Hydroxyphenylpyruvate Dioxygenase Is a Metabolic Immune Checkpoint for UTX-deficient Colorectal Cancer.

BACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood. METHODS: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed time of flight mass cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs. RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid by hydroxyphenylpyruvate dioxygenase. Homogentisic acid modified protein inhibitor of activated STAT3 via carbonylation of Cys 176, and relieved the inhibitory effect of protein inhibitor of activated STAT3 on signal transducer and activator of transcription 5 transcriptional activity. This in turn, promoted MDSC survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits. CONCLUSIONS: Collectively, these findings highlight hydroxyphenylpyruvate dioxygenase as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.

Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

Discovery of extracellular vesicle-delivered miR-185-5p in the plasma of patients as an indicator for advanced adenoma and colorectal cancer.

BACKGROUND: We aimed to evaluate whether extracellular vesicles (EV)-derived microRNAs (miRNAs) can be used as biomarkers for advanced adenoma (AA) and colorectal cancer (CRC). METHODS: We detected the changes in the plasma EV-delivered miRNA profiles in healthy donor (HD), AA patient, and I-II stage CRC patient groups using miRNA deep sequencing assay. We performed the TaqMan miRNA assay using 173 plasma samples (two independent cohorts) from HDs, AA patients, and CRC patients to identify the candidate miRNA(s). The accuracy of candidate miRNA(s) in diagnosing AA and CRC was determined using the area under the receiver-operating characteristic curve (AUC) values. Logistic regression analysis was performed to evaluate the association of candidate miRNA(s) as an independent factor for the diagnosis of AA and CRC. The role of candidate miRNA(s) in the malignant progression of CRC was explored using functional assays. RESULTS: We screened and identified four prospective EV-delivered miRNAs, including miR-185-5p, which were significantly upregulated or downregulated in AA vs. HD and CRC vs. AA groups. In two independent cohorts, miR-185-5p was the best potential biomarker with the AUCs of 0.737 (Cohort I) and 0.720 (Cohort II) for AA vs. HD diagnosis, 0.887 (Cohort I) and 0.803 (Cohort II) for CRC vs. HD diagnosis, and 0.700 (Cohort I) and 0.631 (Cohort II) for CRC vs. AA diagnosis. Finally, we demonstrated that the upregulated expression of miR-185-5p promoted the malignant progression of CRC. CONCLUSION: EV-delivered miR-185-5p in the plasma of patients is a promising diagnostic biomarker for colorectal AA and CRC. Trial registration The study protocol was approved by the Ethics Committee of Changzheng Hospital, Naval Medical University, China (Ethics No. 2022SL005, Registration No. of China Clinical Trial Registration Center: ChiCTR220061592).

Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain-containing protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.

Body Composition and Response and Outcome of Neoadjuvant Treatment for Pancreatic Cancer.

To assess the correlation of body composition with the response and outcome of neoadjuvant treatment (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). One hundred and nineteen PDAC patients underwent curative resection after NAT. Computed tomography scans of the third lumbar vertebra were used to assess the body composition of these patients before and after NAT. Three distinct wasting phenotypes were identified during NAT, with 51 patients (42.9%) developing muscle and fat wasting (MFW), 17 patients (14.3%) developing fat-only wasting (FW), and 51 patients (42.9%) having no wasting (NW). The response rate was higher in the NW phenotype than in the MFW and FW phenotypes (P = 0.007). In univariate and multivariate analyses, histological grade, sarcopenia before NAT, and MFW during NAT were associated with decreased overall survival (OS). Sarcopenia before NAT and MFW during NAT were associated with decreased disease-free survival (DFS). Body composition was associated with the response and outcome of patients undergoing NAT for PDAC. The response rate was higher in patients having NW during NAT. Sarcopenia before NAT and MFW during NAT were associated with decreased OS and DFS.

Short-Term Outcomes of Tri-Staple Versus Universal Staple in Laparoscopic Anterior Resection of Rectal and Distal Sigmoid Colonic Cancer: A Matched-Pair Analysis.

