Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

OBJECTIVE: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors. BACKGROUND: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD. METHODS: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China. The initial trial included 656 eligible patients with pancreatic or periampullary tumors enrolled from May 18, 2018, to December 19, 2019. The participants were randomized preoperatively in a 1:1 ratio to undergo either LPD (n=328) or OPD (n=328). The 3-year overall survival (OS), quality of life, which was assessed using the 3-level version of the European Quality of Life-5 Dimensions, depression, and other outcomes were evaluated. RESULTS: Data from 656 patients [328 men (69.9%); mean (SD) age: 56.2 (10.7) years] who underwent pancreaticoduodenectomy were analyzed. For malignancies, the 3-year OS rates were 59.1% and 54.3% in the LPD and OPD groups, respectively ( P =0.33, hazard ratio: 1.16, 95% CI: 0.86-1.56). The 3-year OS rates for others were 81.3% and 85.6% in the LPD and OPD groups, respectively ( P =0.40, hazard ratio: 0.70, 95% CI: 0.30-1.63). No significant differences were observed in quality of life, depression and other outcomes between the 2 groups. CONCLUSION: In patients with pancreatic or periampullary tumors, LPD performed by experienced surgeons resulted in a similar 3-year OS compared with OPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03138213.

AutoEncoder-Based Computational Framework for Tumor Microenvironment Decomposition and Biomarker Identification in Metastatic Melanoma.

Melanoma is one of the most aggressive cancer types whose prognosis is determined by both the tumor cell-intrinsic and -extrinsic features as well as their interactions. In this study, we performed systematic and unbiased analysis using The Cancer Genome Atlas (TCGA) melanoma RNA-seq data and identified two gene signatures that captured the intrinsic and extrinsic features, respectively. Specifically, we selected genes that best reflected the expression signals from tumor cells and immune infiltrate cells. Then, we applied an AutoEncoder-based method to decompose the expression of these genes into a small number of representative nodes. Many of these nodes were found to be significantly associated with patient prognosis. From them, we selected two most prognostic nodes and defined a tumor-intrinsic (TI) signature and a tumor-extrinsic (TE) signature. Pathway analysis confirmed that the TE signature recapitulated cytotoxic immune cell related pathways while the TI signature reflected MYC pathway activity. We leveraged these two signatures to investigate six independent melanoma microarray datasets and found that they were able to predict the prognosis of patients under standard care. Furthermore, we showed that the TE signature was also positively associated with patients' response to immunotherapies, including tumor vaccine therapy and checkpoint blockade immunotherapy. This study developed a novel computational framework to capture the tumor-intrinsic and -extrinsic features and identified robust prognostic and predictive biomarkers in melanoma.

Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours: a multicentre, open-label, randomised controlled trial.

