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1.  Predicting tumor response after preoperative chemoradiation using clinical parameters in rectal cancer 
AIM: To evaluate the clinical parameters and identify a better method of predicting pathological complete response (pCR).
METHODS: We enrolled 249 patients from a database of 544 consecutive rectal cancer patients who underwent surgical resection after preoperative chemoradiation therapy (PCRT). A retrospective review of morphological characteristics was then performed to collect data regarding rectal examination findings. A scoring model to predict pCR was then created. To validate the ability of the scoring model to predict complete regression.
RESULTS: Seventy patients (12.9%) achieved a pCR. A multivariate analysis found that pre-CRT movability (P = 0.024), post-CRT size (P = 0.018), post-CRT morphology (P = 0.023), and gross change (P = 0.009) were independent predictors of pCR. The accuracy of the scoring model was 76.8% for predicting pCR with the threshold set at 4.5. In the validation set, the accuracy was 86.7%.
CONCLUSION: Gross changes and morphological findings are important predictors of pathological response. Accordingly, PCRT response is best predicted by a combination of clinical, laboratory and metabolic information.
doi:10.3748/wjg.v17.i48.5310
PMCID: PMC3247696  PMID: 22219601
Rectal cancer; Preoperative chemoradiotherapy; Downstaging; Tumor regression; Validation
2.  Hepatectomy vs radiofrequency ablation for colorectal liver metastasis: A propensity score analysis 
AIM: To compare outcomes from radiofrequency ablation (RFA) and hepatectomy for treatment of colorectal liver metastasis (CRLM).
METHODS: From January 2000 to December 2009, 408 patients underwent curative intent treatment for CRLM. We excluded patients using the criteria: size of CRLM > 3 cm, number of CRLM ≥ 5, percutaneous RFA, follow-up period < 12 mo, double primary cancer, or treatment with both RFA and hepatectomy. We matched 51 patients who underwent RFA with 102 patients who underwent hepatectomy by propensity scores.
RESULTS: The median follow-up period was 45 mo (range, 12 mo to 158 mo). Hepatic recurrence was more frequent in the RFA than the hepatectomy group (P = 0.021) although extrahepatic recurrence curves were similar (P = 0.716). Survival curves of hepatectomy group were better than that of RFA for multiple, large (> 2 cm) CRLM (P = 0.034). However, survival curves were similar for single or small (≤ 2 cm) CRLM (P = 0.714, P = 0.740).
CONCLUSION: Hepatectomy is better than RFA for the treatment of CRLM. However, RFA might be suitable for selected patients with single, small (≤ 2 cm) CRLM.
doi:10.3748/wjg.v21.i11.3300
PMCID: PMC4363760  PMID: 25805937
Colorectal neoplasm; Metastasis; Catheter ablation; Hepatectomy; Liver
3.  Repeat hepatic resection in patients with colorectal liver metastases 
AIM: To investigate the survival outcomes of secondary hepatectomy for recurrent colorectal liver metastases (CRLM).
METHODS: From October 1994 to December 2009, patients with CRLM who underwent surgical treatment with curative intent were investigated. Patients were divided into two groups: patients who underwent primary hepatectomy (Group 1) and those who underwent secondary hepatectomy for recurrent CRLM (Group 2).
RESULTS: Survival and prognostic factors were analyzed. A total of 461 patients were included: 406 patients in Group 1 and 55 patients in Group 2. After a median 39-mo (range, 3-195 mo) follow-up, there was a significant difference between Groups 1 and 2 in terms of disease-free survival (P = 0.029) although there was no significant difference in overall survival (P = 0.206). Secondary hepatectomy was less effective in patients with multiple recurrent CRLM than primary hepatectomy for initial CRLM (P = 0.008). Multiple CRLM and radiofrequency ablation therapy were poor prognostic factors of secondary hepatectomy in multivariate Cox regression analysis (P = 0.006, P = 0.004, respectively).
CONCLUSION: Secondary hepatectomy for single recurrent CRLM is as effective as primary surgical treatment for single recurrent CRLM. However, secondary hepatectomy for multiple recurrent CRLM is less effective than that for single recurrent CRLM.
doi:10.3748/wjg.v21.i7.2124
PMCID: PMC4326149  PMID: 25717247
Colorectal neoplasm; Metastasis; Recurrence; Hepatectomy
4.  CD133-positive tumor cell content is a predictor of early recurrence in colorectal cancer 
Background
The aims of this study were to demonstrate the tumorigenicity of CD133+ colon cancer cells in vitro, analyze the correlations between spheroid formation and clinicopathologic variables, and screen for overexpressed genes in CD133+ colon cancer stem cells. Moreover, the aim of this study was to establish a living tumor tissue bank using surgically resected specimens.
Methods
Using LoVo cell line, we isolated CD133+ cells and performed clonogenic assay and animal experiment to test tumorigenicity of CD133+ cells. Twenty-nine surgical samples were freshly collected from 27 patients who received curative or palliative surgery, and the samples were mechanically and enzymatically dissociated into single cells.