BACKGROUND: Anastomotic leakage is a serious complication in laparoscopic colorectal surgeries. To resolve this problem, a new stapling technology (Tri-staple) is developed. In this study, we aim to compare the short-term outcomes of Tri-staple versus Universal staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer. METHODS: A total of 446 patients were admitted to our hospital and received laparoscopic anterior resection for rectal and distal sigmoid colonic cancer between January 2016 and December 2020. Among them, Tri-staples were used in 202 patients, and the Universal staples were used in 244 patients. Propensity score matching was performed, followed by a comparison between the two groups (Tri-staple vs. Universal staple) in the incidences of anastomotic leakage, bleeding, and reoperation. RESULTS: In total, 270 patients were included in this retrospective cohort study by the propensity score matching, with each group having 135 patients. Tri-staple group had a significant lower incidence of anastomotic leakage compared with the Universal staple group (4.44% vs. 11.11%, P < 0.05). The reoperation rate was also lower in Tri-staple group than the Universal staple group (3.70% vs. 8.15%, P < 0.05). The anastomotic bleeding rates, average postoperative hospital stay, average drain indwelling period, and average fasting period had no statistical differences between the two groups. CONCLUSION: The usage of Tri-staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer is associated with lower postoperative complications compared with Universal staple. Future high-quality randomized controlled trials are needed to confirm our findings.

Genomic methylation variations predict the susceptibility of six chemotherapy related adverse effects and cancer development for Chinese colorectal cancer patients.

Colorectal cancer (CRC) remains a major concern with high morbidity and mortality worldwide. Despite the positive influence of chemotherapy on the decline in CRC mortality, the negative influence of chemotherapy-related adverse effects (CRAEs) caused by capecitabine (Cap) remains a challenging problem. DNA methylation alteration plays a pivotal role in gene expression regulation. Here, we aimed to screen reliable and novel biomarkers for CRC diagnosis and CRAE prediction using the advanced Illumina Infinium MethylationEPIC (850 K) BeadChip. Paired tumor and normal tissues from 21 Chinese CRC patients who received Cap-based adjuvant chemotherapy were analyzed. CRC-related methylation was characterized by hypermethylated promoter islands and hypomethylated intragenic openseas; CRAE-related methylation was characterized by hyper- (or hypo-) methylated intragenic (or intergenic) regions. Based on three types of methylation profiles (differentially methylated probes, differentially methylated regions, and gene-function-differentially methylated regions), pathway enrichment analyses revealed that CRC-related genes were significantly enriched in the neuronal system, metabolism of RNA, and extracellular matrix organization; CRAE-related genes were abundantly enriched in pathways controlling regeneration functions and immune response. Finally, based on genes within the mostly related pathways and LASSO logistic regression selection, the integrated-methylation-marker systems developed here demonstrated high discriminative accuracy in both CRC diagnosis (AUROC = 1) and CRAE prediction (AUROC = 0.817-1). In conclusion, we conducted a comprehensive DNA methylation analysis of CRC patients with chemotherapy, which provided new insights into the formation of CRC and CRAEs. Most importantly, our findings identified potentially CRAE-related metabolic pathways and markers, providing a valuable reference for personalized medicine promising better safety. Trail registration:ClinicalTrials.gov,NCT03030508, Registered 25 January 2017,https://www.clinicaltrials.gov/ct2/show/NCT03030508?term=NCT03030508&draw=2&rank=1.

Identification of hub genes and construction of transcriptional regulatory network for the progression of colon adenocarcinoma hub genes and TF regulatory network of colon adenocarcinoma.

