Objective:
The aim of this study is to investigate the current status of the diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms (pNENs) undergoing surgery in China.
Methods:
...This is a multicenter cross-sectional study performed in China. Data from patients with pNENs undergoing surgery at 33 high-volume medical centers, where the number of pancreatectomies exceeds 20 cases per year, were collected and analyzed between March 1, 2016 and February 28, 2017.
Results:
In total, 392 patients with pNENs were enrolled. The male to female ratio was 1.4. The majority of patients were aged between 40 and 70 years. 65.6% of the patients had non-functional tumors. Among those with functional tumors, the percentages of insulinomas, gastrinomas, glucagonomas, and vasoactive intestinal peptide-secreting tumors were 94.8%, 1.5%, 2.2%, and 1.5%, respectively. Multidisciplinary team (MDT) discussion was conducted for 39.0% of the patients. Minimally invasive surgery was performed on 31.1% of the 392 patients. The incidence of grade B/C pancreatic fistula formation was 4.4%. A total of 89.0% of the surgeries achieved R0 resection, and 41.6% of the tumors were well differentiated. Lymph node metastasis was present in 8.9% of the patients. The percentages of patients with grades G1, G2, and G3 disease were 49.2%, 45.7%, and 5.1%, respectively.
Conclusion:
This multicenter cross-sectional study systematically presents the current status of the diagnosis and treatment of patients with pNENs undergoing surgery in China. MDT consultation for pNENs has not been widely implemented in China. Although the incidence of surgical complications is relatively low, minimally invasive procedures should be further promoted. This study shows us how to improve the outcomes of these patients.
OBJECTIVE:The aim of the study was to analyze the outcomes of patients who have undergone laparoscopic pancreaticoduodenectomy (LPD) in China.
SUMMARY BACKGROUND DATA:LPD is being increasingly used ...worldwide, but an extensive, detailed, systematic, multicenter analysis of the procedure has not been performed.
METHODS:We retrospectively reviewed 1029 consecutive patients who had undergone LPD between January 2010 and August 2016 in China. Univariate and multivariate analyses of patient demographics, changes in outcome over time, technical learning curves, and the relationship between hospital or surgeon volume and patient outcomes were performed.
RESULTS:Among the 1029 patients, 61 (5.93%) required conversion to laparotomy. The median operation time (OT) was 441.34 minutes, and the major complications occurred in 511 patients (49.66%). There were 21 deaths (2.43%) within 30 days, and a total of 61 (5.93%) within 90 days. Discounting the effects of the early learning phase, critical parameters improved significantly with surgeons’ experience with the procedure. Univariate and multivariate analyses revealed that the pancreatic anastomosis technique, preoperative biliary drainage method, and total bilirubin were linked to several outcome measures, including OT, estimated intraoperative blood loss, and mortality. Multicenter analyses of the learning curve revealed 3 phases, with proficiency thresholds at 40 and 104 cases. Higher hospital, department, and surgeon volume, as well as surgeon experience with minimally invasive surgery, were associated with a lower risk of surgical failure.
CONCLUSIONS:LPD is technically safe and feasible, with acceptable rates of morbidity and mortality. Nonetheless, long learning curves, low-volume hospitals, and surgical inexperience are associated with higher rates of complications and mortality.
Background
The incidence of postoperative morbidity after pancreaticoduodenectomy (PD) is high; however, whether fluid management after surgery affects postoperative morbidity is unclear. This study ...aimed to determine whether fluid balance in patients undergoing PD is associated with postoperative complications and mortality.
Methods
Data from a computer-based database of patients who underwent PD between 2016 and 2019 were retrospectively analyzed. Patients were stratified into four quartiles according to their fluid balance at 0–24, 24–48, 48–72, and 72–96 h after surgery. The predefined primary outcome measures were morbidity and mortality rates.
Results
A total of 301 patients were included. The morbidity and mortality rates in the cohort were 56.5% and 3.7%, respectively. The most common complications after PD were postoperative pancreatic fistula (31.9%) and delayed gastric emptying (31.6%). Patients with a higher fluid balance in the 0–24-, 24–48-, and 48–72-h postoperative periods had a higher morbidity rate and longer hospital stay than those with a lower fluid balance (all
P
< 0.05). Patients with a fluid balance of 4212 mL during the postoperative 0–72 h were most likely to develop complications (
P
< 0.001). The area under the receiver operating characteristic curve was 0.71 (0.65–0.77), with a sensitivity of 58.24% and a specificity of 77.10%.