BACKGROUND: The benefit and safety of laparoscopic pancreatoduodenectomy (LPD) for the treatment of pancreatic or periampullary tumours remain controversial. Studies have shown that the learning curve plays an important role in LPD, yet there are no randomised studies on LPD after the surgeons have surmounted the learning curve. The aim of this trial was to compare the outcomes of open pancreatoduodenectomy (OPD) with those of LPD, when performed by experienced surgeons. METHODS: In this multicentre, open-label, randomised controlled trial done in 14 Chinese medical centres, we recruited patients aged 18-75 years with a benign, premalignant, or malignant indication for pancreatoduodenectomy. Eligible patients were randomly assigned (1:1) to undergo either LPD or OPD. Randomisation was centralised via a computer-generated system that used a block size of four. The patients and surgeons were unmasked to study group, whereas the data collectors, outcome assessors, and data analysts were masked. LPD and OPD were performed by experienced surgeons who had already done at least 104 LPD operations. The primary outcome was the postoperative length of stay. The criteria for discharge were based on functional recovery, and analyses were done on a modified intention-to-treat basis (ie, including patients who had a pancreatoduodenectomy regardless of whether the operation was the one they were assigned to). This trial is registered with Clinicaltrials.gov, number NCT03138213. FINDINGS: Between May 18, 2018, and Dec 19, 2019, we assessed 762 patients for eligibility, of whom 656 were randomly assigned to either the LPD group (n=328) or the OPD group (n=328). 31 patients in each group were excluded and 80 patients crossed over (33 from LPD to OPD, 47 from OPD to LPD). In the modified intention-to-treat analysis (297 patients in the LPD group and 297 patients in the OPD group), the postoperative length of stay was significantly shorter for patients in the LPD group than for patients in the OPD group (median 15·0 days [95% CI 14·0-16·0] vs 16·0 days [15·0-17·0]; p=0·02). 90-day mortality was similar in both groups (five [2%] of 297 patients in the LPD group vs six [2%] of 297 in the OPD group, risk ratio [RR] 0·83 [95% CI 0·26-2·70]; p=0·76). The incidence rate of serious postoperative morbidities (Clavien-Dindo grade of at least 3) was not significantly different in the two groups (85 [29%] of 297 patients in the LPD group vs 69 [23%] of 297 patients in OPD group, RR 1·23 [95% CI 0·94-1·62]; p=0·13). The comprehensive complication index score was not significantly different between the two groups (median score 8·7 [IQR 0·0-26·2] vs 0·0 [0·0-20·9]; p=0·06). INTERPRETATION: In highly experienced hands, LPD is a safe and feasible procedure. It was associated with a shorter length of stay and similar short-term morbidity and mortality rates to OPD. Nonetheless, the clinical benefit of LPD compared with OPD was marginal despite extensive procedural expertise. Future research should focus on identifying the populations that will benefit from LPD. FUNDING: National Natural Science Foundation of China and Tongji Hospital, Huazhong University of Science and Technology, China.

Metastases with definitive pathological diagnosis but no detectable primary tumor: A surveillance epidemiology and end results-based study.

BACKGROUND: This study investigates the characteristics of a special type of cancer of unknown primary site (CUP, type 2), which is a metastasis of a definite pathological diagnosis without a detectable primary site. PATIENTS AND METHODS: Patients diagnosed between 2004 and 2014 were identified from the Surveillance Epidemiology and End Results (SEER) database. The characteristics of type 2 CUP from different sources were analyzed. For each source of type 2 CUP, tumors of the corresponding Tn N0-X M1 stage were used as controls. RESULTS: A total of 8505 patients with type 2 CUP were included in this analysis. Type 2 CUP shows an increasing trend, while type 1 shows the opposite. Type 2 CUPs have significant differences with stage IV of the same pathological primary lesion. Many characteristics influenced the prognosis of type 2 CUP patients, including marital status, age, race, sex, registration time, lymph node metastasis, surgery, chemotherapy, and radiation. CONCLUSION: Our study suggests that identifying the source of metastasis is the key to the selection of treatment and the determination of the prognosis for CUP.

Downregulation of long noncoding RNA SNHG1 inhibits cell proliferation, metastasis, and invasion by suppressing the Notch-1 signaling pathway in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) has become the fourth most lethal among human cancers. Long noncoding RNAs (lncRNAs) have been reported to play a role in the progression of a variety of cancers. However, the role of lncRNA SNHG1 in PC is not clear. METHODS: Real-time Quantitative PCR Detection System (qPCR) was used to detect the expression of SNHG1 in PC cells. Then, the SNHG1 knockdown cell was constructed with si-SNHG1. AsPC-1 and PANC1 cells were used to analyze the ability of cell proliferation, invasion, and migration. MTT assay was used to analyze the proliferation ability. Transwell experiments and wound healing experiments were used to detect the capacity of invasion and migration. Finally, Western blot analysis was used to explore the mechanism of SNHG1 in PC. RESULTS: SNHG1 was significantly upregulated in PC cells. Knockdown of SNHG1 could obviously suppress cell proliferation, invasion, and migration. Furthermore, SNHG1 knockdown inhibited the activation of the Notch-1 signaling pathway and inhibited the expression of N-cadherin, Hes1, Vimentin, Notch-1. The inhabitation was reversed when Notch-1 was overexpressed in si-SNHG1 cells. CONCLUSION: The lncRNA SNHG1 promotes cell growth and metastasis in PC through activation of the Notch-1 signaling pathway in PC.

