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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.  Predicting multi-class responses to preoperative chemoradiotherapy in rectal cancer patients 
Background
Preoperative chemoradiotherapy (CRT) has become a widely used treatment for improving local control of disease and increasing survival rates of rectal cancer patients. We aimed to identify a set of genes that can be used to predict responses to CRT in patients with rectal cancer.
Methods
Gene expression profiles of pre-therapeutic biopsy specimens obtained from 77 rectal cancer patients were analyzed using DNA microarrays. The response to CRT was determined using the Dworak tumor regression grade: grade 1 (minimal, MI), grade 2 (moderate, MO), grade 3 (near total, NT), or grade 4 (total, TO).
Results
Top ranked genes for three different feature scores such as a p-value (pval), a rank product (rank), and a normalized product (norm) were selected to distinguish pre-defined groups such as complete responders (TO) from the MI, MO, and NT groups. Among five different classification algorithms, supporting vector machine (SVM) with the top 65 norm features performed at the highest accuracy for predicting MI using a 5-fold cross validation strategy. On the other hand, 98 pval features were selected for predicting TO by elastic net (EN). Finally we combined TO- and MI-finder models to build a three-class classification model and validated it using an independent dataset of rectal cancer mRNA expression.
Conclusions
We identified MI- and TO-finders for predicting preoperative CRT responses, and validated these data using an independent public dataset. This stepwise prediction model requires further evaluation in clinical studies in order to develop personalized preoperative CRT in patients with rectal cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-016-0623-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13014-016-0623-9
PMCID: PMC4804643  PMID: 27005571
Prediction model; Rectal cancer; Chemoradiotherapy; Dworak classification; Microarray
14.  Risk Factors of Anastomotic Leakage and Long-Term Survival After Colorectal Surgery 
Medicine  2016;95(8):e2890.
Abstract
Anastomotic leakage (AL) is one of the most serious complications of colorectal surgery. It can affect long-term oncologic outcomes, but the impact on long-term survival remains uncertain. The aim of this study is to evaluate the operative characteristics of leakage and no leakage groups and to analyze long-term oncologic outcomes.
We prospectively enrolled 10,477 patients from 2000 to 2011 and retrospectively reviewed the data.
Male sex (odds ratio [OR], 3.90; P < 0.001), intraoperative transfusion (OR, 2.31; P = 0.042), and operative time (OR, 1.73; P = 0.032) were independent risk factors of AL in the colon. In the rectum, male sex (OR, 2.37; P < 0.001), neoadjuvant chemoradiotherapy (OR, 2.26; P < 0.001), and regional lymph node metastasis (OR, 1.43; P = 0.012) were independent risk factors of AL, and diverting stoma (OR, 0.24; P < 0.001) was associated with a deceased risk of AL. AL in the rectum without a diverting stoma was associated with disease-free survival (DFS, OR, 1.47; P = 0.037). Colonic leakage was not associated with 5-year DFS (leakage group vs nonleakage group, 72.4% vs 80.9%, P = 0.084); however, in patients undergoing rectal resection, there was a significant difference in 5-year DFS (67.0% vs 76.6%, P = 0.005, respectively).
AL in the rectum is associated with worse long-term DFS and overall survival. A diverting stoma was shown to protect against this effect and was associated with long-term survival in rectal surgery. Therefore, creating a diverting stoma should be considered in high-risk patients undergoing rectal surgery.
doi:10.1097/MD.0000000000002890
PMCID: PMC4779025  PMID: 26937928
15.  The impact of KRAS mutations on prognosis in surgically resected colorectal cancer patients with liver and lung metastases: a retrospective analysis 
BMC Cancer  2016;16:120.
Background
KRAS mutations are common in colorectal cancer (CRC). The role of KRAS mutation status as a prognostic factor remains controversial, and most large population-based cohorts usually consist of patients with non-metastatic CRC. We evaluated the impact of KRAS mutations on the time to recurrence (TTR) and overall survival (OS) in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy.