Results
We confirmed the enhanced tumorigenicity of CD133+ cells isolated from LoVo cell line both in vitro and in vivo. Of these 29 samples, 8 (28%) contained >3% CD133+ cells. Sphere formation was significantly higher in samples from patients with lymphatic invasion than in those without lymphatic invasion [54.5% (6/11) vs. 12.5% (2/16); P=0.033] and in samples containing >3% of CD133+ cells than in those containing ≤3% of CD133+ cells [36.4% (4/11) vs. 0% (0/16); P=0.019].
Conclusions
These findings indicate that CD133 is a valid marker for identifying cancer stem cells from fresh surgically resected colorectal cancer tissues. Furthermore, we successfully established a living tumor tissue bank using surgically resected colorectal tissues with a viability of >70%.
doi:10.3978/j.issn.2078-6891.2014.071
PMCID: PMC4226826  PMID: 25436124
CD133; colorectal cancer; cancer stem cell
5.  hMLH1 promoter methylation and BRAF mutations in high-frequency microsatellite instability colorectal cancers not fulfilling the revised Bethesda guidelines 
Purpose
Sporadic colorectal cancers with high-frequency microsatellite instability (MSI-H) are related to hypermethylation of mismatch repair (MMR) genes and a higher frequency of BRAF mutations than Lynch syndrome. We estimated the feasibility of hereditary colorectal cancer based on hMLH1 methylation and BRAF mutations.
Methods
Between May 2005 and June 2011, we enrolled all 33 analyzed patients with MSI-H cancer (male:female, 23:10; mean age, 65.5 ± 9.4 years) from a prospectively maintained database that didn't match Bethesda guidelines and who had results of hMLH1 methylation and BRAF mutations.
Results
Among the 33 patients, hMLH1 promoter methylation was observed in 36.4% (n = 12), and was not significantly related with clinicopathologic variables, including MLH1 expression. BRAF mutations were observed in 33.3% of the patients (n = 11). Four of 11 and five of 22 patients with MSI-H colon cancers were BRAF mutation (+)/hMLH1 promoter methylation (-) or BRAF mutation (-)/hMLH1 promoter methylation (+). Of the 33 patients, 21.2% were BRAF mutation (+)/hMLH1 promoter methylation (+), indicating sporadic cancers. Seventeen patients (51.5%) were BRAF mutation (-)/hMLH1 promoter methylation (-), and suggested Lynch syndrome.
Conclusion
Patients with MSI-H colorectal cancers not fulfilling the Bethesda guidelines possibly have hereditary colorectal cancers. Adding tests of hMLH1 promoter methylation and BRAF mutations can be useful to distinguish them from sporadic colorectal cancers.
doi:10.4174/astr.2014.87.3.123
PMCID: PMC4170578  PMID: 25247165
Colorectal neoplasms; hMLH1; BRAF; Hereditary colorectal cancer
6.  Oncologic Outcomes of Stage IIIA Colon Cancer for Different Chemotherapeutic Regimens 
Purpose
Adjuvant chemotherapy is currently recommended for Stage IIIA colon cancers. This study aimed to elucidate the oncologic outcomes of Stage IIIA colon cancer according to the chemotherapeutic regimen based on a retrospective review.
Methods
From 1995 to 2008, Stage IIIA colon cancer patients were identified from a prospectively maintained database at a single institution. Exclusion criteria were as follows: rectal cancer, another malignancy other than colon cancer, no adjuvant chemotherapy and unknown chemotherapeutic regimen. One hundred thirty-one patients were enrolled in the study, and the clinicopathologic and the oncologic characteristics were analyzed. The number of males was 72, and the number of females was 59; the mean age was 59.5 years (range, 25 to 76 years), and the median follow-up period was 33 months (range, 2 to 127 months).
Results
Of the 131 patients, fluorouracil/leucovorin (FL)/capecitabine chemotherapy was performed in 109 patients, and FOLFOX chemotherapy was performed in 22 patients. When the patients who received FL/capecitabine chemotherapy and the patients who received FOLFOX chemotherapy were compared, there was no significant difference in the clinicopathologic factors between the two groups. The 5-year overall survival and the 5-year disease-free survival were 97.2% and 94.5% in the FL/capecitabine patient group and 95.5% and 90.9% in the FOLFOX patient group, respectively, and no statistically significant differences were noted between the two groups.
Conclusion
Stage IIIA colon cancer showed good oncologic outcomes, and the chemotherapeutic regimen did not seem to affect the oncologic outcome.
doi:10.3393/jksc.2012.28.5.259
PMCID: PMC3499427  PMID: 23185706
Stage IIIA; Colon neoplasm; Chemotherapeutic agent; Prognosis
7.  Oncologic Outcome after Cessation or Dose Reduction of Capecitabine in Patients with Colon Cancer 
Purpose
Oral capecitabine has been used as adjuvant therapy for colorectal cancer patients since the 1990s. Patient-initiated cessation or reduced use of capecitabine occurs widely for various reasons, yet the consequences of these actions are unclear. The present study sought to clarify treatment outcomes in such patients.
