrio-seq) technique to examine the mutations, transcriptome, and methylome within colorectal cancer tumors and metastases from 10 individual patients. The analysis provided insights into tumor evolution, linked DNA methylation to genetic lineages, and showed that DNA methylation levels are consistent within lineages but can differ substantially among clones. Science , this issue p. 1060 A multiomics approach reconstructs genetic lineages and epigenomic and transcriptomic dynamics of patient-derived disseminating tumors. Although genomic instability, epigenetic abnormality, and gene expression dysregulation are hallmarks of colorectal cancer, these features have not been simultaneously analyzed at single-cell resolution. Using optimized single-cell multiomics sequencing together with multiregional sampling of the primary tumor and lymphatic and distant metastases, we developed insights beyond intratumoral heterogeneity. Genome-wide DNA methylation levels were relatively consistent within a single genetic sublineage. The genome-wide DNA demethylation patterns of cancer cells were consistent in all 10 patients whose DNA we sequenced. The cancer cells’ DNA demethylation degrees clearly correlated with the densities of the heterochromatin-associated histone modification H3K9me3 of normal tissue and those of repetitive element long interspersed nuclear element 1. Our work demonstrates the feasibility of reconstructing genetic lineages and tracing their epigenomic and transcriptomic dynamics with single-cell multiomics sequencing.

BackgroundNeuroendocrine tumors (NETs) are a group of heterogenous tumors originating from neuroendocrine system. Approximately, 40 percent will go through liver metastases, and liver-directed therapy was proved to improve the survival outcome. Parenchyma-sparing hepatectomy is advocated for the resection of NETs liver metastases while the possible relatively low negative margin rate is concerned. Indocyanine green (ICG) fluorescence imaging provides a real-time navigation on determination of surgical margins in colorectal cancer liver metastases. However, there was no previous study that reported the applications of ICG fluorescence imaging in NETs liver metastases. The present study aimed to evaluate the feasibility and security of using ICG fluorescence imaging to determine surgical margins of NETs liver metastases during operation.MethodsA retrospective two-arm cohort study was performed on 25 consecutive patients with NETs liver metastases who underwent laparoscopic parenchyma-sparing hepatectomy (LPSH). Patients were divided into two groups according to whether or not the ICG fluorescence imaging was used. Data on sociodemographic characteristics, laboratory parameters, pathology results, and surgical outcomes were collected.ResultsA total of 145 tumors pathologically diagnosed with NETs liver metastases were resected from 25 patients. The pathological results indicated negative margins in all tumors (102/102) in LPSH with ICG fluorescence imaging group. The negative margin rate was significantly higher in LPSH using the ICG fluorescence imaging (100% v.s 88.4%, p = 0.002). Surgical outcomes, including operation time, estimated blood loss, intraoperative transfusion rate, and postoperative morbidity, were comparable between LPSH with and without ICG fluorescence imaging groups.ConclusionICG fluorescence imaging showed the potential to identify tumor boundaries and determine surgical margins. This technique may serve as a valuable intraoperative navigation in patients with NETs liver metastases.

IntroductionPostoperative pancreatic fistula (POPF) remains one of the main complications following pancreatic resection. Despite pancreatic fistula having a low postoperative mortality rate, the readmission and intervention rates in patients with pancreatic fistula are still considerable. Although there are several studies on pancreatic fistula development after pancreaticoduodenectomy, there are only a few studies on the feeding protocols applied after distal pancreatectomy or enucleation of pancreatic tumours. We designed this trial to test the hypothesis that early feeding does not increase the incidence of POPF and positively influences the long-term prognosis in patients who undergo distal pancreatectomy or enucleation of pancreatic tumours.Methods and analysisThis is a prospective randomised controlled trial that will be conducted in a single centre. A total of 106 patients undergoing distal pancreatectomy or enucleation of pancreatic tumours will be recruited after providing informed consent. They will be randomly assigned to either an early or late feeding group. The early feeding group will begin enteral nutrition on postoperative day (POD) 3, and the late feeding group will begin enteral nutrition on POD7. The primary outcome is the incidence of POPF. The secondary outcomes include the length of postoperative hospital stay, postoperative complications, and indicators of long-term prognosis.Ethics and disseminationPeking University Third Hospital Medical Science Research Ethics Committee approved the study (M2021395). Findings will be disseminated in a peer-reviewed journal and in national and/or international meetings to guide future practice.Trial registration numberChiCTR2100053978.