Conclusions
Higher postoperative fluid balance seems to be associated with increased morbidity after PD compared to lower fluid balance. Surgeons should pay close attention to the occurrence of complications in patients with a high fluid balance.
Hepatocellular carcinoma (HCC) is a cancer with multiple aetiologies and widespread prevalence. Largely refractory to current treatments, HCC is the fourth leading cause of cancer-related deaths ...worldwide. MicroRNAs (miRNAs) are important regulators in HCCs. We aimed to identify tumour suppressor miRNAs during tumour regression in a conditional c-MYC-driven mouse model (LT2/MYC) of HCC, and to evaluate their therapeutic potential for HCC treatment.
We performed miRNA expression profiling of developed and regressing LT2/MYC tumours and in-depth in vitro gain- and loss-of-function analyses. The effect of adeno-associated virus (AAV) vector-mediated miR-342-3p treatment was evaluated in 3 HCC mouse models.
We identified miR-342-3p as a tumour suppressor miRNA in HCC, with increased expression in regressing tumours. Forced miR-342-3p expression in hepatoma cells showed significantly decreased cell proliferation, migration, and colony formation. In vivo administration of AAV-miR-342-3p led to significant attenuation of tumour development and increased overall survival. We identified monocarboxylic acid transporter 1 (MCT1) as a bona fide target of miR-342-3p in HCC. We show that the tumour suppressor role of miR-342-3p is executed partly by modulating the lactate transport function of MCT1. Importantly, we find miR-342-3p downregulated in tumours from patients with HCC compared with matched non-tumour tissues, inversely correlating with MCT1 expression. We observed similar findings in TCGA-LIHC data.
In our study, we identified and validated miR-342-3p as a tumour suppressor miRNA in HCC. We demonstrated its therapeutic efficacy in significantly attenuating tumour development, and prolonging survival, in different HCC mouse models. Identification of miR-342-3p as an effective tumour suppressor opens a therapeutic avenue for miRNA-mediated attenuation of HCC development.
Hepatocellular carcinoma (HCC), the most common type of liver cancer, affects diverse populations and has a global impact, being the fourth leading cause of cancer deaths worldwide. There are currently no systemic therapies for HCC that can significantly prolong long-term survival. Thus, novel effective treatment options are urgently required. To understand the molecular basis of tumour regression, we compared tumours and regressing liver tumours in mice. We show that a small non-coding miRNA, miR-342-3p, is a tumour suppressor in HCC. Expression of miR-342-3p is low in tumours and high in regressing tumours. When miR-342-3p is delivered to mouse livers with HCC, it can significantly slow down liver tumour development and improve survival. Our study highlights the promising therapeutic potential of miR-342-3p intervention in HCC.
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•Distinct global microRNA landscape in regressing liver tumours compared with tumours.•Identification and validation of miR-342-3p as a tumour suppressor in HCCs.•MiR-342-3p significantly attenuates tumour development in 3 mouse models of HCC.•MiR-342-3p prolongs survival of LT2/MYC and LT2/RAS mice with liver tumours.•MiR-342-3p plays a role in metabolic reprogramming in HCC, by targeting MCT1.
For decades researches of genomic transcription of all kinds of species have demonstrated that the important role of Long non-coding RNAs (LncRNAs) in whole process of life entity has been more and ...more attached. Owing to constant developing of advanced technology, especially the emerge of next generation sequencing, researchers could explore further in the depth and breadth of LncRNAs. Given that the unique RNA loci location with its corresponding sense gene, antisense long noncoding RNAs (AS-lncRNAs), which are one of the main categories of LncRNAs classification, would have existed an identified close connection between them in a natural physiological state. This review characterizes the patterns of regulation between AS-lncRNAs and corresponding sense genes during the process of cancer progression in human, with emphases on the regular modulation ways of the potential molecular mechanism of AS-lncRNAs and the summary of underlying treatment targets in human cancers.
The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by ...Inula helenium, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.
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•Alantolactone was a pharmacological inhibitor of autophagy in pancreatic cancer cells.•Alantolactone enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.•Alantolactone-induced apoptosis was dependent on cytotoxic autophagosomes.•TFEB plays a key role in Alantolactone-induced apoptosis and cell death in pancreatic cancer cells.
We sought to combine skeletal muscle index and inflammatory immune markers to stratify long-term survival in patients with pancreatic cancer after pancreatoduodenectomy (PD).
