Monitoring perioperative serum albumin can identify anastomotic leakage in colorectal cancer patients with curative intent

SummaryBackgroundPreoperative hypoalbuminemia is a well-known risk factor for anastomotic leakage after colorectal surgery, but the association between perioperative albumin level and anastomotic leakage has not been fully investigated in curative colorectal cancer (CRC) patients.MethodsIn total, 200 CRC patients (Stage I–III) undergoing curative laparoscopic surgery between January 2004 and December 2013 were enrolled in this study. We collected data on surgical factors, perioperative levels of serum albumin and inflammatory markers, and perioperative factors affecting hypoalbuminemia from 196 CRC patients to assess the relation to anastomotic leakage.ResultsAnastomotic leakage occurred in 11 cases (5.6%) and the frequency was higher in rectal cancer patients (p = 0.0044). There was no significant difference of preoperative serum albumin level between the anastomotic leakage group (AL) and the nonanastomotic leakage group (NAL). Postoperative serum albumin levels in AL were significantly lower than in NAL [postoperative day (POD) 0, p = 0.0004; POD1, p = 0.0001; POD3, p = 0.0004; and POD7, p = 0.0021]. On multivariate analysis, lower average level of serum albumin on POD1 and POD3 {odds ratio (OR) [95% confidence interval (CI)] = 7.53 (1.60–55.80), p = 0.0095}, higher average level of serum white blood cells on POD1 and POD3 [OR (95% CI) = 7.24 (1.40–59.25), p = 0.0165], and surgery for rectal cancer [OR (95% CI) = 15.18 (3.26–93.99), p = 0.0004] were independent risk factors for anastomotic leakage.ConclusionLower early postoperative serum albumin levels are a potentially valuable indicator of anastomotic leakage in CRC patients undergoing curative surgery

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, gamma-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenograft model of gastric cancer using two-photon laser scanning microscopy

application/pdfBackground We previously visualized in vivo responses to chemotherapy in a colorectal liver metastatic xenograft model using in vivo real-time and time-series intravital two-photon laser scanning microscopy (TPLSM). In this study, we established the method for evaluating the response of peritoneal xenografts to chemotherapy of metastatic gastric cancer using intravital TPLSM. Methods Red fluorescent protein-expressing gastric cancer cells (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein nude mice. Results Laparotomy revealed that 2 weeks after inoculation, macroscopic peritoneal metastatic nodules were formed. The first intravital TPLSM session revealed that they were composed of red tumor cell clusters and green surrounding stroma. Paclitaxel was administered intraperitoneally after the first TPLSM three times a week for 7 days in the treatment group. At the second laparotomy, there were significantly fewer and smaller nodules in the treated mice than in the controls. The second intravital TPLSM session showed tumor cell fragmentation, swelling, and nuclear condensation in the metastatic nodules—a response to chemotherapy. There were multinuclear tumor cells in the paclitaxel-treated living mice. Conclusions Our method may become a powerful tool for evaluating the efficacy of novel anti-gastric cancer drugs in a preclinical murine model with minimum interindividual variation.本文/Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan10

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic zenograft model of gastric cancer using two-photon laser scanning microscopy

application/pdf内容の要旨・審査結果の要旨 / 三重大学大学院医学系研究科生命医科学専攻病態修復医学講座消化管・小児外科学分

Intussusception of Rectosigmoid Colon Cancer Mimicking a Pedunculated Tumor

Intussusception in adults is a rare phenomenon involving the colon in approximately 20% of cases. A 65-year-old man was hospitalized with anorexia, anemia, dehydration, and melena. Digital rectal examination revealed a palpable mass approximately 5 cm from the anal verge. The mass moved between the rectosigmoid colon and the rectum below the peritoneal reflection during radiographic examinations and during sigmoidoscopy. We strongly suspected a rectosigmoid pedunculated tumor and performed a low anterior resection. Intraoperatively we observed intussusception of the rectosigmoid colon with easy manual reduction. The tumor was palpable in the rectosigmoid colon. The postoperative course was uneventful. This case illustrates intussusception of a rectosigmoid type 1 colon adenocarcinoma mimicking a pedunculated tumor

Mesenteric lipoblastoma presenting as a small intestinal volvulus in an infant: A case report and literature review

A 1-year-old boy with no underlying disorder presented with non-bilious vomiting since 4 days before admission. He was referred to our hospital and was diagnosed with a small bowel obstruction due to an intraabdominal tumor. Laparotomy revealed an intestinal volvulus with a soft and lobulated tumor arising from the mesentery. The resected tumor with a small part of the small bowel was diagnosed as lipoblastoma histologically. From a literature review, mesenteric lipoblastoma with an intestinal volvulus showed different characteristics such as greater frequency of vomiting and less frequency of abdominal mass as clinical symptoms, and the size of the tumor was smaller than that of the tumor without the intestinal volvulus

Esophageal Cancer with Bone Marrow Hyperplasia Mimicking Bone Metastasis: Report of a Case