The aim of this study was to identify key genes related to the progression of colon adenocarcinoma (COAD), and to investigate the regulatory network of hub genes and transcription factors (TFs). Dataset GSE20916 including 44 normal colon, 55 adenoma, and 36 adenocarcinoma tissue samples was used to construct co-expression networks via weighted gene co-expression network. Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for the objective module were performed using the online Database for Annotation, Visualization and Integrated Discovery. Hub genes were identified by taking the intersection of differentially expressed genes between dataset GSE20916 and GSE39582 and validated using The Cancer Genome Atlas (TCGA) database. The correlations between microRNA (miRNA) and hub genes were analyzed using the online website StarBase. Cytoscape was used to establish a regulatory network of TF-miRNA-target gene. We found that the orange module was a key module related to the tumor progression in COAD. In datasets GSE20916 and GSE39582, a total of eight genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) were selected, which were closely related with patients' survivals in TCGA database and dataset GSE20916. COAD patients with higher expressions of each hub gene had a worse prognosis than those with lower expressions. A regulatory network of TF-miRNA-target gene with 144 TFs, 26 miRNAs, and 7 hub genes was established, including model KLF11-miR149-BGN, TCEAL6-miR29B2-COL1A1, and TCEAL6-miR29B2-COL1A2. In conclusion, during the progression of COAD, eight core genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) play vital roles. Regulatory networks of TF-miRNA-target gene can help to understand the disease progression and optimize treatment strategy.

Gut microbiota dysbiosis signature is associated with the colorectal carcinogenesis sequence and improves the diagnosis of colorectal lesions.

BACKGROUND AND AIM: The gut microbiota is associated with colorectal lesions in cases of precancer and colorectal cancer (CRC). However, there are apparent differences in studies on the gut microbiota in the pathogenic sequence from precancer to cancer. Here, we characterize the gut microbiota signatures of colorectal precancer and cancer and test their utility in detecting colorectal lesions in two independent Chinese cohorts. METHODS: Stool samples collected from patients with precancer and CRC were subjected to 16S ribosomal RNA gene sequencing and metagenomic shotgun sequencing analyses, which revealed the microbial signatures of the two disease stages. RESULTS: In comparison with healthy controls, lower microbial richness and diversity were observed in precancer and intensive interbacterial associations were found in CRC. We identified 41 bacteria that showed gradual increases while 12 bacteria showed gradual decreases at the genus level gradually during the development of CRC. Novel CRC-associated pathogenetic species were identified. Species units that contributed to altered microbial functions were identified in CRC patients and healthy controls. The microbial panel showed a comparable ability to fecal immunochemical test (FIT) in detecting CRC. However, the combination of microbes and FIT significantly improved the detection ability and sensitivity of colon lesions based on 18 genera. Microbial network analysis revealed a significant positive correlation among beneficial microbes and a negative correlation in detrimental phenotypes. CONCLUSIONS: Microbial dysbiosis was revealed in colorectal lesions. The combination of microbial markers and FIT improved the CRC detection ability, which might assist in the early diagnosis of CRC.

Surgical Resection for Metastatic Tumors in the Pancreas: A Single-Center Experience and Systematic Review.

BACKGROUND: Metastatic lesion to the pancreas accounts for approximately 2% of pancreatic neoplasms. There is no prospective, randomized or case-controlled study evaluating the role of pancreatic metastasectomy. METHODS: The PubMed, EMBASE, and Cochrane Library electronic databases were searched for studies published between January 1, 2001 and December 31, 2017. Studies with five or more patients who received pancreatic metastasectomy and data from our institution (29 patients) were included. The Kaplan-Meier method was used for survival analysis. RESULTS: A total of 414 patients from 20 institutions who underwent pancreatic resections were included. Of the reported 31 kinds of primary neoplasms, renal-cell carcinoma (RCC) comprised the most (54.3%). At the time of diagnosis, although 40.3% patients were asymptomatic, abdominal pain (34.8%) and jaundice (20.6%) were relatively common. As for surgical type, pancreatoduodenectomy, total pancreatectomy, distal pancreatectomy, and enucleation took up 37.9%, 11.4%, 43.5%, and 7.2% respectively. The mortality and morbidity rates were 1.4% and 48.3% respectively. Patients with symptoms at the time of diagnosis had significantly shorter survival compared with asymptomatic patients (p = 0.017). Those with RCC as primary tumor had significantly longer survival compared with non-RCC patients (p < 0.001). Positive margin also predicts worse prognosis (p = 0.035). CONCLUSIONS: Pancreatic metastasectomy is safe and associated with acceptable short- and intermediate-term results. In the conditions of RCC as the primary tumor, being asymptomatic, or negative resection margin, a better prognosis after resection can be achieved.