A total of 581 patients ...with pancreatic cancer underwent PD were included, and divided into the training and validation cohort. Image analysis of computed tomography scans was used to calculate the ratio of skeletal muscle (SM) area to body mass index (BMI). Naples prognostic score (NPS) was calculated from blood-test inflammatory immune markers. Propensity score matching (PSM) analysis was performed to minimize biases of clinicopathological characteristics. To estimate the overall survival (OS), a nomogram was developed using the training cohort. The predictive accuracy of nomogram was estimated by concordance index (C-index), calibration curve, and receiver operating characteristics (ROC) curve.
After PSM analysis, SM/BMI ratio, NPS, lymph node metastasis, TNM stage, surgical margin, tumor grade and adjuvant therapy were independent predictors of OS, which were all assembled into nomogram. The SM/BMI ratio was the best single-predictor for 3- and 5-year OS, with an AUC of 0.805 (95% CI: 0.755–0.855) and 0.812 (95% CI: 0.736–0.888), respectively. Harrell's c-index of the nomogram in the training cohort was 0.786 (95% CI: 0.770–0.802), and the area under ROC curve of 1-year, 3- and 5-year OS prediction were 0.869 (95%CI: 0.837–0.901), 0.846 (95%CI: 0.810–0.882) and 0.849 (95%CI: 0.801–0.896).
The nomogram based on SM/BMI ratio and NPS had excellent predictive performance, which should be incorporated to conventional risk scores to stratify survival of patients with PDAC after PD.
There is currently limited knowledge regarding the involvement of long non-coding RNAs (lncRNAs) in cancer development. We aimed to identify lncRNAs with important roles in pancreatic cancer ...progression. We screened for lncRNAs that were differentially expressed in pancreatic cancer tissues. Among 349 differentially expressed lncRNAs, Linc01060 showed the lowest expression in pancreatic cancer tissues compared with normal pancreatic tissues. Lower Linc01060 expression in pancreatic cancer tissues was significantly associated with a poor prognosis. Linc01060 inhibited pancreatic cancer proliferation and invasion in vitro and in vivo. Vinculin overexpression inhibited Linc01060KD-mediated increases in FAK and paxillin phosphorylation, whereas vinculin knockdown reversed the Linc01060-mediated repression of FAK and inactivation of focal adhesion turnover. Vinculin knockdown also accelerated pancreatic cancer cell proliferation by upregulating ERK activity. In biological function analyses, vinculin overexpression abrogated Linc01060-mediated repression of pancreatic cancer cell proliferation and invasion, whereas vinculin counteracted the Linc01060-mediated repression of PC cell proliferation and invasion. These data demonstrate that Linc01060 plays a key role in suppressing pancreatic cancer progression by regulating vinculin expression. These findings suggest that the Linc01060-vinculin-focal adhesion axis is a therapeutic target for pancreatic cancer treatment.
•Linc01060 was significantly downregulated in pancreatic cancer tissues.•Lower Linc01060 expression in pancreatic cancer tissues was associated with a poor prognosis.•Linc01060 plays a key role in suppressing pancreatic cancer invasion and metastasis.•Linc01060 inhibits vinculin and increases FAK and paxillin phosphorylation.•Linc01060 promotes focal adhesion turnover and enhancing cell motility.
With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has ...resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.
Many studies have shown the short-term feasibility and effectiveness of laparoscopic pancreaticoduodenectomy (LPD) are comparable to open pancreaticoduodenectomy (OPD). However, the long-term ...oncological safety of LPD in patients with pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated.
Patients who underwent LPD or OPD between July 2014 and July 2018 at our institution were identified, and those with resectable, pathologically diagnosed PDAC were analyzed. The primary outcome was overall survival (OS). Propensity score-matching (PSM) analysis was performed to balance the baseline characteristics between groups. Cox proportional hazards model was constructed to determine independent predictors of OS.
The original cohort consisted of 64 LPD and 80 OPD cases, in which, the laparoscopic group had a significantly longer median OS (25 vs. 17 months; P = 0.034). A higher proportion of laparoscopic patients received adjuvant therapy (51.6 vs. 32.5%; P = 0.021). PSM analysis identified 47 patient pairs. No significant differences in OS (21 vs. 17 months; P = 0.220) or adjuvant therapy utilization (53.2 vs. 38.3%; P = 0.248) were observed between the matched groups. Multivariate Cox analyses showed that receiving adjuvant therapy (HR = 0.44; 95% CI, 0.28–0.68), histopathological differentiation (poor vs. moderate-to-well differentiation; HR = 1.93; 95% CI, 1.26–2.95), and sex (female vs. male, HR = 0.47, 95% CI, 0.30–0.75) were independent predictors of OS.
LPD can be comparable to OPD in terms of long-term safety for patients with resectable pancreatic ductal adenocarcinoma when performed in a high-volume center.
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