Methods
The study included 173 patients who had been diagnosed with stage II or III colon cancer according to the pathologic report after radical surgery at Samsung Medical Center from May 2005 to June 2007 and who had received capecitabine as adjuvant therapy. The patients were divided into groups according to whether the dose was reduced (I, dose maintenance; II, dose reduction) or stopped (A, cycle completion; B, cycle cessation). Recurrence and disease-free survival rates between the two groups each were analyzed.
Results
Of the 173 patients, 128 (74.6%) experienced complications, most frequently hand-foot syndrome (n = 114). Reduction (n = 35) or cessation (n = 18) of medication was most commonly due to complications. Concerning reduced dosage, both groups displayed no statistically significant differences in recurrence rate and 3-year disease-free survival rate. Concerning discontinued medication use, the cycle completion group showed an improved recurrence rate (P = 0.048) and 3-year disease-free survival rate (P = 0.028).
Conclusion
The results demonstrate that maintaining compliance with capecitabine as an adjuvant treatment for colon cancer to preventing complications positively affects patient prognosis.
doi:10.3393/jksc.2010.26.4.287
PMCID: PMC2998011  PMID: 21152231
Colon cancer; Capecitabine; Dose; Cycle; Disease-free survival
8.  Fatal Peripheral Candidal Suppurative Thrombophlebitis in a Postoperative Patient 
Journal of Korean Medical Science  2008;23(6):1094-1096.
We report a case of fatal fungal peripheral suppurative thrombophlebitis, caused by Candida albicans, which was disseminated to the blood, lungs, eyes, and spine. Clinical suspicion and aggressive management are important in managing fungal peripheral suppurative thrombophlebitis. Early clinical suspicion is important in managing fungal peripheral suppurative thrombophlebitis, and radical excision of the affected veins, recognition of metastatic foci, and use of systemic antifungal agents are essential to avoid septic shock and death.
doi:10.3346/jkms.2008.23.6.1094
PMCID: PMC2610646  PMID: 19119456
Candidemia; Shock, Septic; Thrombophlebitis
9.  CpG Island Methylation in Familial Colorectal Cancer Patients Not Fulfilling the Amsterdam Criteria 
Journal of Korean Medical Science  2008;23(2):270-277.
To determine the role of methylation in colorectal cancer patients with a family history, we enrolled 25 colorectal cancer patients with a family history of colorectal cancer but without a mutation in the hMLH1 and hMSH2 genes. Thirty patients with sporadic colorectal cancer were included as control. The methylation status of COX2, MGMT, hMLH1, TIMP3, p16, and MINT2 in normal mucosa and tumor were assessed using methylation-specific PCR. In patients with a family history, the methylation frequency ranged from 4.0% for TIMP3 to 44.4% for MGMT, whereas, in patients with sporadic colorectal cancer, it ranged from 6.7% for TIMP3 to 50.0% for p16. Nine of the 25 patients with family history (36.0%) were classified as methylation-prone, and nine of the 30 patients with sporadic cancers (30.0%) were as methylation-prone, making their methylation indices 0.19 and 0.16, respectively (p=0.522). As for the individual genes, the methylation rate of MGMT was higher in colorectal cancer patients with family history (44.0% vs. 13.0%, p=0.016), whereas the methylation rate of p16 was higher in sporadic colorectal cancers (50.0% vs. 8.7%, p=0.046). While CpG island methylation of tumor suppressor genes may play a role in colorectal carcinogenesis, the genes involved may be different between tumors of patients with and without a family history of colorectal cancer.
doi:10.3346/jkms.2008.23.2.270
PMCID: PMC2526421  PMID: 18437011
Colorectal Neoplasms; Familial; Carcinogenesis; Methylation; Microsatellite Instability
10.  Solitary Preleukemic Granulocytic Sarcoma as a Cause of Small Bowel Obstruction 
Gut and Liver  2007;1(1):82-86.
Granulocytic sarcoma is an extramedullary tumor composed of immature granulocytic cells. These tumors usually occur simultaneously with or follow after the onset of acute myeloid leukemia (AML) or other myeloproliferative disorders. Rarely, it is the first manifestation of AML which appears several months before the onset of leukemia. We report a case of a 48-year-old man presenting with symptoms of small bowel obstruction. Laparotomy and open biopsy were performed. Immunohistochemical studies showed that the neoplastic cells were of myeloid lineage positive for myeloperoxidase and leukocyte common antigen, but negative for CD3, 20, 56, 79a, and cytokeratin. Initially, there was no evidence of blood or bone marrow involvement suggesting acute leukemia or other myeloproliferative disorders. The findings were consistent with the diagnostic findings of solitary granulocytic sarcoma (preleukemic). However, one month later, bone marrow biopsy revealed 57% myeloblasts. Sequentially, the patient developed FAB M2 acute myeloid leukemia. Induction chemotherapy including cytarabine and idarubicine was done which led to complete remission. Allograft bone marrow transplantation was performed later, and there is no evidence of recurrence till present.
doi:10.5009/gnl.2007.1.1.82
PMCID: PMC2871656  PMID: 20485664
Granulocytic sarcoma; Acute myeloid leukemia; Small bowel obstruction
11.  A Giant Colonic Hamartoma and Multiple Colonic Hamartomatous Polyps in a Middle-Aged Man 
Yonsei Medical Journal  2006;47(5):755-758.
