WITHDRAWN: Individualized and pancreatic duct diameter-based strategy for pancreaticoenteric anastomosis during pancreaticoduodenectomy.

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Pure laparoscopic radical resection for type IIIa hilar cholangiocarcinoma.

BACKGROUND: Pure laparoscopic radical resection of hilar cholangiocarcinoma is still a challenging procedure, in which laparoscopic lymphadenectomy, hemihepatectomy with caudate lobectomy, and hepaticojejunostomy were included [1-4]. Relative report is rare in the world up to now. Hilar cholangiocarcinoma has a poor prognosis, especially when it occurs with lymph node metastasis or vessel invasion [5, 6]. We recently had a patient who underwent a pure laparoscopic extended right hepatectomy and lymph node dissection and hepaticojejunostomy for a type IIIa hilar cholangiocarcinoma. METHODS: The tumor was 20 × 15 × 12 mm in diameter and located in the right bile duct and common hepatic duct. Radiological examination showed that hepatic artery and portal vein was not invaded. After the division and mutilation of the right hepatic artery and the right portal vein, short hepatic veins were divided and cut off with clip and ultrasound knife from the anterior face of the vena cava. Mobilization was performed after the devascularization of the right liver, followed by the transection of liver parenchymal with CUSA and ultrasound knife. Finally, left hepatic bile duct jejunum Roux-en-Y reconstruction was performed. RESULTS: This patient underwent successfully with a totally laparoscopic procedure. An extended right hepatectomy (right hemihepatectomy combined with caudate lobectomy) and complete lymph node dissection and hepaticojejunostomy were performed in this operation. The operation time was nearly 590 min, and the intraoperative blood loss was about 300 ml. No obvious complication was observed and the postoperative hospital stay was 11 days. The final diagnosis of the hilar cholangiocarcinoma with no lymph node metastasis was pT2bN0M0 stage II (American Joint Committee on Cancer, AJCC). CONCLUSIONS: Pure laparoscopic resection for hilar cholangiocarcinoma was proved safe and feasible, which enabled the patient to recover early and have an opportunity to receive chemotherapy as soon as possible. We present a video of the described procedure.

Indocyanine green retention is a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients.

BACKGROUND: Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD. METHODS: From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child-Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively. RESULTS: Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020). CONCLUSIONS: ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress.

Chemotherapy drugs themselves may act as stressors to induce adaptive responses to promote the chemoresistance of cancer cells. Our previous research showed that sirtuin 1 (SIRT1) was overexpressed in pancreatic cancer patients and deregulation of SIRT1 with RNAi could enhance chemosensitivity. Thus, we hypothesized that SIRT1 might facilitate chemoresistance in pancreatic cancer cells through regulating the adaptive response to chemotherapy-induced stress. In the present study, SIRT1 in PANC-1, BXPC-3, and ASPC-1 cells was upregulated after treatment with gemcitabine. Moreover, the decrease in SIRT1 activity with special inhibitor EX527 had a synergic effect on chemotherapy with gemcitabine in PANC-1 and ASPC-1 cell lines, which significantly promoted apoptosis, senescence, and G0 /G1 cycle arrest. Western blot results also showed that SIRT1, acetylated-p53, FOXO3a, and p21 were upregulated after combined treatment, whereas no obvious change was evident in total p53 protein. To further confirm the role of SIRT1 in clinical chemotherapy, SIRT1 was detected in eight pancreatic cancer tissues acquired by endoscopy ultrasonography guided fine needle aspiration biopsy before and after chemotherapy. Compared to before chemotherapy, SIRT1 was significantly increased after treatment with gemcitabine in six cases. Thus, our results indicated a special role for SIRT1 in the regulation of adaptive response to chemotherapy-induced stress, which is involved in chemoresistance. Moreover, it indicates that blocking SIRT1 activity with targeting drugs might be a novel strategy to reverse the chemoresistance of pancreatic cancer.

Cordycepin down-regulates multiple drug resistant (MDR)/HIF-1α through regulating AMPK/mTORC1 signaling in GBC-SD gallbladder cancer cells.