IntroductionPancreatic cancer (PC) is one of the most aggressive malignancies, and it’s difficult to diagnosis PC at an early stage, which leads to the poor prognosis of PC.ObjectivesTo identifiy the possible prognosis or dignosis metabolite biomarkers in the serum exosome of PC patients.MethodsWe employed LC-DDA-MS based untargeted lipidomic analysis to search for potential candidate biomarkers in the serum exosome of PC patients. Then LC-MRM-MS based targeted lipid quantification was used to validate the trends of the candidate biomarkers in larger sample cohorts.ResultsAbout 270 lipids belonging to 20 lipid species were found significantly dysregulated between the serum exosome of PC patients and healthy controls. 61 of them were validated in larger samples size. We further analysis the correlation between these dysregulated lipids and other PC related factors, and results show that LysoPC 22:0, PC (P-14:0/22:2) and PE (16:0/18:1) are all associated with tumor stage, CA19-9, CA242 and tumor diameter. What’s more, PE (16:0/18:1) is also found to be significantly correlated with the patient’s overall survival.ConclusionThese data reveal dysregulated lipids in serum exosome of PC patients, which have potential to be biomarkers for diagnosis, or unveil pathological relationship between exosome and PC progress.

BackgroundPancreatic cancer (PC) is a highly aggressive and refractory disease, with disappointing 5-year survival rates. Regarding the wide application of neoadjuvant treatment in patients with PC, how the post-neoadjuvant Carbohydrate antigen 19-9 (CA19-9) response could translate into a survival benefit is not clearly understood. We aimed to evaluate the correlation of the CA19-9 response with overall survival (OS) in patients with PC receiving neoadjuvant therapy.MethodsAn extensive electronic search in PubMed, Embase, and the Cochrane Library was performed to identify relevant articles, from which data relevant to independent correlations of the CA19-9 response with overall survival (OS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs).ResultsAltogether, 17 eligible studies were identified in the systematic review. Pooled analysis showed that CA19-9 response > 50% (HR, 0.43; 95% CI 0.29–0.56; P < 0.001) and normalization of CA19-9 (HR, 0.52; 95% CI 0.42–0.63; P < 0.001) after neoadjuvant treatment are significantly associated with promising overall survival. The results also showed that optimal CA19-9 response after neoadjuvant treatment was significantly related to a favorable prognosis (HR = 0.49, 95% CI 0.42–0.55, P < 0.001; I2 = 45.1%, P = 0.04). Subgroup analysis revealed there were no prognostic difference between CA19-9 > 50% and normalization of CA19-9 after neoadjuvant treatment (P = 0.338), but the duration of neoadjuvant chemotherapy over 4 months was significantly associated with expanded postoperative survival (P = 0.013).ConclusionsSerum CA19‑9 is valuable in determining the effect of neoadjuvant treatment in patients with PC. Post-neoadjuvant CA19-9 response > 50% or CA19-9 normalization was related to a more promising overall survival, suggesting that optimal CA19-9 response may be a suitable prognostic index to guide treatment decisions.

