Overexpression of C16orf74 is involved in aggressive pancreatic cancers

Clinical outcome of pancreatic ductal adenocarcinoma (PDAC) has not been improved in the last three decades due to the lack of effective molecular-targeted drugs. To identify a novel therapeutic target for PDAC, we have performed genome-wide anamysis and found that Homo sapiens chromosome 16 open reading frame 74 (C16orf74) was up-regulated in the vast majority of PDAC. Overexpression of C16orf74 protein detected by immunohistochemical analysis was an independent prognostic factor for patients with PDAC. The knockdown of endogenous C16orf74 expression in the PDAC cell lines KLM-1 and PK-59 by vector-based small hairpin-RNA (shRNA) drastically attenuated the growth of those cells, whereas ectopic C16orf74 overexpression in HEK293T and NIH3T3 cells promoted cell growth and invasion, respectively. More importantly, the endogenous threonine 44 (T44)-phosphorylated form of C16orf74 interacted with the protein phosphatase 3 catalytic subunit alpha (PPP3CA) via the PDIIIT sequence in the PPP3CA-binding motif within the middle portion of C16orf74 in PDAC cells. The overexpression of mutants of C16orf74 lacking the PDIIIT sequence or T44 phosphorylation resulted in the suppression of invasive activity compared with wild-type C16orf74, indicating that their interaction should be indispensable for PDAC cell invasion. These results suggest that C16orf74 plays an important role for PDAC invasion and proliferation, and is a promising target for a specific treatment for patients with PDAC

Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation

Background: Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo. Method: TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects. Result: DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR. Conclusion: The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo

Delphi Method Consensus-Based Identification of Primary Trauma Care Skills Required for General Surgeons in Japan

Purpose General surgeons at regional hospitals should have the primary trauma care skills necessary to treat critically ill trauma patients to withstand transfer. This study was conducted to identify a consensus on primary trauma care skills for general surgeons. Methods An initial list of acute care surgical skills was compiled, and revised by six trauma experts (acute care surgeons); 33 skills were nominated for inclusion in the Delphi consensus survey. Participants (councilors of the Japanese Society for Acute Care Surgery) were presented with the list of 33 trauma care skills and were asked (using web-based software) to rate how strongly they agreed or disagreed (using a 5-point Likert scale) with the necessity of each skill for a general surgeon. The reliability of consensus was predefined as Cronbach’s α ≥ 0.8, and trauma care skills were considered as primarily required when rated 4 (agree) or 5 (strongly agree) by ≥ 80% participants. Results There were 117 trauma care specialists contacted to participate in the Delphi consensus survey panel. In the 1st round, 85 specialists participated (response rate: 72.6%). In the 2nd round, 66 specialists participated (response rate: 77.6%). Consensus was achieved after two rounds, reliability using Cronbach’s α was 0.94, and 34 items were identified as primary trauma care skills needed by general surgeons. Conclusion A consensus-based list of trauma care skills required by general surgeons was developed. This list can facilitate the development of a new trauma training course which has been optimized for general surgeons

A new prognostic scoring system using factors available preoperatively to predict survival after operative resection of perihilar cholangiocarcinoma

Background: Perihilar cholangiocarcinoma has one of the poorest prognoses of all cancers. However, mortality and morbidity rates after surgical resection are 0-15% and 14-66%, respectively. Additionally, the 5-year overall survival rates are reported at 22-40%. These findings indicate that only selected patients achieve satisfactory beneficial effects from operative treatment. This retrospective study sought to investigate preoperatively available prognostic factors and establish a new preoperative staging system to predict survival after major hepatectomy of perihilar cholangiocarcinoma. Patients and methods: We evaluated 121 consecutive patients who underwent operative exploration for perihilar cholangiocarcinoma. Results: Univariate and multivariate analysis using the identified preoperative factors revealed that 4 factors (platelet-lymphocyte ratio [PLR] > 150, serum C-reactive protein [CRP] levels > 0.5 mg/dL, albumin levels 7.0 ng/mL) were independent prognostic factors of postoperative survival. These 4 preoperative factors were allocated 1 point each. The total score was defined as the Preoperative Prognostic Score (PPS). Patients with a PPS of 0, 1, 2, or 3/4 had a 5-year survival of 84.3%, 51.3%, 46.4%, and 0%, respectively. There were also differences in the 5-year survival according to the PPS (0 vs 1 [P = .013] and 2 vs 3/4 [P < .001]). Patients with a total PPS of 3/4 had a dismal prognosis, with a median survival of 11.3 months. Conclusion: A new preoperative scoring system using PLR, serum CRP, albumin, and CEA levels could predict postoperative survival resection of perihilar cholangiocarcinoma