Gallbladder cancer is the most common malignancy of the bile duct, with low 5-year survival rate and poor prognosis. Novel effective treatments are urgently needed for the therapy of this disease. Here, we showed that cordycepin, the bioactive compound in genus Cordyceps, induced growth inhibition and apoptosis in cultured gallbladder cancer cells (Mz-ChA-1, QBC939 and GBC-SD lines). We found that cordycepin inhibited mTOR complex 1 (mTORC1) activation and down-regulated multiple drug resistant (MDR)/hypoxia-inducible factor 1α (HIF-1α) expression through activating of AMP-activated protein kinase (AMPK) signaling in gallbladder cancer GBC-SD cells. Contrarily, AMPKα1-shRNA depletion dramatically inhibited cordycepin-induced molecular changes as well as GBC-SD cell apoptosis. Further, our results showed that co-treatment with a low concentration cordycepin could remarkably enhance the chemosensitivity of GBC-SD cells to gemcitabine and 5-fluorouracil (5-FU), and the mechanism may be attributed to AMPK activation and MDR degradation. In summary, cordycepin induces growth inhibition and apoptosis in gallbladder cancer cells via activating AMPK signaling. Cordycepin could be a promising new drug or chemo-adjuvant for gallbladder cancer.

[RAD001 reverses radio-resistance and exerts synergistic tumor inhibition with 5-fluorouracil].

OBJECTIVE: To explore the in vitro synergistic anti-tumor efficacy of mammalian target of rampamycin (mTOR) inhibitor (RAD001) and 5-fluorouracil (5-FU) for radio-resistant tumors. METHODS: Radio-resistant cells of human pancreatic cancer cell and human colon cancer cell were established. The expression profiles of VEGF (vascular endothelial growth factor) and TP (thymidine phosphorylase) were compared between parental and radio-resistant tumor cells. The tumor proliferation was analyzed after 5-FU alone or in combination with a mTOR inhibitor. RESULTS: After several cycles of radiation induction (3 Gy), the radio-resistant cells of human pancreatic cancer (AsPCres) and colon cancer (HT29res) were established. There was a higher expression of VEGF in radio-resistant tumor cells than their parental cells. They were 1215 ± 67 pg/ml in AsPCres and 689 ± 25 pg/ml in HT29res respectively (P < 0.01). The up-regulation of TP was observed in both AsPC-res and HT29-res. The combined therapy of 5-FU plus a mTOR inhibitor might exert synergistic tumor inhibition. CONCLUSION: RAD001 decreases the radiation-induced expression of VEGF in tumor. And the post-radiation up-regulation of TP promotes the efficacy of 5-FU. The combined therapy of RAD001 and 5-FU may inhibit synergistically the growth of radio-resistant tumors.

[Binding pancreatic duct to mucosa anastomosis].

OBJECTIVE: To study the feasibility of binding pancreatic duct to mucosa anastomosis (BDM)-a complementary procedure to both binding pancreaticojejunostomy and binding pancreaticogastrostomy. METHODS: (1) Animal experimental study:gastrostomy and jejunostomy were performed on six adult New Zealand rabbits. The gastrostomy and jejunostomy shared a same stent (rubber urethral catheter, silicone tube or plastic infusion tube). Both ends of the stent were placed in gastric and enteric cavity. Purse-string suture was performed around the stent before the jejunum and the stomach were brought together for fixation by few stitches. And to observe whether the purse-string suture around a plastic tube, rubber tube or silicon tube inserted into jejunum and/or stomach can prevent leaking out of the jejunal or gastric content to cause peritonitis. (2) Clinically 7 patients were performed with BDM anastomosis. The procedure was consisted of five steps: preparation of the pancreatic stump;preparation of the jejunum; preparation of the fixing sutures between the pancreatic stump and the jejunum; implementation of the anastomosis; lastly, fixation of the jejunum beside the pancreas stump. Post-operative periodic examination of the blood amylase and the amylase in the abdominal drainage. Pancreatic fistula was classified in to two categories: parenchymal fistula (pancreatic cut surface fistula) and anastomotic leakage. RESULTS: Animal experiment did not show any leakage around the plastic tube or silicon tube inserted into jejunum and(or) stomach. There was no anastomotic leak in all the patients. There was transient increase of amylase in two cases, but the volume of drainage did not exceed 50 ml/d and the recovery of the patients was not affected. CONCLUSIONS: BDM is a simple, safe and easy procedure to perform. It provides to the surgeons with a new option in different situations to achieve the most ideal surgical result.

Aptamers: an emerging navigation tool of therapeutic agents for targeted cancer therapy.