Laparoscopic-Assisted Modified Intersphincter Resection for Ultralow Rectal Cancer.

BACKGROUND: Intersphincter resection (ISR) is considered to be a superior technique offering sphincter preservation in patients with ultralow rectal cancer.1 Because high-definition laparoscopy offers wider and clearer vision into the narrow pelvic cavity and intersphincteric space, ISR has been further refined.2 However, functional outcome after ISR has not been optimal. More than half of patients receiving ISR suffer partial or even complete anal incontinence.3 We therefore propose a laparoscopic-assisted modified ISR, with the aim of improving sphincter function following ISR. METHODS: The video describes the technique for performing such laparoscopic-assisted modified ISR in a 62-year-old woman with ultralow rectal cancer (3 cm from anal verge). Preoperative staging by endorectal ultrasound and pelvic magnetic resonance imaging revealed stage I rectal cancer (cT2N0M0). The operation consisted of an abdominal and a perineal phase. The abdominal phase routinely involved colonic mobilization with high ligation of inferior mesenteric vessels, total mesorectal excision (TME), as well as transabdominal intersphincteric dissection. The procedure for laparoscopic TME was performed according to our published method.4 Along the TME dissection plane, the puborectalis could be reached and the intersphincteric space was entered posterolaterally. The hiatal ligament at the posterior side of the rectum was transected afterwards. The dissection of the intersphincteric space was continued caudally at the anterior side of the rectum. The distal bowel wall was mobilized for 2 cm from the lower edge of the tumor to obtain adequate distal margin. At this point, circular dissection of the intersphincteric space was completed. After the abdominal phase, perineal dissection was performed with wide exposure by use of a hooked self-retaining retractor. The lower margin of the tumor was identified under direct vision. We developed a modified ISR technique. Resection of the mucosa and internal sphincter was initiated 2 cm distal to the lower edge of the tumor at the tumor side to obtain the necessary distal margin. Meanwhile, at the opposite side of the tumor, the resection line was just above the dentate line so that partial dentate line could be preserved. After removal of the specimen en bloc per anus, the pelvic cavity was generously irrigated with diluted povidone iodine solutions. The distal margin of the specimen was then examined by frozen section for presence of cancer. If clear, coloanal anastomosis was performed using a handsewn technique. The colon was rotated 90° and anastomosed to the anal canal with interrupted absorbable 3-0 sutures. Finally, a pelvic suction drain was placed, and a temporary diverting stoma made in the terminal ileum. RESULTS: There were no intraoperative complications. The operating time was 180 min. Blood loss was 50 mL. The distal margin was clear, and the final pathology was pT2N0M0. The patient underwent an uneventful recovery. She began sphincter-strengthening exercises 2 weeks after surgery. The stoma was closed after examinations 3 months later. No local recurrence or distant metastasis was found. At 12-month follow-up, in terms of sphincteric function, the patient was continent to solids, liquids, and flatus. CONCLUSIONS: Laparoscopic-assisted modified intersphincter resection for ultralow rectal cancer is safe and feasible. This technique should be considered whenever possible as a means to offer sphincter preservation and improve sphincter function in patients with ultralow rectal cancer.

Negative lymph node count is an independent prognostic factor for patients with rectal cancer who received preoperative radiotherapy.

BACKGROUND: Negative lymph node (NLN) count has been reported to provide more accurate prognostic information than the N stage alone in patients with rectal cancer (RC). Since preoperative radiotherapy (Pre-RT) can significantly affect the LN status, it is unclear whether NLN count still has prognostic value count on survival of patients with RC who received Pre-RT. METHODS: In this study, clinicopathological characteristics, number of positive LNs and survival time were collected from Surveillance, Epidemiology, and End Results Program (SEER)-registered RC patients. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors for survival. RESULTS: X-tile plots identified 9 (P < 0.001) as the optimal cutoff NLN value to divide the patients into high and low risk subsets in terms of cause specific survival (CSS). NLN count was validated as independently prognostic factor in univariate and multivariate analysis (P < 0.001). Subgroup analysis showed that NLN count was an independently prognostic factor for patients with stage ypII (P = 0.002) and ypIII (P < 0.001). CONCLUSIONS: Our results firmly demonstrated that NLN count provides accurate prognostic information for RC patients with Pre-RT.

Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation.

BACKGROUND: Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Reactive oxygen species (ROS) plays a key role in the chemosensitivity of cancer cells. In the present study, emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells. METHODS: Cell viability and apoptosis rate of different treatment groups were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM). The expression of transporters was measured at both the transcription and translation levels using PCR and western blotting. In vitro findings were confirmed by in vivo experiments using tumor-bearing mice. The expression of multidrug resistance-associated protein 1 (MRP1) in tumour tissue was measured using immunohistochemistry and side effects of the emodin/cisplatin co-treatment were investigated by histological examination. RESULTS: Emodin increased the cellular ROS level and effectively enhanced the cisplatin-induced cytotoxicity of T24 and J82 human bladder cancer cells through decreasing glutathione-cisplatin (GSH-cisplatin) conjugates. It blocked the chemoresistance of T24 and J82 cells to cisplatin through suppressing the expression of MRP1. This effect was specific in T24 and J82 cells but not in HCV-29 normal bladder epithelial cells. Consistent with in vitro experiments, emodin/cisplatin co-treatment increased the cell apoptosis and repressed the MRP1 expression in xenograft tumors, and without obvious systemic toxicity. CONCLUSIONS: This study revealed that emodin could increase the cisplatin-induced cytotoxicity against T24 and J82 cells via elevating the cellular ROS level and downregulating MRP1 expression. We suggest that emodin could serve as an effective adjuvant agent for the cisplatin-based chemotherapy of bladder cancer.

Nerve-guided laparoscopic total mesorectal excision for distal rectal cancer.

BACKGROUND: Urogenital dysfunctions are well-recognized problems after rectal cancer surgery and are often due to autonomic nerve damage. Although following holy planes during total mesorectal excision (TME) reduces the possibility of damage to the autonomic nerve fibers, these could still be affected in some critical areas.1 (,) 2 To improve the quality of surgery and prevent nerve damage, accurate intraoperative anatomical orientation of autonomic nerve is essential.3 Thanks to advancement of the high-definition laparoscopic technology, even the finest nerve fibers deep in the pelvic cavity can be identified through illumination and magnification.4 We aim to present a surgical technique of using the autonomic nerves as landmarks to guide laparoscopic TME for distal rectal cancer, with the purpose of preventing autonomic nerve damage to the largest extent. METHODS: The video describes the technique of performing nerve-guided laparoscopic TME in a 50-year-old man with a rectal cancer (7 cm from anal verge). Preoperative staging by endorectal ultrasound and pelvic magnetic resonance imaging is stage I rectal cancer (cT2N0M0). Five trocars (two 12 mm and three 5 mm) are used. All procedures are performed with conventional laparoscopic instruments. The sigmoid colon is mobilized using a medial approach. The superior hypogastric plexus lies just posterior to the inferior mesenteric artery (IMA) are clearly identified and protected. Then the root of the IMA is ligated and cut. The left Toldt space is dissected, followed by complete mobilization of the sigmoid colon. The superior hypogastric plexus nerve fibers combine to a strong pair of hypogastric nerves as they enter the pelvic cavity, and can be clearly identified when the mesorectum is lifted. Then the mesorectum is separated from the hypogastric nerves by sliding down along the nerves. Dissection of the mesorectum is continued in the loose areolar plane along the midline down to the sacrococcygeal junction. Then the mesorectum is dissected laterally from posterior midline up to 9 o'clock on the left and to 3 o'clock on the right side. The splanchnic nerves can be identified as they swing from the sacrum and straight into the pelvic plexus. The peritoneum is dissected in an arc line about 0.5 cm above the line of rectovesical pouch. After the anterior side of the rectum is mobilized, the mesorectum is dissected along the seminal vesicles downward and sideward to the lateral margin. The neurovascular bundle of Walsh at the anterolateral side of the rectum is clearly identified and protected. The mobilization of the mesorectum ceases at the tendinous arch of levator ani. Then the rectum is only fixed to the pelvic side wall by its lateral ligaments, which are consisted by rectal branch of the inferior pelvic plexus and vessels. Thus care should be taken to cut only those rectal nerve fibers, leaving the inferior pelvic plexus intact. The mesorectum is divided 5 cm distal to the lesion with one firing of an endoscopic stapler. The specimen is extracted through a 3 cm transumbilical laparotomy. End-to-end anastomosis using a circular stapler is performed intra-abdominally. RESULTS: There were no intraoperative complications. The operating time was 160 min. Blood loss was 20 mL. The patient underwent an uneventful recovery and was discharged home on postoperative day 6. Final pathology was pT2N0M0. At 6-month follow-up, the patient had no urogenital dysfunctions. CONCLUSIONS: Nerve-guided laparoscopic total mesorectal excision for distal rectal cancer is safe and feasible. This technique should be considered whenever possible as a means to prevent autonomic nerve damage and subsequent loss of urogenital function.