Colonic hamartomas are rare polypoid lesions. We report an unusual case of multiple colonic hamartomatous polyps, including a giant hamartoma, unrelated to hereditary or familial polyposis syndromes, in a 48-year-old man. The diameter of the largest polyp was 9.5 cm, and endoscopy revealed that the lesion caused colonic obstruction. The clinical, endoscopic and histological aspects of this case are discussed.
doi:10.3349/ymj.2006.47.5.755
PMCID: PMC2687766  PMID: 17066524
Hamartoma; giant hamartoma
12.  Cutoff Values of Preoperative s-CEA Levels for Predicting Survivals after Curative Resection of Colorectal Cancer 
Journal of Korean Medical Science  2005;20(4):624-627.
Serum carcinoembryonic antigen (s-CEA) is used to detect recurrence and predict prognosis in colorectal cancer. However, the cutoff values of s-CEA for prognosis have not been determined. We therefore tried to determine the preoperative s-CEA levels predictive of survivals in colorectal cancer patients. We retrospectively analyzed the medical records of 989 patients who underwent curative resection for colorectal cancer between July 1990 and December 1997, with a mean follow-up of 46 months (range, 3-129 months). When patients were divided into four subgroups with the cutoff values of s-CEA at 3,6, and 17 ng/mL, their 5-yr disease-free survival rates were 85.3% (<3.0 ng/mL), 70.0% (3-6 ng/mL), 64.2% (6-17 ng/mL), and 55.2% (>17 ng/mL) (p<0.001). Multivariate analysis showed that factors predictive of survival included age (p=0.028), tumor stage (p<0.001), cell differentiation (p=0.016), and gross type (p=0.007), location (p=0.003) and preoperative s-CEA (p<0.001). Using the above-described cutoff levels, a significant difference in survival was observed only in patients with stage III tumors (p=0.007) when analyses were performed by stage. We can suggest the new cutoff values of s-CEA used in the present study.
doi:10.3346/jkms.2005.20.4.624
PMCID: PMC2782159  PMID: 16100455
Carcinoembryonic Antigen; Prognosis; Colonic Neoplasm
13.  Can we omit prophylactic inguinal nodal irradiation in anal cancer patients? 
Radiation Oncology Journal  2015;33(2):83-88.
Purpose
To evaluate the appropriateness of prophylactic inguinal nodal irradiation (PINI), we analyzed patterns of failure in anal cancer patients who were inguinal node-negative at presentation and did not receive PINI.
Materials and Methods
We retrospectively reviewed the records of 33 anal cancer patients treated by definitive concurrent chemoradiation therapy (CCRT) between 1994 and 2013. Radiotherapy consisted of a total dose of 44-45 Gy (22-25 fractions in 5 weeks) on the whole pelvis, anus, and perineum. Except inguinal lymphadenopathy was present at initial diagnosis, the entire inguinal chain was not included in the radiation field. In other words, there was no PINI.
Results
The median follow-up duration was 50 months (range, 4 to 218 months). Median survival and progression-free survival (PFS) were 57 months (range, 10 to 218 months) and 50 months (range, 4 to 218 months), respectively. Among the survival, the median follow-up duration was 51 months (range, 12 to 218 months). The 5-year overall survival and PFS rates were 93.4% and 88.8%, respectively. Although none of the patients received inguinal node irradiation for prophylactic purposes, there was no inguinal recurrence.
Conclusion
Treatment of anal cancer by omitting PINI might be considered in selected patients with clinically uninvolved inguinal nodes.
doi:10.3857/roj.2015.33.2.83
PMCID: PMC4493432  PMID: 26157677
Anus neoplasms; Prophylactic; Radiotherapy; Inguinal; Lymph nodes
14.  Learning curves for single incision and conventional laparoscopic right hemicolectomy: a multidimensional analysis 
Purpose
This study aimed to compare the learning curves and early postoperative outcomes for conventional laparoscopic (CL) and single incision laparoscopic (SIL) right hemicolectomy (RHC).
Methods
This retrospective study included the initial 35 cases in each group. Learning curves were evaluated by the moving average of operative time, mean operative time of every five consecutive cases, and cumulative sum (CUSUM) analysis. The learning phase was considered overcome when the moving average of operative times reached a plateau, and when the mean operative time of every five consecutive cases reached a low point and subsequently did not vary by more than 30 minutes.