Chemotherapeutic agents have been used for the treatment of numerous cancers, but due to poor selectivity and severe systemic side effects, their clinical application is limited. Single-stranded DNA (ssDNA) or RNA aptamers could conjugate with highly toxic chemotherapy drugs, toxins, therapeutic RNAs or other molecules as novel aptamer-drug conjugates (ApDCs), which are capable of significantly improving the therapeutic efficacy and reducing the systemic toxicity of drugs and have great potential in clinics for targeted cancer therapy. In this review, we have comprehensively discussed and summarized the current advances in the screening approaches of aptamers for specific cancer biomarker targeting and development of the aptamer-drug conjugate strategy for targeted drug delivery. Moreover, considering the huge progress in artificial intelligence (AI) for protein and RNA structure predictions, automatic design of aptamers using deep/machine learning techniques could be a powerful approach for rapid and precise construction of biopharmaceutics (i.e., ApDCs) for application in cancer targeted therapy.

[Binding pancreaticogastrostomy].

OBJECTIVE: To discuss the value of a new technique of the binding pancreaticogastrostomy (BPG) in pancreaticoduodenectomy. METHODS: From May 2008 to October 2008, 15 patients were performed with BPG, included pancreatic head cancer in 7 cases, duodenal adenocarcinoma in 2 cases,mass-type chronic pancreatitis with pancreatolithiasis in 1 case, ampullary carcinoma in 1 case, gallbladder cancer in 1 case, islet cell tumor in 1 case and cholangiocarcinoma in 2 cases. The main procedures of BPG included: isolating remnant pancreas; slitting partial posterior wall of stomach and preplaced with seromuscular purse-string suture; cutting gastric anterior wall; performing pancreaticogastrostomy (binding of outer seromuscular and inner mucous layer of stomach). RESULTS: The procedures were successful in 15 patients. Postoperative complications included small amount of pleural effusion in 2 cases, delayed gastric emptying in 2 cases and bile leakage in 2 cases. All patients were cured in 2 weeks. No mortality and anastomosis leakage occurred. CONCLUSION: The application of BPG technique can prevent the anastomosis leakage and improve the safety for pancreaticoduodenectomy.

[A pancreas suture-less type II binding pancreaticogastrostomy].

OBJECTIVE: To explore the feasibility and safety of type II binding pancreaticogastrostomy (BPG) in pancreaticoduodenectomy and mid-segmentectomy of pancreas. METHODS: From November 2008 to May 2009, 26 patients underwent pancreaticoduodenectomy and mid-segmentectomy of pancreas with type II BPG reconstruction, including 13 cases of pancreatic head cancer, 3 cases of duodenal adenocarcinoma, 2 cases of ampullary carcinoma, 4 cases of cholangiocarcinoma, 1 case of bile duct cell severe atypical hyperplasia, and 1 case of stomach cancer. The process of type II BPG was described as the following: after pancreas remnant was mobilized for 2-3 cm, a piece of sero-muscular layer at the posterior gastric wall was excised and then a sero-muscular depth purse-suturing with 3-0 prolene was pre-placed (outer purse-string). Incising anterior gastric wall or opening part of the closed distal gastric stump, the mucosa layer at the sero-muscular defect was incised and then purse-suture at the mucosal tube was pre-placed (inner purse-string). Through the two pre-placed purse-strings, the pancreas remnant was pulled into the gastric lumen and then posterior gastric wall was pushed backward to keep it closely in contact with the retro-peritoneal wall. Thereafter, the outer purse-string was tied (outer binding) and then the inner purse-string was tied (inner binding). RESULTS: All cases underwent BPG of type II. The operative time ranged from 3 to 5.5 hours. The postoperative hospital stay ranged from 6 to 48 days. Postoperative complications included 1 case of ascites, 2 cases of delayed gastric emptying and 1 case of intra-abdominal bleeding. All cases with complications were cured after nonsurgical treatment. No mortality or pancreatic leakage occurred. CONCLUSIONS: Pancreaticogastrostomy is good for accommodating a large pancreas stump. Binding technique is very helpful in minimizing the leak rate of pancreaticogastrostomy. While type I BPG is safe and easy to perform, type II is even safer and easier to be done.

Novel insights into the role of aptamers in the fight against cancer.