SHCBP1 is a novel target and exhibits tumor­promoting effects in gastric cancer.

The present study investigated the expression and potential influence of SHC SH2 domain­binding protein 1 (SHCBP1) in gastric cancer (GC) cells. SHCBP1 is closely related to cell proliferation and cell cycle progression, but its role in GC remains unclear. The TCGA database revealed that SHCBP1 is highly expressed in GC tissues. Furthermore, SHCBP1 was revealed to be highly expressed in GC cell lines MGC­803 and SGC­7901 cells, and downregulation of SHCBP1 significantly inhibited GC cell proliferation. Furthermore, SHCBP1 expression promoted cell cycle progression and inhibition of apoptosis. Since the CDK4, cyclin D1 and caspase family proteins play important roles in cell cycle and apoptosis regulation, it was examined whether there was an association between SHCBP1 and these signaling pathways in GC. Our results revealed that SHCBP1 promoted cell cycle progression by regulating the CDK4­cyclin D1 cascade and suppressed caspase­3, caspase PARP­dependent apoptotic pathways. Cell invasion and metastasis experiments also revealed that SHCBP1 promoted tumor growth and invasiveness. These tumor­promoting functions of SHCBP1 may provide a potential molecular basis for the diagnosis and targeted therapy of GC.

Splenic Bed Laparoscopic Splenectomy Approach for Massive Splenomegaly Secondary to Portal Hypertension and Liver Cirrhosis.

This study was performed to evaluate the feasibility of the splenic bed laparoscopic splenectomy approach (SBLS) for massive splenomegaly (≥30 cm) in patients with hypersplenism secondary to portal hypertension and liver cirrhosis. Patients who underwent laparoscopic splenectomy (LS) from January 2012 to December 2016 were retrospectively reviewed. We performed LS in 83 patients with massive splenomegaly (≥30 cm) secondary to portal hypertension and liver cirrhosis. Of these patients, 37 underwent the SBLS and 46 underwent anterior LS (ALS). Five patients in the ALS group and none in the SBLS group underwent conversion to open surgery. The operation time, intraoperative blood loss volume, transfusion volume, frequency of transfusion, hemorrhage of short gastric vessels, conversion rate, postoperative hospital stay, and incidence of pancreatic fistula were all significantly lower in the SBLS than ALS group (all P < 0.05). No death or postoperative bleeding occurred in the two groups, and there were no significant differences in age, gender, spleen size, hemoglobin level, platelet count, prothrombin time, Child-Pugh class, hypoproteinemia, or ascites (all P > 0.05). The SBLS is more feasible and effective than ALS in patients with massive splenomegaly (≥30 cm) secondary to portal hypertension and liver cirrhosis.

Laparoscopic Liver Resection can be an Effective Way in Obese Patients: A Single Center of 2-Year Experience.

OBJECTIVE: To evaluate the feasibility and safety of laparoscopic liver resection in obese patients, we compared the operative outcomes between obese and nonobese patients, also between laparoscopic liver resection and open liver resection of obese and nonobese patients. MATERIALS AND METHODS: A total of 86 patients suffering from liver resection in our department from January 2013 to December 2014 were divided into 3 groups: the obese patients group for laparoscopic liver resection, the nonobese patients group for laparoscopic liver resection and the obese patients group for open liver resection. Characteristics and clinic data of 3 groups were studied. RESULTS: Characteristics of patients and clinic data were equivalent between the 3 groups. The groups were well matched in age, sex distribution, and liver function (P>0.05). There were no significant differences in the operative time, estimated blood loss, time to oral intake, and postoperative hospital stay in the 3 groups. Tumor diameter of laparoscopic liver resection groups in obese patients was smaller than open liver resections groups in obese patients (P<0.05), but there were no obvious difference of tumor diameter in the laparoscopic liver resection groups of the obese patients and the nonobese patients. CONCLUSIONS: Obesity should not be seen as a contraindication for laparoscopic liver resection, which is a safe and feasible procedure for obese patients.