Results
Six patients with missing data in the CL RHC group were excluded from the analyses. According to the mean operative time of every five consecutive cases, learning phase of SIL and CL RHC was completed between 26 and 30 cases, and 16 and 20 cases, respectively. Moving average analysis revealed that approximately 31 (SIL) and 25 (CL) cases were needed to complete the learning phase, respectively. CUSUM analysis demonstrated that 10 (SIL) and two (CL) cases were required to reach a steady state of complication-free performance, respectively. Postoperative complications rate was higher in SIL than in CL group, but the difference was not statistically significant (17.1% vs. 3.4%).
Conclusion
The learning phase of SIL RHC is longer than that of CL RHC. Early oncological outcomes of both techniques were comparable. However, SIL RHC had a statistically insignificant higher complication rate than CL RHC during the learning phase.
doi:10.4174/astr.2015.88.5.269
PMCID: PMC4422880  PMID: 25960990
Single-incision; Laparoscopy; Colectomy; Learning curve; CUSUM
15.  Risk Factors of Permanent Stomas in Patients with Rectal Cancer after Low Anterior Resection with Temporary Stomas 
Yonsei Medical Journal  2015;56(2):447-453.
Purpose
The aim of this study was to identify risk factors influencing permanent stomas after low anterior resection with temporary stomas for rectal cancer.
Materials and Methods
A total of 2528 consecutive rectal cancer patients who had undergone low anterior resection were retrospectively reviewed. Risk factors for permanent stomas were evaluated among these patients.
Results
Among 2528 cases of rectal cancer, a total of 231 patients had a temporary diverting stoma. Among these cases, 217 (93.9%) received a stoma reversal. The median period between primary surgery and stoma reversal was 7.5 months. The temporary and permanent stoma groups consisted of 203 and 28 patients, respectively. Multivariate analysis showed that independent risk factors for permanent stomas were anastomotic-related complications (p=0.001) and local recurrence (p=0.001). The 5-year overall survival for the temporary and permanent stoma groups were 87.0% and 70.5%, respectively (p<0.001).
Conclusion
Rectal cancer patients who have temporary stomas after low anterior resection with local recurrence and anastomotic-related complications may be at increased risk for permanent stoma.
doi:10.3349/ymj.2015.56.2.447
PMCID: PMC4329357  PMID: 25683994
Stoma; rectal cancer; low anterior resection
16.  Immunohistochemical Detection of p53 Expression in Patients with Preoperative Chemoradiation for Rectal Cancer: Association with Prognosis 
Yonsei Medical Journal  2014;56(1):82-88.
Purpose
The expression of p53 in patients with rectal cancer who underwent preoperative chemoradiationand and its potential prognostic significance were evaluated.
Materials and Methods
p53 expression was examined using immunohistochemistry in pathologic specimens from 210 rectal cancer patients with preoperative chemoradiotherapy and radical surgery. All patients were classified into two groups according to the p53 expression: low p53 (<50% nuclear staining) and high p53 (≥50%) groups.
Results
p53 expression was significantly associated with tumor location from the anal verge (p=0.036). In univariate analysis, p53 expression was not associated with disease-free survival (p=0.118) or local recurrence-free survival (p=0.089). Multivariate analysis showed that tumor distance from the anal verge (p=0.006), ypN category (p=0.011), and perineural invasion (p=0.048) were independent predictors of disease-free survival; tumor distance from the anal verge was the only independent predictor of local recurrence-free survival. When the p53 groups were subdivided according to ypTNM category, disease-free survival differed significantly in patients with ypN+ disease (p=0.027) only.
Conclusion
Expression of p53 in pathologic specimens as measured by immunohistochemical methods may have a significant prognostic impact on survival in patients with ypN+ rectal cancer with preoperative chemoradiotherapy. However, it was not an independent predictor of recurrence or survival.
doi:10.3349/ymj.2015.56.1.82
PMCID: PMC4276781  PMID: 25510750
p53; rectal cancer; immunohistochemistry
17.  Activated cMET and IGF1R-Driven PI3K Signaling Predicts Poor Survival in Colorectal Cancers Independent of KRAS Mutational Status 
PLoS ONE  2014;9(8):e103551.
Background
Oncogenic mutational analysis provides predictive guidance for therapeutics such as anti-EGFR antibodies, but it is successful only for a subset of colorectal cancer (CRC) patients.
Method
A comprehensive molecular profiling of 120 CRC patients, including 116 primary, 15 liver metastasis, and 1 peritoneal seeding tissue samples was performed to identify the relationship between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) WT and mutant CRC tumors and clinical outcomes. This included determination of the protein activation patterns of human epidermal receptor 1 (HER1), HER2, HER3, c-MET, insulin-like growth factor 1 receptor (IGF1R), phosphatidylinositide 3-kinase (PI3K), Src homology 2 domain containing (Shc), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) kinases using multiplexed collaborative enzyme enhanced reactive (CEER) immunoassay.