Short- and long-term outcomes of LigaSure versus conventional surgery for curative gastric cancer resection: a matched pair analysis.

BACKGROUND: The LigaSure vessel sealing system allows dissection and hemostasis in a safe and quick way, and it has been reported to be an effective tool to shorten operative time and reduce intraoperative blood loss for various surgeries. However, short- and long-term outcomes in comparison with conventional surgery for gastric cancer resection are limited. METHODS: Between January 2005 and December 2009, 121 patients underwent curative resection for gastric cancer with LigaSure. Perioperative and long-term results were compared with those of 242 matched patients who received curative resection for gastric cancer with the conventional technique. Immediate operation outcomes, operation morbidity, recurrence and survival were compared between groups. RESULTS: In the LigaSure group compared with the conventional group, operation time was 156 versus 183 min (P < 0.0001), intraoperative blood loss was 181 versus 236 ml (P = 0.042), intraoperative blood transfusion was 68 versus 161 ml (P = 0.014), and hospital stay was 11.9 versus 13.6 days (P = 0.001). There were no differences in operation morbidity, recurrence rates, overall and disease-free survival between the LigaSure and conventional groups. CONCLUSIONS: LigaSure is associated with shorter operation time and hospital stay, less blood loss and transfusion, and comparable operation morbidity and long-term outcomes in comparison with conventional surgery for curative gastric cancer resection.

Preoperative oral carbohydrate improved postoperative insulin resistance in rats through the PI3K/AKT/mTOR pathway.

BACKGROUND: Preoperative oral carbohydrate (OCH) improves postoperative insulin resistance (PIR) and insulin sensitivity. However, the exact mechanisms involved in the improvement of PIR with respect to preoperative OCH are still not clear. The aim of this study was to investigate the involvement of preoperative OCH and PI3K/AKT/mTOR pathway in reducing PIR in rats. MATERIAL AND METHODS: Forty male Sprague-Dawley rats were randomly assigned to PreOp, glucose, saline, and fasting groups. Rats in the PreOp, glucose, and saline groups received OCH, 5% glucose solution, and saline, respectively. Rats in the fasting group did not receive anything but were fasted 3 h before surgery. Blood glucose, insulin and leucine levels, and insulin resistance, secretion, and sensitivity indexes were measured before and after surgery. mRNA and protein (total and phosphorylated) levels of mTOR, IRS-1, PI3K, PKB/AKT, and GlUT4 were measured using real-time polymerase chain reaction and Western blot in skeletal muscles. RESULTS: In the PIR experiment, blood glucose, serum insulin, insulin resistance, and serum leucine levels were all significantly lower in the PreOp group than in the other 3 groups (P<0.05) after surgery. HOMA-ISI were higher in the PreOp group vs the other 3 groups after surgery (P<0.05), and HOMA-b in the PreOp group was higher than that in the other 3 groups at 30 and 120 min after surgery. Additionally, post-operative phosphorylated IRS-1, PI3K, and AKT protein levels were significantly higher in the PreOp group than in the other 3 groups (P<0.05), but no significant differences were observed in their respective protein levels (P>0.05). CONCLUSIONS: OCH decreases postoperative insulin resistance and improves postoperative insulin sensitivity in skeletal muscles through the PI3K/AKT/mTOR pathway.