Laparoscopic Splenectomy and Esophagogastric Devascularization for Liver Cirrhosis and Portal Hypertension Is a Safe, Effective, and Minimally Invasive Operation.

BACKGROUND: In the recent years, laparoscopic splenectomy and esophagogastric devascularization (LSD) for liver cirrhosis and portal hypertension rapidly gained the interest of hepatobiliary surgeons due to its minimal invasion. This study aimed to gather and analyze available data from the observational studies that have compared LSD and open splenectomy and esophagogastric devascularization (OSD) for liver cirrhosis and portal hypertension. MATERIALS AND METHODS: All the studies comparing LSD and OSD for liver cirrhosis and portal hypertension were searched on the available databases, including the Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database, and China Biomedical Database. Data were analyzed using Review Manager software version 5.0. RESULTS: After the literature search, a total of 17 studies were included in the meta-analysis, which involved 1093 patients: 552 in the laparoscopic group and 541 in the open group. The laparoscopic group was shown to have a lower overall postoperative complication rate (0.43; 95% confidence interval [CI; 0.29-0.64]) than the open group (P < .0001), which was not associated with heterogeneity between the studies. The laparoscopic group was shown to have a lower intraoperative blood loss (-320.62; 95% CI [-552.35 to -88.9]), shorter time of oral intake (-29.08 hours; 95% CI [-35.28 to -22.88]), and shorter hospital stay (95% CI [-6.19 to -2.19]) than those of the open group (P < .00001). The operative time of the laparoscopic group was 42.16 minutes longer (95% CI [32.20-52.11]) compared with the open group (P < .00001). There was no significant difference of hospitalization costs between the studies. CONCLUSION: This meta-analysis demonstrated that laparoscopic left lateral resection is a safe and feasible option associated with a reduced overall complication rate. The current evidence suggested that it could be performed routinely in liver centers.

YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells.

The expression of Yes-associated protein (YAP) has been reported to be dysregulated in pancreatic cancer. However, its contributions to tumor formation and progression remain to be elucidated. The present study demonstrated that YAP overexpression promoted the epithelial­mesenchymal transition (EMT) in a manner associated with pancreatic cancer invasion in vitro. RNA interference­mediated silencing of YAP attenuated cell invasion in vitro. Mechanistically, the present study demonstrated that YAP overexpression fosters pancreatic cancer progression by inducing the EMT in pancreatic cancer cells by activating the AKT cascade, which can counteract the effect of gemcitabine. These data suggested that the YAP acts synergistically to promote pancreatic cancer progression by hyperactivation of AKT signaling. The present study revealed YAP as a potential therapeutic target for pancreatic cancer and a biomarker for predicting gemcitabine treatment response.

Preparation of three-dimensional macroporous chitosan-gelatin B microspheres and HepG2-cell culture.