Methods
Patients who underwent curative resection for primary and synchronous metastases were retrospectively collected in a single institution during a 6 year period between January 2008 and June 2014. Patients with positive surgical margins, those with known BRAF mutation, or those with an unknown KRAS mutation status were excluded, and a total of 82 cases were identified. The pathological and clinical features were evaluated. Patients’ outcome with KRAS mutation status for TTR and OS were investigated by univariate and multivariate analysis.
Results
KRAS mutations were identified in 37.8 % of the patients and not associated with TTR or OS between KRAS wild type and KRAS mutation cohorts (log-rank p = 0.425 for TTR; log-rank p = 0.137 for OS). When patients were further subdivided into three groups according to mutation subtype (wild-type vs. KRAS codon 12 mutation vs. KRAS codon 13 mutation) or amino acid missense mutation type (G > A vs. G > T vs. G > C), there were no significant differences in TTR or OS. Mutational frequencies were significantly higher in patients with lung metastases compared with those with liver and ovary/bladder metastases (p = 0.039), however, KRAS mutation status was not associated with an increased risk of relapsed in the lung.
Conclusions
KRAS mutation was not associated with TTR or OS in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy.
doi:10.1186/s12885-016-2141-4
PMCID: PMC4758097  PMID: 26887348
Colorectal cancer; KRAS mutation; Prognosis; Metastases
16.  Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors 
Oncotarget  2015;7(4):4024-4035.
Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.
doi:10.18632/oncotarget.6602
PMCID: PMC4826187  PMID: 26684240
neuroendocrine tumors; BRAFV600E mutation; pazopanib
17.  Prospective blinded study of somatic mutation detection in cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients 
Oncotarget  2015;6(37):40360-40369.
Sequencing of the mutant allele fraction of circulating cell-free DNA (cfDNA) derived from tumors is increasingly utilized to detect actionable genomic alterations in cancer.
We conducted a prospective blinded study of a comprehensive cfDNA sequencing panel with 54 cancer genes. To evaluate the concordance between cfDNA and tumor DNA (tDNA), sequencing results were compared between cfDNA from plasma and genomic tumor DNA (tDNA). Utilizing next generation digital sequencing technology (DST), we profiled approximately 78,000 bases encoding 512 complete exons in the targeted genes in cfDNA from plasma. Seventy-five patients were prospectively enrolled between February 2013 and March 2014, including 61 metastatic cancer patients and 14 clinical stage II CRC patients with matched plasma and tissue samples. Using the 54-gene panel, we detected at least one somatic mutation in 44 of 61 tDNA (72.1%) and 29 of 44 (65.9%) cfDNA. The overall concordance rate of cfDNA to tDNA was 85.9%, when all detected mutations were considered. We collected serial cfDNAs during cetuximab-based treatment in 2 metastatic KRAS wild-type CRC patients, one with acquired resistance and one with primary resistance. We demonstrate newly emerged KRAS mutation in cfDNA 1.5 months before radiologic progression. Another patient had a newly emerged PIK3CA H1047R mutation on cfDNA analysis at progression during cetuximab/irinotecan chemotherapy with gradual increase in allele frequency from 0.8 to 2.1%. This blinded, prospective study of a cfDNA sequencing showed high concordance to tDNA suggesting that the DST approach may be used as a non-invasive biopsy-free alternative to conventional sequencing using tumor biopsy.
PMCID: PMC4741900  PMID: 26452027
cell-free DNA (cfDNA); digital sequencing; genomic test
18.  The NEXT-1 (Next generation pErsonalized tX with mulTi-omics and preclinical model) trial: prospective molecular screening trial of metastatic solid cancer patients, a feasibility analysis 
Oncotarget  2015;6(32):33358-33368.
We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.
PMCID: PMC4741771  PMID: 26396172
molecular profiling; genome; ampliseq
19.  Gastrointestinal malignancies harbor actionable MET exon 14 deletions 
Oncotarget  2015;6(29):28211-28222.
Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.
PMCID: PMC4695055  PMID: 26375439
MET exon 14 skipping; colorectal carcinoma; MET monoclonal antibodies; crizotinib; gastrointestinal malignancies
20.  Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening 
Oncotarget  2015;6(27):24320-24332.
Purpose
Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies.
Experimental designs
Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial.
Results
Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.
Conclusions
ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
PMCID: PMC4695188  PMID: 26172300
colorectal carcinoma; anaplastic lymphoma kinase (ALK) rearrangement; immunohistochemistry; next generation sequencing
21.  Correlation between tumor engraftment in patient-derived xenograft models and clinical outcomes in colorectal cancer patients 
Oncotarget  2015;6(18):16059-16068.
Despite numerous studies involving patient-derived xenograft (PDX) models, few studies have investigated the relationship between the ability of the tumor to engraft (tumorigenicity) and the clinical features of colorectal cancer (CRC). The aim of this study was to determine whether tumorigenicity correlates with clinical outcomes of CRC patients. We included 241 CRC patients who underwent radical surgery from 2010 to 2013. PDX models were established by implanting tumor fragments obtained from these patients into the subcutaneous layer of immunodeficient mice. Xenografts were successfully established from 62.2%. Successful engraftment was associated with advanced stage (p < 0.001) and moderate/poor differentiation (p = 0.029). Three-year disease-free survival (DFS) rates were lower for patients with tumorigenicity (p = 0.011). In stage III patients, tumorigenicity was an independent predictor of poor DFS (p = 0.034). In addition, mutation of TP53 was most frequently detected in stage III patients with tumorigenicity. Two models of stage IV disease without KRAS mutations showed high sensitivity to EGFR-targeted agents, while none of the models with KRAS mutations showed high sensitivity. In conclusion, PDX models may provide an effective preclinical tool for predicting cancer progression and could be used to further genomic and pharmacologic research on personalized treatments.
PMCID: PMC4599256  PMID: 25965827
colorectal cancer; survival; xenograft; genomic profile; drug response
22.  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
23.  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
24.  Prognostic Comparison Between Mucinous and Nonmucinous Adenocarcinoma in Colorectal Cancer 
Medicine  2015;94(15):e658.
Abstract
Mucinous adenocarcinoma (MAC) is a histological subtype of colorectal cancer. The oncologic behavior of MAC differs from nonmucinous adenocarcinoma (non-MAC). Our aim in this study was to characterize patients with colorectal MAC through evaluation of a large, institutional-based cohort with long-term follow-up.
A total of 6475 patients with stages I to III colorectal cancer who underwent radical surgery were enrolled from January 2000 to December 2010. Prognostic comparison between MAC (n = 274, 4.2%) and non-MAC was performed.
The median follow-up period was 48.0 months. Patients with MAC were younger than those without MAC (P = 0.012) and had larger tumor size (P < 0.001), higher preoperative carcinoembryonic antigen (P < 0.001), higher pathologic T stage (P < 0.001), more right-sided colon cancer (49.3%, P < 0.001), and more frequent high-frequency microsatellite instability (10.2%, P < 0.001). Five-year disease-free survival (DFS) was 76.5% in the MAC group and 83.2% in the non-MAC group (P = 0.008), and 5-year overall survival was 81.4% versus 87.4%, respectively (P = 0.005). Mucinous histology (MAC vs non-MAC) in the entire cohort was not an independent prognostic factor of DFS but had a statistical tendency (P = 0.071). In subgroup analysis of colon cancer without rectal cancer, mucinous histology was an independent prognostic factor (P = 0.026).
MAC was found at more advanced stage, located mainly at the right side and was an independent factor of survival in colon cancer. Because of the unique biological behavior of MAC, patients with MAC require special consideration during follow-up.
doi:10.1097/MD.0000000000000658
PMCID: PMC4602499  PMID: 25881840
25.  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

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