Lymphocyte to monocyte ratio (LMR) was recently reported as a prognostic factor of pancreatic cancer (PC). However, the prognostic role of LMR in PC remains inconsistent and inconclusive. The aim of this study was to assess the prognostic value of LMR in patients with PC through meta-analysis. Eligible studies inquiring into the connection between LMR and survival of patients with PC were collected and extracted by searching PubMed, Embase, Cochrane Library and Web of Science up to May 9, 2017. Pooled hazard ratios (HRs) and the 95% CIs were calculated to assess the prognostic value of LMR on overall survival (OS) and disease-free survival/recurrence-free survival/time to progression (DFS/RFS/TTP). A total of 1,795 patients with PC from 8 studies were included in the meta-analysis. Pooled analysis indicated that elevated LMR predicted a favorable OS (HR =0.56, 95% CI: 0.38-0.83, =0.004) and DFS/RFS/TTP in PC patients (HR =0.38, 95% CI: 0.15-0.95, =0.04). Prognostic values of LMR on OS were observed in subgroups with all ethnicities, treatment with surgery, American Joint Committee on Cancer (AJCC) stage of III-IV, and LMR cut-off value ≥3. In addition, low LMR was significantly connected with gender and AJCC stage. An elevated LMR is associated with favorable survival in patients with pancreatic cancer.

Background It has recently been shown that mut-L homolog 1 (MLH1), frequently lost in cancer initiation and progression, inhibited pancreatic cancer metastatic potential by downregulating G-protein coupled receptor C5C (GPRC5C). However, their expression and prognostic significance in hepatocellular carcinoma (HCC) has not been elucidated, especially for GPRC5C. Methods We detected MLH1 and GPRC5C expression using the tissue microarray-based immunohistochemical staining in tumor and matched adjacent non-tumor liver (ANL) specimens from 230 patients who underwent radical resection for HCC. The correlations between staining H-scores and clinicopathologic parameters, overall and disease-free survival were then evaluated. Finally, the prognostic value of the genes was evaluated in the online publicly available Kaplan-Meier Plotter database. Results Firstly, MLH1 expression was much lower in HCC than in ANL tissues, while GPRC5C had the opposite change. Spearman’s correlation coefficient analysis showed that MLH1 and GPRC5C were of a strong negative correlation ( P  < 0.001). In addition, MLH1 was negatively related to AFP level, and GPRC5C was positively linked to tumor size and vascular invasion. Univariately, high MLH1 or GPRC5C expression was remarkably associated with better or poorer overall and disease-free survival, respectively. In multivariate analyses, GPRC5C remains to be a powerful determinant for both overall and disease-free survival, while MLH1 was significant only for overall survival. Lastly, MLH1 predicted recurrence-free and progression-free survival in the Kaplan-Meier Plotter, GPRC5C might have the adverse effect, although being not statistically significant. Conclusion MLH1 and GPRC5C have divergent expressions with an inverse correlation and function as promising novel prognostic indicators in resectable HCC.

Magnetic resonance imaging (MRI) has been shown to be associated with prognosis in some tumors; however, the correlation in pancreatic ductal adenocarcinoma (PDAC) remains inconclusive. In this retrospective study, we ultimately included 136 patients and analyzed quantitative MRI parameters that are associated with prognosis and recurrence patterns in PDAC using survival analysis and competing risks models; all the patients have been operated on with histopathology and immunohistochemical staining for further evaluation. In intravoxel incoherent motion diffusion-weighted imaging (DWI), we found that pure-diffusion coefficient D value was an independent risk factor for overall survival (OS) (HR: 1.696, 95% CI: 1.003–2.869, p = 0.049) and recurrence-free survival (RFS) (HR: 2.066, 95% CI: 1.252–3.409, p = 0.005). A low D value (≤1.08 × 10−3 mm2/s) was significantly associated with a higher risk of local recurrence (SHR: 5.905, 95% CI: 2.107–16.458, p = 0.001). Subgroup analysis revealed that patients with high D and f values had significantly better outcomes with adjuvant chemotherapy. Distant recurrence patients in the high-D value group who received chemotherapy may significantly improve their OS and RFS. It was found that preoperative multiparametric quantitative MRI correlates with prognosis and recurrence patterns in PDAC. Diffusion coefficient D value can be used as a noninvasive biomarker for predicting prognosis and recurrence patterns in PDAC.