Chitosan-gelatin B microspheres with an open, interconnected, highly macroporous (100-200 µm) structure were prepared via a three-step protocol combining freeze-drying with an electrostatic and ionic cross-linking method. Saturated tripolyphosphate ethanol solution (85% ethanol) was chosen as the crosslinking agent to prevent destruction of the porous structure and to improve the biostability of the chitosan-gelatin B microspheres, with N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide/N-hydroxysuccinimide as a second crosslinking agent to react with gelatin A and fixed chitosan-gelatin B microspheres to attain improved biocompatibility. Water absorption of the three-dimensional macroporous chitosan-gelatin B microspheres (3D-P-CGMs) was 12.84, with a porosity of 85.45%. In vitro lysozyme degradation after 1, 3, 5, 7, 10, 14, and 21 days showed improved biodegradation in the 3D-P-CGMs. The morphology of human hepatoma cell lines (HepG2 cells) cultured on the 3D-P-CGMs was spherical, unlike that of cells cultured under traditional two-dimensional conditions. Scanning electron microscopy and paraffin sections were used to confirm the porous structure of the 3D-P-CGMs. HepG2 cells were able to migrate inside through the pore. Cell proliferation and levels of albumin and lactate dehydrogenase suggested that the 3D-P-CGMs could provide a larger specific surface area and an appropriate microenvironment for cell growth and survival. Hence, the 3D-P-CGMs are eminently suitable as macroporous scaffolds for cell cultures in tissue engineering and cell carrier studies. Copyright © 2014 John Wiley & Sons, Ltd.

Laparoscopic Versus Open Resection for Liver Cavernous Hemangioma: A Single Center of 2-Year Experience.

OBJECTIVE: To evaluate the feasibility and safety of laparoscopic versus open resection for liver cavernous hemangioma (LCH). MATERIALS AND METHODS: A total of 131 patients suffering from LCH operated in our department between January 2013 and December 2014 were divided into 2 groups: 31 for laparoscopic liver resection (LR) and 100 for open liver resection (OR). RESULTS: Age, sex, presence or absence of chronic liver disease, tumor size, tumor location, type of resection, estimated intraoperative blood loss, operative time, length of postoperative hospital stay, morbidity, and mortality were equivalent between the 2 groups. There were no significant differences in estimated intraoperative blood loss between the LR and OR groups. The operation time of the LR group was longer than the OR group and the hospitalization expenses less than the OR group. However, the time of postoperative hospital stay and time of oral intake were shorter in the LR group than the OR group. The tumor of the LR group was smaller than the OR group. In liver function, alanine aminotransferase after operation of the LR group was lower than the OR group, the same as aspartate transaminase after operation. But there were no significant differences in total bilirubin after operation. CONCLUSIONS: Laparoscopic resection for LCH is a safe and feasible procedure as OR.

Expression and clinical significance of HMGB1 in human liver cancer: Knockdown inhibits tumor growth and metastasis in vitro and in vivo.

The high-mobility group box 1 (HMGB1) signaling pathway plays a crucial role in tumorigenesis and progression of many malignant cancers. The present study aimed to investigate the expression and clinical significance of HMGB1 in human primary liver cancer, and further explore the molecular mechanisms of HMGB1 in tumor growth and metastasis. Forty cases of human liver cancer and normal liver tissues were collected. The expression of HMGB1 was assessed using RT-PCR and western blot assays in biopsy samples. The HMGB1 pathway in vitro was blocked using transfection of the recombinant small hairpin RNA adenovirus vector rAd5-HMGB1 into the human liver cancer cell line SMMC-7721. The expression of HMGB1, phosphorylated AKT (p-AKT), Ki-67 and matrix metallopeptidase-2 (MMP-2) was detected by Real-PCR and western blot assays. Cell proliferative activities and metastatic capability were determined by MTT and Transwell assays. Cell cycle distribution and apoptosis were detected by flow cytometry. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-HMGB1 on tumor growth in vivo. As a consequence, HMGB1 was found to be highly expressed in liver cancer compared with normal tissues, and was positively associated with pathological grade and distant metastases of liver cancer. Knockdown of HMGB1 downregulated the expression of p-AKT, Ki-67 and MMP-2, inhibited the proliferative activities and metastatic potential of SMMC-7721 cells, induced cell cycle arrest and apoptosis, and slowed the growth of xenograft tumors. Altogether, the expression of HMGB1 is closely correlated with pathological grade and distant metastases of liver cancer, and knockdown of HMGB1 inhibits liver cancer growth and metastasis, suggesting that HMGB1 may be involved in liver cancer development and progression through AKT-mediated regulation of Ki-67 and MMP-2 expression, and represent a potential therapeutic target for this aggressive malignancy.