Results
KRAS WT and mutated CRCs were not different with respect to the expression of the various signaling molecules. Poor prognosis in terms of early relapse (<2 years) and shorter disease-free survival (DFS) correlated with enhanced activation of PI3K signaling relative to the HER kinase pathway signaling, but not with the KRAS mutational status. KRAS WT CRCs were identified as a mixed prognosis population depending on their level of PI3K signaling. KRAS WT CRCs with high HER1/c-MET index ratio demonstrated a better DFS post-surgery. c-MET and IGF1R activities relative to HER axis activity were considerably higher in early relapse CRCs, suggesting a role for these alternative receptor tyrosine kinases (RTKs) in driving high PI3K signaling.
Conclusions
The presented data subclassified CRCs based on their activated signaling pathways and identify a role for c-MET and IGF1R-driven PI3K signaling in CRCs, which is superior to KRAS mutational tests alone. The results from this study can be utilized to identify aggressive CRCs, explain failure of currently approved therapeutics in specific CRC subsets, and, most importantly, generate hypotheses for pathway-guided therapeutic strategies that can be tested clinically.
doi:10.1371/journal.pone.0103551
PMCID: PMC4121133  PMID: 25090459
18.  The EF-hand calcium-binding protein tescalcin is a potential oncotarget in colorectal cancer 
Oncotarget  2014;5(8):2149-2160.
Tescalcin (TESC) is an EF-hand calcium binding protein that is differentially expressed in several tissues, however it is not reported that the expression and functional roles of TESC in colorectal cancer. Levels of messenger RNA (mRNA) and protein expression of TESC in colorectal cancer tissues were assessed using RT-PCR, real time PCR, immunohistochemistry, and clinicopathologic analyses. Quantitative analysis of TESC levels in serum specimens was performed using sandwich ELISA. Colorectal cancer cells transfected with TESC small interfering RNA and short hairpin RNA were examined in cell proliferation assays, phospho-MAPK array, and mouse xenograft models. Here we demonstrated that TESC is overexpressed in colorectal cancer (CRC), but was not expressed in normal mucosa and premalignant dysplastic lesions. Furthermore, serum TESC levels were elevated in patients with CRC. Knockdown of TESC inhibited the Akt-dependent NF-κB pathway and decreased cell survival in vitro. Depletion of TESC reduced tumor growth in a CRC xenograft model. Thus, TESC is a potential diagnostic marker and oncotarget in colorectal cancer.
PMCID: PMC4039152  PMID: 24811141
Tescalcin; colorectal cancer; cell growth; tumor growth, NF-κB
19.  Collagen Triple Helix Repeat Containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells 
Oncotarget  2014;5(2):519-529.
Collagen triple helix repeat-containing 1 (CTHRC1) is known to be aberrantly upregulated in most human solid tumors, although the functional roles of CTHRC1 in colorectal cancer remain unclear. In this study, we investigated the occurrence of CTHRC1 upregulation and its role in vivo and in vitro. The expression profile and clinical importance of CTHRC1 were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses in normal and tumor patient samples. CTHRC1 was detectable in normal tissues, but also was highly expressed in tumor specimens. CTHRC1 upregulation was significantly associated with demethylation of the CTHRC1 promoter in colon cancer cell lines and tumor tissues. Clinicopathologic analyses showed that nodal status and expression of CTHRC1 (95% CI 0.999–3.984, p=0.05) were significant prognostic factors for disease-free survival. Promoter CpG methylation and hypermethylation status were measured by bisulfite sequencing and pyrosequencing analysis. Furthermore, we showed that overexpression of CTHRC1 in the SW480 and HT-29 cell lines increased invasiveness, an effect mediated by extracellular signal-regulated kinase (ERK)-dependent upregulation of matrix metalloproteinase 9 (MMP9). Consistent with this, we found that knockdown of CTHRC1 attenuated ERK activation and cancer cell invasivity. These results demonstrate that CTHRC1 expression is elevated in human colon cancer cell lines and clinical specimens, and promotes cancer cell invasivity through ERK-dependent induction of MMP9 expression. Our results further suggest that high levels of CTHRC1 expression are associated with poor clinical outcomes.
PMCID: PMC3964226  PMID: 24504172
CTHRC1; ERK; MMP9; Invasion; Colorectal cancer
20.  Alcohol dehydrogenase, iron containing, 1 promoter hypermethylation associated with colorectal cancer differentiation 
BMC Cancer  2013;13:142.
Background
The aberrant methylation of CpG islands in the promoter is associated with colorectal cancer (CRC) carcinogenesis. In our previous study, the promoter of alcohol dehydrogenase, iron containing, 1 (ADHFE1) was most highly methylated in CRC compared to normal colorectal mucosa. In this study, we examined the expression and function of the ADHFE1 in CRC.