PURPOSE: Aptamers are a class of single-stranded nucleic acid (DNA or RNA) oligonucleotides that are screened in vitro by a technique called systematic evolution of ligands by exponential enrichment (SELEX). They have stable three-dimensional structures that can bind to various targets with high affinity and specificity. Due to distinct properties such as easy synthesis, high stability, small size, low toxicity and immunogenicity, they have been largely studied as anticancer agents/tools. Consequently, aptamers are starting to play important roles in disease prevention, diagnosis and therapy. This review focuses on studies that evaluated the effect of aptamers on various aspects of cancer therapy. It also provides novel and unique insights into the role of aptamers on the fight against cancer. METHODS: We reviewed literatures about the role of aptamers against cancer from PUBMED databases in this article. RESULTS: Here, we summarized the role of aptamers on the fight against cancer in a unique point of view. Meanwhile, we presented novel ideas such as aptamer-pool-drug conjugates for the treatment of refractory cancers. CONCLUSIONS: Aptamers and antibodies should form a "coalition" against cancers to maximize their advantages and minimize disadvantages.

Rapid identification of specific DNA aptamers precisely targeting CD33 positive leukemia cells through a paired cell-based approach.

Aptamers are short single-stranded DNA or RNA molecules, which have recently been developed for potential broad applications such as clinical therapeutics, diagnosis and tumor-targeted drug delivery. However, the selection of specific aptamers is often unsatisfactory using the classical protein or cell-based SELEX. Herein, we modified the paired cell line approach to identify aptamers targeting leukemia cells expressing the CD33 antigen. Our strategy artfully used the same cells for negative (HEK293T cells) and positive (CD33 transfected-HEK293T cells) aptamer selections, and the negative selections were performed adequately before the positive selection to remove unspecific sequences. The advantages of this strategy are that it is fast and accurate, where only a few rounds of selection together with PCR amplifications are sufficient to obtain high binding affinity antigen-targeted aptamers. By using our modified approach, we successfully obtained the CD33-targeting aptamer S30, which could highly recognize the C2 domain of the CD33 antigen in vitro and in vivo. Moreover, the optimized aptamer S30-T1 (i.e., core region of S30) was conjugated with doxorubicin (Dox) to synthesize S30-T1-Dox conjugates, which could specifically inhibit CD33 positive acute myeloid leukemia HL-60 cell proliferation by arresting the cell cycle at the G2 phase. Thus, our modified approach can rapidly screen reliable, stable and high binding affinity aptamers for precise cancer treatment.

Better surgical treatment method for hepatocellular carcinoma with portal vein tumor thrombus.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is a disease that is not uncommon, but the treatments vary drastically between Eastern and Western countries. In Europe and America, the first line of treatment is systemic therapy such as sorafenib and the surgical treatment is not a recommend option. While an increasing number of studies from China and Japan have suggested that surgical treatment results in better outcomes when compared to transcatheter arterial chemoembolization (TACE), sorafenib, or other nonsurgical treatments, and two classification systems, Japanese Vp classification and Chinese Cheng's classification, were very useful to guide the surgical treatment. We have also found that surgical treatment may be more effective, as we have performed surgical treatment for HCC-PVTT patients over a period of approximately 15 years and achieved good results with the longest surviving time being 13 years and onward. In this study, we review the efficacy and principles of current surgical treatments and introduce our new, more effective surgical technique named "thrombectomy first", which means the tumor thrombus in the main portal vein, the bifurcation or the contralateral portal vein should be removed prior to liver resection. Thus, compression and crushing of PVTT during the operation could be avoided and new intrahepatic metastases caused by tumor thrombus to the remnant liver minimized. The new technique is even beneficial to the prognosis of Cheng's classification Types III and IV PVTT. The vital tips and tricks for the surgical approach are described.

[Laparoscopic splenectomy and pericardial devascularization for treatment of portal hypertension due to liver cirrhosis].

OBJECTIVE: To evaluate the safety and efficacy of laparoscopic splenectomy (LS) and pericardial devascularization in treatment of portal hypertension due to liver cirrhosis. METHODS: Twenty three cases with hepatitis B and schistosoma cirrhosis and portal hypertension underwent LS and paraesophagogastric devascularization performed by one treatment team. Follow-up was conducted for 9 months. RESULTS: LS combined with pericardial devascularization was successfully performed on these 20 cases. Three cases were converted to open surgery due to intra-operative bleeding. The mean operative time was 235 min (180 - 350), and mean intra-operative blood loss was 520 ml (200 - 1600 ml). All patients were treated with plasma transfusion, antibiotics, and abdominal drainage post-operatively. Peristalsis of stomach and intestine recovered 24 - 72 hours after operation. The mean hospitalization time was 8.5 days (6 - 17 days). The peri-operative complication included plural effusion in 3 cases and subphrenic abscess in one case, .mild ascites in two cases, and wound dehiscence in one case. No mortality occurred. Rebleeding rare was 0%. CONCLUSION: LS combined with pericardial devascularization is relatively safe and effective in treatment of portal hypertension due to liver cirrhosis. The keys to success include experienced laparoscopic skills, use of harmonic scalpel and careful manipulation.