A 63-year-old man visited the clinic with numbness in the right hand. Magnetic resonance imaging demonstrated multiple low-intensity lesions in the cervical vertebrae and sacrum, which was suspicious of cervical bone metastasis. Fluorodeoxyglucose positron emission tomography/computed tomography revealed areas of increased fluorodeoxyglucose uptake in the thoracic esophagus, sternum and sacrum. A flat, elevated esophageal cancer was identified by upper gastrointestinal endoscopy, and the macroscopic appearance indicated early-stage disease. From the cervical, thoracic and abdominal computed tomography images, there were no metastatic lesions except for the bone lesions. To confirm whether the bone lesions were metastatic, we performed bone biopsy. The histopathological diagnosis was bone marrow hyperplasia. It was crucial for treatment planning to establish whether the lesions were distant metastases. Here, we report a case of esophageal cancer with bone marrow hyperplasia mimicking bone metastasis

Double inferior vena cava, an uncommon but relevant anatomical anomaly in surgery for lower rectal cancer: a report of two cases

Abstract Background Double inferior vena cava (DIVC) is rare and usually detected incidentally. DIVC may be associated with several anatomical variants of the retroperitoneal and pelvic veins. These variants can pose a clinical problem during colorectal surgery. We present two patients with lower rectal cancer who also had a DIVC. Case presentation Case 1 was a 72-year-old man with advanced lower rectal cancer (T3N0M0) who underwent robot-assisted low anterior resection after neoadjuvant therapy. A DIVC was detected on preoperative computed tomography (CT). During the operation, a presacral vein was injured while mobilizing the rectum and hemostasis could not be achieved. We converted to open surgery and packed the pelvic cavity for hemostasis. Retrospective analysis suggested the injured vein arose from an interiliac vein of the presacral pelvic venous plexus. Case 2 was a 50-year-old woman with lower rectal cancer (T3N0M0), immune thrombocytopenic purpura, and a DIVC. Although preoperative three-dimensional CT angiography showed no obvious pelvic vein abnormalities, a short course of preoperative radiotherapy was delivered to avoid lateral pelvic lymph node dissection. Chemotherapy was deferred owing to her thrombocytopenic disease. Laparoscopic abdominoperineal resection was performed meticulously to minimize bleeding and achieve rapid hemostasis. No intraoperative complications occurred. Conclusion DIVC is often accompanied by venous malformations that may pose a problem when mobilizing the mesorectum from the retroperitoneum. Preoperative assessment of pelvic vessel anatomy using three-dimensional CT is essential in patients with a DIVC who undergo rectal surgery

Abstract 762: A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. Recent advances in treatment paradigms have been encouraging; however, identification of appropriate patient populations and a better understanding of the underlying tumor heterogeneity could further improve patient outcomes. Recently, four distinct molecular subtypes of PDAC were established, and in particular, squamous subtype was attributed with worse prognosis. Nonetheless, the clinical application of genome-wide transcriptome-based subtyping is cumbersome. Therefore, in this study, we identified miRNA networks regulating the expression of various genes in each PDAC subtype, with a goal to develop tissue and liquid biopsy-based miRNA biomarkers that can be translated into the clinic. Experimental Design: We used a mRNA-miRNA network-based approach to unravel miRNA networks regulating various PDAC subtypes. Using logistic regression models and area under the curve (AUC) analysis, we evaluated the performance of a miRNA-signature for identifying poor molecular subtypes of PDAC. Using qRT-PCR assays, we also analyzed the prognostic significance of the miRNA panel in 433 PDAC patients, including TCGA (n=183), multiple in-house retrospective, tissue cohorts (n=199) and a prospective, preoperative serum cohort (n=51). Univariate and multivariate Cox-proportional hazard models were used for data analysis, and Youden’s index derived cut-off thresholds were used to plot the Kaplan Meier (KM) curves for overall survival. Results: We identified a panel of 9-miRNAs that were significantly dysregulated (upregulated: miR-205-5p and -934; downregulated: miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p and 1251-5p) in squamous subtype; and was highly accurate in identifying all poor molecular PDAC subtypes proposed previously (Squamous AUC=0.90, Basal AUC=0.89 and Quasimesenchymal AUC=0.83). Intriguingly, expression level of all these 9-miRNAs clearly stratified overall survival (OS) in patient subgroups, and patients with high-risk scores exhibited significantly worse OS (Hazard ratio (HR): 2.48, p<0.0001). Intriguingly, our miRNA signature was equally robust even in pre-operative serum specimens for identifying patients with poor OS (HR: 2.85, p=0.02), highlighting its significance for treatment decision-making in the clinic. Conclusions: We for the first time report a unique miRNA signature for identifying patients with poor molecular subtype PDAC who are at risk for worse overall survival. Our 9-miRNA signature can be easily adapted into the clinical setting using simple qRT-PCR based assays. The discrimination of high-risk patients even in the preoperative setting could improve the selection of PDAC patients for neoadjuvant treatment, especially in those with unresectable disease. Citation Format: Raju Kandimalla, Tadanobu Shimura, Saurav Mallik, Susan Tsai, Douglas B. Evans, Hideo Baba, Yasuhiro Kodera, Xi Chen, Ajay Goel. A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 762