Systematic review and meta-analysis of somatostatin analogues in the prevention of postoperative complication after pancreaticoduodenectomy.

BACKGROUND: The use of somatostatin analogues (SAs) following pancreaticoduodenectomy (PD) is controversial. METHOD: Literature databases were searched systematically for relevant articles. A meta-analysis of all randomized controlled trials (RCTs) evaluating prophylactic SAs in PD was performed. RESULTS: Fifteen RCTs involving 1,352 patients were included. There was a towards reduced incidences of pancreatic fistulas (p = 0.26), clinically significant pancreatic fistulas (p = 0.08), and bleeding (p = 0.05) in prophylactic SAs group. In subgroup analyses, prophylactic somatostatin significantly reduced the incidence of pancreatic fistulas(p = 0.02), with a nonsignificant trend toward reduced incidence of clinically significantly pancreatic fistulas (p = 0.06).Pasireotide significantly reduced the incidence of clinically significantly pancreatic fistulas (p = 0.03). Octreotide had no influence on the incidence of pancreatic fistulas. CONCLUSION: The current best evidence suggests prophylactic treatment with somatostatin or pasireotide has a potential role in reducing the incidence of pancreatic fistulas, while octreotide had no influence on the incidence of pancreatic fistulas.High-quality RCTs assessing the role of somatostatin and pasireotide are required for further verification.

A simple, secure and universal two-layer continuous running suture pancreaticojejunostomy following pancreaticoduodenectomy.

Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy. We introduce here a simple, secure and universal technique for pancreaticojejunostomy with a two-layer continuous running suture. We also report on the preliminary results for grades of pancreatic fistulas among patients who underwent this new technique. 51 consecutive cases were successfully performed using this new technique during pancreaticoduodenectomy. The overall morbidity was 29.4%. Only 3 (5.9%) grade B pancreatic fistulas were observed postoperatively, and were successfully treated with conservative management. The time taken to create the pancreatic anastomosis was less than 15 minutes in all cases. In conclusion, this novel pancreatic anastomosis technique is easy and quick to perform, universally applicable, and appears to be a secure technique that reduces pancreatic fistula rates after pancreaticoduodenectomy.

Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential.

BACKGROUND & AIMS: Migrating cancer stem cells (MCSCs) are believed to form metastases. We sought to identify markers of MCSCs from human colorectal cancers (CRCs) and determine their roles in organ-specific metastasis. METHODS: To identify colorectal MCSCs that contribute to organ-specific metastasis, we developed a model of liver or lung metastasis using primary tumor cells from patients with CRC who had liver and lung metastases. Distinct organ-specific metastatic cells were isolated by 6 cycles of selecting for cells that formed liver and lung tumors after subcutaneous injection into mice. Microarray analysis was used to identify markers of the organ-specific MCSCs. We then measured levels of these markers in CRC cell lines and 128 CRC samples. We characterized the functional roles of these markers in organ-specific metastasis. RESULTS: We identified CD110 and CDCP1 as cell surface markers of MCSCs from human colorectal tumors that metastasized to liver and lung. We observed a distinct pattern of CD110 and CDCP1 in a panel of primary colorectal tumor samples and their matched liver or pulmonary metastases, indicating that these proteins might serve as biomarkers of organ-specific metastasis. Functional studies showed that thrombopoietin attracts CD110(+) CSCs and increases their self-renewal to promote formation of liver metastases. CDCP1 promoted adhesion of CRC cells to the lung endothelium. CONCLUSIONS: We isolated MCSCs from primary human CRCs and found that the CD110(+) and CDCP1(+) subpopulations mediate organ-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.