Methods
We examined the promoter methylation and mRNA expression of ADHFE1 with 5-aza-2′-deoxycytidine (5-Aza-2-dC) in 12 CRC cell lines, 124 paired CRC and adjacent normal mucosa, and 59 advanced adenomas. To confirm methylation of ADHFE1, we performed bisulfite genomic sequencing in 3 CRC cell lines, 6 paired CRC and adjacent normal mucosa. ADHFE1 protein expression was studied using western blot and immunohistochemistry, respectively in the 36 and 243 paired CRC and adjacent normal tissue. We transfected the DLD-1 with pcDNA3.1 vector containing ADHFE1 and examined the expression of differentiation marker, such as ALP, CEA and Cdx2. We examined the ADHFE1 expression at distinct developmental stages in mouse embryos.
Results
The ADHFE1 promoter was hypermethylated in all CRC cell lines, 81.8% in CRCs, and 84.7% in advanced adenomas, with reciprocal change by 5-Aza-2-dC. The expression of ADHFE1 mRNA was down-regulated in all CRC cell lines and 96.3% in CRC tissues. The expression of ADHFE1 protein was down-regulated in 91.7% of CRC tissues. In the immunohistochemistry, normal epithelial cells at the crypt top showed very strong ADHFE1 expression, whereas they were much weaker at the crypt base. In CRC, the good differentiation was significantly associated with high ADHFE1 expression. The activity of differentiation marker, such as ALP and CEA, was higher in pcDNA3.1-ADHFE1 transfected CRC cells with consistent correlation with ADHFE1 protein than control. In mouse embryos, ADHFE1 in the large intestine was the first detected at E15.5. At E18.5, ADHFE1 was predominantly expressed in the top of the mature crypt epithelium.
Conclusions
It showed that the hypermethylation of ADHFE1 promoter in CRC is concordance with down-regulation of ADHFE1 mRNA and ADHFE1 protein. ADHFE1 has an important role of differentiation in CRC, as well as normal colorectal mucosa and embryonic developmental processes.
doi:10.1186/1471-2407-13-142
PMCID: PMC3618294  PMID: 23517143
ADHFE1; Promoter methylation; Colorectal cancer; Differentiation
21.  Outcome of total proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis 
Purpose
We evaluated the risk factors for late complications and functional outcome after total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC).
Methods
Pre- and postoperative clinical status and follow-up data were obtained for 55 patients who underwent TPC with IPAA between 1999 and 2010. The median follow-up duration was 4.17 years. Late complications were defined as those that appeared at least one month after surgery. For a functional assessment, telephone interviews were conducted using the Global Assessment of Functioning Scale. Twenty-eight patients completed the interview.
Results
Late complications were found in 20 cases (36.3%), comprising pouchitis (n = 8), bowel obstruction (n = 5), ileitis (n = 3), pouch associated fistula (n = 2), and intra-abdominal infection (n = 2). The preoperative serum albumin level for patients with late complications was lower than for patients without (2.4 ± 0.5 vs. 2.9 ± 0.7, P = 0.04). Functional outcomes were not significantly associated with clinical characteristics, follow-up duration, operation indication, or late complications.
Conclusion
This study demonstrated that a low preoperative albumin level could be a risk factor for late complications of TPC with IPAA. Preoperative nutritional support, especially albumin, could reduce late complications. Functional outcomes are not related to late complications.
doi:10.4174/jkss.2012.83.3.135
PMCID: PMC3433549  PMID: 22977759
Ulcerative colitis; Proctocolectomy; Complications
22.  Negative impact of pretreatment anemia on local control after neoadjuvant chemoradiotherapy and surgery for rectal cancer 
Radiation Oncology Journal  2012;30(3):117-123.
Purpose
Although anemia is considered to be a contributor to intra-tumoral hypoxia and tumor resistance to ionizing radiation in cancer patients, the impact of pretreatment anemia on local control after neoadjuvant concurrent chemoradiotherapy (NACRT) and surgery for rectal cancer remains unclear.
Materials and Methods
We reviewed the records of 247 patients with locally advanced rectal cancer who were treated with NACRT followed by curative-intent surgery.
Results
The patients with anemia before NACRT (36.0%, 89/247) achieved less pathologic complete response (pCR) than those without anemia (p = 0.012). The patients with pretreatment anemia had worse 3-year local control than those without pretreatment anemia (86.0% vs. 95.7%, p = 0.005). Multivariate analysis showed that pretreatment anemia (p = 0.035), pathologic tumor and nodal stage (p = 0.020 and 0.032, respectively) were independently significant factors for local control.
Conclusion
Pretreatment anemia had negative impacts on pCR and local control among patients who underwent NACRT and surgery for rectal cancer. Strategies maintaining hemoglobin level within normal range could potentially be used to improve local control in rectal cancer patients.
doi:10.3857/roj.2012.30.3.117
PMCID: PMC3496845  PMID: 23170290
Anemia; Rectal cancer; Neoadjuvant therapy; Concurrent chemoradiotherapy
23.  Epigenomic Analysis of Aberrantly Methylated Genes in Colorectal Cancer Identifies Genes Commonly Affected by Epigenetic Alterations 
Annals of Surgical Oncology  2011;18(8):2338-2347.
