Yuan-Tzu Lan

CIP2A is a predictor of poor prognosis in colon cancer.

PurposeThe cancerous inhibitor of protein phosphatase 2A (CIP2A) oncoprotein is overexpressed in colon cancer tissue compared to normal colon mucosa. We investigated the impact of CIP2A on colon cancer.MethodsA tissue microarray consisting of 167 colon cancer specimens was investigated. The association between CIP2A and clinicopathological parameters was analyzed using the χ2 test. Survival was analyzed using the Kaplan–Meier method. The impact of CIP2A on proliferation and drug resistance was evaluated using the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide test. An anchorage-independent colony formation assay was also performed.ResultsCIP2A was an independent prognostic factor in colon cancer after controlling for other clinical confounding factors, such as stage and lymphovascular invasion, particularly in stages III and IV (hazard ratio = 2.974, P < 0.001). The knockdown of CIP2A reduced the proliferation and anchorage-independent colony formation of colon cancer cells. Knockdown of CIP2A decreased the resistance of the cells to 5-fluorouracil, oxaliplatin, and SN38 (an active metabolite of irinotecan). Treatment with 5-fluorouracil, oxaliplatin, and SN38 decreased CIP2A expression.ConclusionsCIP2A is a prognostic factor in colon cancer. The knockdown of CIP2A reduced proliferation and anchorage-independent colony formation and increased 5-fluorouracil, oxaliplatin, and SN38 efficacy in colon cancer cell lines.

BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy

In metastatic colorectal cancer, v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a predictive biomarker for anti‐epidermal growth factor receptor (EGFR) treatment and V‐raf murine sarcoma viral oncogene homolog B1 (BRAF) is a prognostic biomarker. We aimed to determine the impact of KRAS and BRAF mutation as determined from liver metastases specimens on overall survival (OS) in patients following colorectal liver metastasectomy.

The Influence of Fecal Diversion and Anastomotic Leakage on Survival after Resection of Rectal Cancer

BackgroundWe analyzed factors associated with the occurrence of anastomotic leakage (AL) and its impact on long-term survival in patients who have undergone resection for rectal cancer. We also investigated the effect of fecal diversion on survival.MethodClinical data of patients who received surgery for rectal cancer were reviewed. The difference in AL incidence among different groups was compared and survival rates were calculated. Cox’s proportional hazards model was used to compare survival in patients who developed AL or received diversion stoma with those who did not.ResultsOf 999 patients who received resection and anastomosis, 53 patients experienced AL. Multivariate analysis revealed advanced age (P = 0.009) and operative method (P = 0.002) were independent risk factors for AL. Anastomotic leakage was an independent risk factor for overall recurrence (HR 2.30; 95% CI 1.12–4.73). Anastomotic leakage and fecal diversion were independent prognostic factors of overall survival (P = 0.002 and P < 0.001, respectively), cancer-specific survival (P = 0.002 and P < 0.001, respectively), and disease-free survival (P < 0.001, respectively).ConclusionsPatients who are older and have anastomosis at the anorectal junction or dentate line have an increased risk of AL. A diversion stoma does not appear to decrease the incidence of anastomotic leakage, but may decrease the need of reoperation when leakage occurred. Anastomotic leakage and fecal diversion are independent prognostic factors of overall, cancer-specific, and disease-free survival.

Analysis of the seventh edition of American Joint Committee on colon cancer staging

PurposeThe seventh edition of the American Joint Committee on Cancer (AJCC) staging system has new substages for colon cancer. We used survival data from a single medical center to analyze this new AJCC edition.MethodsThe colon cancer database of Taipei Veterans General Hospital provided 1,865 patient records covering from 1999 to 2005. Survival rates were evaluated using the Kaplan–Meier method.ResultsThere were 268, 607, 561, and 421 patients in stages I, II, III, and IV disease with 5-year observed survival rates of 86.3%, 79.2%, 65.4%, and 12.8%, respectively. Survival rates were not significantly different between those with T4a and T4b disease (P = 0.806). The outcome of N1c disease was similar to N1a and N1b but worse than N0 (P = 0.004). Survival rates for M1a and M1b disease became different after reclassifying solely peritoneal seeding as M1a (P < 0.001). No discrepancy of outcomes between stage IIIA and stage IIB/IIC remained in the seventh edition.ConclusionsEvolution from the fifth to seventh edition of the AJCC staging system is successful in separating prognostic groups by substaging. But some issues remain unresolved, including the subdivision of T4, N1, and M1.

Targeting Signal Transducer and Activator of Transcription 3 Pathway by Cucurbitacin I Diminishes Self-Renewing and Radiochemoresistant Abilities in Thyroid Cancer-Derived CD133+ Cells

Anaplastic thyroid cancer (ATC) is a lethal solid tumor with poor prognosis because of its invasiveness and its resistance to current therapies. Recently, ATC-CD133+ cells were found to have cancer stem cell (CSC) properties and were suggested to be important contributors to tumorigenicity and cancer metastasis. However, the molecular pathways and therapeutic targets in thyroid cancer-related CSCs remain undetermined. In this study, ATC-CD133+ cells were isolated and found to have increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared with ATC-CD133− cells. Microarray bioinformatics analysis suggested that the signal transducer and activator of transcription 3 (STAT3) pathway could be important in regulating the stemness signature in ATC-CD133+ cells; therefore, the effect of the potent STAT3 inhibitor cucurbitacin I in ATC-CD133+ cells was evaluated in this study. Treatment of ATC-CD133+ cells with cucurbitacin I diminished their CSC-like abilities, inhibited their stemness gene signature, and facilitated their differentiation into ATC-CD133− cells. Of note, treatment of ATC-CD133+ cells with cucurbitacin I up-regulated the expression of thyroid-specific genes and significantly enhanced radioiodine uptake. Furthermore, cucurbitacin I treatment increased the sensitivity of ATC-CD133+ cells to radiation and chemotherapeutic drugs through apoptosis. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiochemotherapy significantly suppressed tumorigenesis and improved survival in immunocompromised mice into which ATC-CD133+ cells were transplanted. In summary, these results show that the STAT3 pathway plays a key role in mediating CSC properties in ATC-CD133+ cells. Targeting STAT3 with cucurbitacin I in ATC may provide a new approach for therapeutic treatment in the future.