[Comparison of laparoscopic cholecystectomy combined with intraoperative endoscopic sphincterotomy and combined with laparoscopic common bile duct exploration in treatment of: cholelithiasis and calculus of common bile duct].

OBJECTIVE: To explore the best mini-invasive treatment for cholelithiasis and calculus of common bile duct. METHODS: 275 patients diagnosed as with cholelithiasis and choledocholithiasis were divided randomly into 2 groups: laparoscopic cholecystectomy (LC) combined with intraoperative endoscopic sphincterotomy (IOEST) and laparoscopic exploration of the common bile duct (LCBDE) LC- LCBDE group, n = 146), and LC combined with intraoperative endoscopic sphincterotomy (IOEST) (LC-IOEST group, n = 129). The surgical time, surgical successful rate, stone number, complication rate, residual common bile duct stone rate, postoperative hospital stay, and hospitalization cost were compared. RESULTS: No difference was found between these two groups in terms of the surgical time, surgical successful rate, the stone number, complication rate, residual common bile duct stone rate, postoperative hospital stay, and hospitalization cost. CONCLUSION: LC-IOEST and LC-LCBDE are both effective minimally invasive treatments for cholelithiasis and calculus of common bile duct.

[Mesenchymal stem cells inhibit the expression of CD25 on phytohaemagglutinin-activated lymphocytes].

OBJECTIVE: To investigate the regulatory effects of rat mesenchymal stem cell (MSC) on T lymphocyte proliferation by examining the early activated markers such as CD25 and CD69. METHODS: MSC had been isolated and expanded in vitro. Then it was identified by cell morphology, membrane phenotype, and differentiation potential. Nylon wool column was applied to purify T-lymphocytes. MSCs and T-lymphocytes were cultured together and were stimulated by phytohaemagglutinin (PHA), and then the expressions of CD25 and CD69 were assessed. The levels of TGF-beta1 and IL-10 in the supernatants of MSC cultures were detected by using ELISA. RESULTS: (1) The expression of CD25 is suppressed in a dose-dependent manner when the T-lymphocytes are co-cultured with 10,000 MSCs or more, while 100 MSCs have no detectable effect; (2) The suppression of CD25 can be lasted more than 96 hrs; (3) The down regulation of CD25 is mediated by some soluble factors; (4) The reduced expression of CD25 caused by MSC inhibition is not mediated by TGF-beta1 and IL-10. CONCLUSION: MSCs have significant immune regulatory effects on PHA-stimulated T-lymphocyte culture. It might provide a remarkable immune suppression in organ-transplantation to achieve better outcome in the near future.

[Role of pancreatic hilar vascular occlusion in sophisticated pancreaticoduodenectomy].

OBJECTIVE: To discuss the value of a simple occlusive technique of the triple vessels, ie, portal vein, superior mesenteric vessels and splenic vein, in complicated pancreaticoduodenectomy. METHODS: The technique was fulfilled with a No.8 urethral catheter to encycle the portal vein, superior mesenteric vessels and its near tissue plus pancreatic tail and splenic vein than the neck of pancreas was transected and well exposure superior mesenteric vein and complete transaction of uncinate. From November 2005 to November 2006 the technique was applied to 12 cases of pancreatic malignancy which presented very infiltrated and adhesive to the hilar vascular structure. RESULTS: The 12 cases were accomplished according with this technique. The operating time was (292.4 +/- 36.3) min (270 - 390 min) and the intraoperative blood loss was (833.3 +/- 618.4) ml (300 - 2500 ml). The postoperative complication included one case of lymphatic leakage, two cases of pneumonia, one case of abdominal infection and two cases of wound infection. There was no perioperative mortality. The postoperative hospital stay was 17 d (11 - 29 d). CONCLUSIONS: Use this triple vessels occlusive technique can improve the safety and feasibility in complicated cases of pancreaticoduodenectomy.