Background
Determination of the profile of genes that are commonly methylated aberrantly in colorectal cancer (CRC) will have substantial value for diagnostic and therapeutic applications. However, there is limited knowledge of the DNA methylation pattern in CRC.
Materials and Methods
We analyzed the methylation profile of 27,578 CpG sites spanning more than 14,000 genes in CRC and in the adjacent normal mucosa using beadchip array-based technology.
Results
We identified 621 CpG sites located in promoter regions and CpG islands that were significantly hypermethylated in CRC compared to normal mucosa. The genes on chromosome 18 showed promoter hypermethylation most frequently. According to gene ontology analysis, the most common biologically relevant class of genes affected by methylation was the class associated with the cadherin signaling pathway. Compared to the genome-wide expression array, mRNA expression was more likely to be down-regulated in the genes demonstrating promoter hypermethylation, even though this was not statistically significant. We validated 10 CpG sites that were hypermethylated (ADHFE1, BOLL, SLC6A15, ADAMTS5, TFPI2, EYA4, NPY, TWIST1, LAMA1, GAS7) and 2 CpG sites showing hypomethylation (MAEL, SFT2D3) in CRC compared to the normal mucosa in the array studies using pyrosequencing. The methylation status measured by pyrosequencing was consistent with the methylation array data.
Conclusions
Methylation profiling based on beadchip arrays is an effective method for screening aberrantly methylated genes in CRC. In addition, we identified novel methylated genes that are candidate diagnostic or prognostic markers for CRC.
doi:10.1245/s10434-011-1573-y
PMCID: PMC3393129  PMID: 21298349
24.  Transanal Endoscopic Microsurgery for the Treatment of Well-Differentiated Rectal Neuroendocrine Tumors 
Purpose
Recently, an increase in well-differentiated rectal neuroendocrine tumors (WRNETs) has been noted. We aimed to evaluate transanal endoscopic microsurgery (TEM) for the treatment of WRNETs.
Methods
Between December 1995 and August 2009, 109 patients with WRNETs underwent TEM. TEM was performed for patients with tumors sizes of up to 20 mm and without a lymphadenopathy. These patients had been referred from other clinics after having been diagnosed with WRNETs by using a colonoscopic biopsy; they had undergone a failed endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) and exhibited an involved resection margin and remaining tumor after ESD or EMR, regardless of the distance from the anal verge. This study included 38 patients that had more than three years of follow-up.
Results
The mean age of the patients was 51.3 ± 11.9 years, the mean tumor size was 8.0 ± 3.9 mm, and no morbidity occurred. Thirty-five patients were asymptomatic. TEM was performed after a colonoscopic resection in 13 cases because of a positive resection margin, a residual tumor or a non-lifting lesion. Complete resections were performed in 37 patients; one patient with a positive margin was considered surgically complete. In one patient, liver metastasis and a recurrent mesorectal node occurred after five and 10 years, respectively.
Conclusion
TEM might provide an accessible and effective treatment either as an initial or as an adjunct after a colonoscopic resection for a WRNET.
doi:10.3393/jksc.2012.28.4.201
PMCID: PMC3440489  PMID: 22993706
Well-differentiated rectal neuroendocrine tumors; Transanal endoscopic microsurgery; Colonoscopic resection; Treatment
25.  Metastasis of Neuroendocrine Tumors Are Characterized by Increased Cell Proliferation and Reduced Expression of the ATM Gene 
PLoS ONE  2012;7(4):e34456.
Purpose
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis.
Experimental Design
To investigate differential gene expression signatures of metastatic vs non-metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation.
Results
We first delineated six candidate genes for metastasis including ATM, CCND2, RBL2, CDKN3, CCNB1, and GTSE1. ATM was negatively correlated with metastatic NETs (p<0.001) with more than 2-fold change compared to non-metastatic NETs. Overexpression of ATM protein by IHC was strongly correlated with high ATM mRNA levels and low Ki-67 labeling index. Patients with ATM-negativity by IHC showed significantly decreased overall survival than patients with ATM-positivity (median OS, metastatic vs non-metastatic NETs; 2.7 years vs not reached; p = 0.003) and 85.7% of metastatic NETs were ATM-negative. In another validation set of GEP-NETs, decreased mRNA of ATM gene was associated with metastasis and remained significant (p = 0.023).
Conclusions
ATM down-regulation was strongly associated with metastatic NETs when compared with non-metastatic NETs and ATM may be a potential predictive marker for metastasis as well as a novel target in metastatic GEP-NETs.
doi:10.1371/journal.pone.0034456
PMCID: PMC3317775  PMID: 22485171

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