Oct4-related cytokine effects regulate tumorigenic properties of colorectal cancer cells

Oct4, a member of the POU-domain transcription factor family, has been implicated in the cancer stem cell (CSC)-like properties of various cancers. However, the precise role of Oct4 in colorectal CSC initiation remains uncertain. Numerous studies have demonstrated a strong link between inflammation and tumorigenesis in colorectal cancers. In this study, we demonstrated that Oct4 overexpression enhances CSC-like properties of colorectal cancer cells (CRCs), including sphere formation, cell colony formation, cell migration, invasiveness, and drug resistance. In addition, putative CSC markers, stemness genes, drug-resistant genes, as well as interleukin (IL)-8 and IL-32 were upregulated. Microarray-based bioinformatics of CRCs showed higher expression levels of embryonic stem cell-specific genes in cells that overexpressed Oct4. Neutralization of either IL-8 or IL-32 with specific antibodies partially blocked the tumorigenic effects induced by either Oct4 overexpression or by the addition of conditioned media from Oct4-overexpressing CRCs. In addition, the presence of Oct4-overexpressing CRCs enhanced the tumorigenic potential of parental CRCs in vivo. In summary, these data suggest that IL-8 and IL-32 play a role in regulating the CSC-like properties that promote tumorigenesis of CRCs in both autocrine and paracrine manners.

Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers.

Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR‐targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence.

Comparison of the Operative Outcomes and Learning Curves between Laparoscopic and Robotic Gastrectomy for Gastric Cancer

Background Minimally invasive surgery, including laparoscopic and robotic gastrectomy, has become more popular in the treatment of gastric cancer. However, few studies have compared the learning curves between laparoscopic and robotic gastrectomy for gastric cancer. Methods Data were prospectively collected between July 2008 and Aug 2014. A total of 145 patients underwent minimally invasive gastrectomy for gastric cancer by a single surgeon, including 73 laparoscopic and 72 robotic gastrectomies. The clinicopathologic characteristics, operative outcomes and learning curves were compared between the two groups. Results Compared with the laparoscopic group, the robotic group was associated with less blood loss and longer operative time. After the surgeon learning curves were overcome for each technique, the operative outcomes became similar between the two groups except longer operative time in the robotic group. After accumulating more cases of robotic gastrectomy, the operative time in the laparoscopic group decreased dramatically. Conclusions After overcoming the learning curves, the operative outcomes became similar between laparoscopic and robotic gastrectomy. The experience of robotic gastrectomy could affect the learning process of laparoscopic gastrectomy.

The prognostic role of microsatellite instability, codon-specific KRAS, and BRAF mutations in colon cancer

This study aimed to establish a correlation between MSI, KRAS mutations, and BRAFV600E in colon cancer and to investigate the prognostic effect.

Synergistic effects of carboxymethyl-hexanoyl chitosan, cationic polyurethane-short branch PEI in miR122 gene delivery: accelerated differentiation of iPSCs into mature hepatocyte-like cells and improved stem cell therapy in a hepatic failure model.

MicroRNA122 (miR122), a liver-specific microRNA, plays critical roles in homeostatic regulation and hepatic-specific differentiation. Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but it remains unknown whether non-viral vector-mediated miR122 delivery can enhance the differentiation of iPSCs into hepatocyte-like cells (iPSC-Heps) and rescue thioacetamide-induced acute hepatic failure (AHF) in vivo. In this study, we demonstrated that embedment of miR122 complexed with polyurethane-graft-short-branch polyethylenimine copolymer (PU-PEI) in nanostructured amphiphatic carboxymethyl-hexanoyl chitosan (CHC) led to dramatically enhanced miR122 delivery into human dental pulp-derived iPSCs (DP-iPSCs) and facilitated these DP-iPSCs to differentiate into iPSC-Heps (miR122-iPSC-Heps) with mature hepatocyte functions. Microarray and bioinformatics analysis further indicated that CHC/PU-PEI-miR122 promoted the gene-signature pattern of DP-iPSCs to shift into a liver-specific pattern. Furthermore, intrahepatic delivery of miR122-iPSC-Heps, but not miR-Scr-iPSC-Heps, improved liver functions and rescued recipient survival, and CHC-mediated delivery showed a better efficacy than that using phosphate buffered saline as a delivery vehicle. In addition, these transplanted miR122-iPSC-Heps remained viable and could produce circulatory albumin for 4 months. Taken together, our findings demonstrate that non-viral delivery of miR122 shortens the time of iPSC differentiation into hepatocytes and the delivery of miR122-iPSC-Heps using CHC as a vehicle exhibited promising hepatoprotective efficacy in vivo. miR122-iPSC-Heps may represent a feasible cell source and provide an efficient and alternative strategy for hepatic regeneration in AHF.