Pathological Confirmation of Para-Aortic Lymph Node Status as a Potential Criterion for the Selection of Intrahepatic Cholangiocarcinoma Patients for Radical Resection with Regional Lymph Node Dissection

Para-aortic lymph node (PAN) metastasis traditionally has been defined as distant metastasis. Many studies suggest that lymph node metastasis in intrahepatic cholangiocarcinoma (ICC) is one of the strongest prognostic factors for patient survival; however, the status of the PAN was not examined separately from regional lymph node metastasis in these reports. Here, we investigated whether regional lymph node metastasis without PAN metastasis in ICC can be classified as resectable disease and whether curative resection can have a prognostic impact. Between 1998 and 2010, a total of 47 ICC patients underwent hepatic resection and systematic lymphadenectomy with curative intent. We routinely dissected the PANs and had frozen-section pathological examinations performed intraoperatively. If PAN metastases were identified, curative resection was abandoned. We retrospectively investigated the prognostic factors for patient survival after curative resection for ICC without PAN metastases, with particular attention paid to the prognostic impact of lymphadenectomy. Univariate analysis identified concomitant portal vein resection, concomitant hepatic artery resection, intraoperative blood loss, intraoperative transfusion, and residual tumor as significant negative prognostic factors. However, lymph node status was not identified as a significant prognostic factor. The 14 patients with node-positive cancer had a survival rate of 20 % at 5 years. Based on multivariate analysis, intraoperative transfusion was an independent prognostic factor associated with a poor prognosis (risk ratio = 4.161; P = 0.0056). Regional lymph node metastasis in ICC should be classified as resectable disease, because the survival rate after surgical intervention was acceptable when PAN metastasis was pathologically negative

Adjuvant surgical therapy for patients with initially-unresectable pancreatic cancer with long-term favorable responses to chemotherapy

Background: To evaluate the prognostic impact of surgical intervention for initially-unresectable pancreatic ductal adenocarcinomas with long-term favorable responses to chemotherapy. Method: Twelve patients with initially-unresectable pancreatic ductal carcinomas who underwent radical surgery after a favorable response to chemotherapy for six months or longer in principle were enrolled in this study. We retrospectively reviewed the charts of these 12 patients and performed a survival analysis. Results: Initially, the included patients were unable to undergo resection secondary to locally-advanced disease in eight patients and metastatic disease in four patients. The length of preoperative therapy was five to 44 months (median 12). The operative procedure included resection of the area initially involved by tumor and regional major vessels. The postoperative mortality and morbidity rates were 0% and 50%, respectively. R0 resection was achieved in nine patients (75%) and pathological CR was seen in one patient. Estimated overall five-year survival from initial therapy was 50.0%. The survival rate (0% at 5 years) of the four patients with metastatic disease as the cause of initial unresectability was significantly worse than that (100% at 5 years) of the eight patients with locally-advanced disease (P = 0.0014). Conclusion: Surgical intervention should be considered for patients with initially-unresectable pancreatic cancers who demonstrate long-term favorable responses to chemotherapy. R0 resection may significantly contribute to cure, especially in patients with initially locally-advanced disease. Large cohort prospective studies will be necessary to demonstrate the efficacy of this strategy