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Background Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers. Methods This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap. Results On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer. Conclusions Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer.

The effects of primary tumor location on colorectal liver metastasis (CRLM) and post-hepatic-metastasectomy overall survival (OS) are controversial. This study evaluated the difference in post-hepatic-metastasectomy OS among right-sided colon, left-sided colon, and rectal cancer groups. In total, 381 patients who underwent curative-intent CRLM resection were enrolled. Patients were grouped based on the primary tumor location (right-sided, left-sided, and rectum). The Kaplan–Meier analysis and log-rank test were performed for survival analysis. The univariate and multivariate analyses of clinical and pathological factors were performed using the Cox proportional hazards model. Significant OS difference was noted among the three groups (log-rank, p = 0.014). The multivariate analysis revealed a 32% lower death risk in left-sided colon cancer compared with right-sided colon cancer (hazard ratio [HR] 0.68, p = 0.042), whereas no OS difference was noted between the rectal cancer and right-sided colon cancer groups. The left- versus right-sided OS advantage was noted only in the KRAS wild-type subgroup (HR 0.46, p = 0.002), and a rectal versus right-sided OS disadvantage was noted in the KRAS mutant subgroup (HR 1.78, p = 0.03). The CRLM post-hepatic-metastasectomy OS was superior in left-sided colon cancer than in right-sided colon cancer and was similar in rectal and right-sided colon cancer. The OS difference in different primary tumor locations is dependent on KRAS mutation status, with a decreased left- versus right-sided death risk noted only in KRAS wild-type colon cancer and an increased rectal versus right-sided death risk noted only in KRAS mutant colon cancer.

Given the unclear preference criteria for regorafenib in treating refractory metastatic colorectal cancer (mCRC), this study aimed to construct an algorithm in selecting right patients for regorafenib. This was a multicenter retrospective cohort study. Patients with pathology confirmed mCRC and administered with regorafenib for > 3 weeks were enrolled. Patients with good response were defined to have progression-free survival (PFS) of ≥ 4 months. The Kaplan–Meier plot was used to analyze survival. A Cox proportional hazards model was used to analyze univariate and multivariate prognostic factors and was visualized using forest plot. A clustering heatmap was used to classify patients according to responses. The decision tree and nomogram were used to construct the approaching algorithm. A total of 613 patients was analyzed. The median PFS and overall survival (OS) were 2.7 and 10.6 months, respectively. The partial response and stable disease rate are 2.4% and 36.4%. The interval between metastasis (M1) and regorafenib, metastatic status (number, liver, and brain), and CEA level were independent prognostics factors of PFS that classifies patients into three groups: good, bad and modest-1/modest-2 group with PFS > = 4 months rates of 51%, 20%, 39% and 30%, respectively. Results were used to develop the decision tree and nomogram for approaching patients indicated with regorafenib. The preference criteria for regorafenib in treating patients with refractory mCRC are small tumor burden (CEA), slow growth (interval between metastasis and regorafenib) and poor/scanty spread (metastatic status: number and sites of metastasis): The 3S rules. TRIAL registration ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03829852","term_id":"NCT03829852"}}NCT03829852; Date of first registration (February 11, 2019).

BACKGROUND Both regorafenib and reduced-intensity FOLFOXIRI (riFOLFOXIRI) prolong survival in patients with metastatic colorectal cancer (mCRC). However, the sequence in which they should be administrated first in late-line treatment for refractory mCRC remains unclear. PATIENTS AND METHODS This study was a single-center retrospective cohort study that reviewed data from patients at Taipei Veterans General Hospital, Taiwan, with mCRC refractory to fluorouracil, irinotecan, oxaliplatin, cetuximab (wild-type RAS), and bevacizumab. Patients were divided into 2 groups: a regorafenib-first group and a riFOLFOXIRI-first group. The Kaplan-Meier method and log-rank test were used to analyze survival, and a Cox proportional hazards model was used for univariate, multivariate, and subgroup analyses. RESULTS A total of 136 and 55 patients followed a regorafenib-first or riFOLFOXIRI-first treatment strategy, respectively. At baseline, patient characteristics were similar between the groups, except for younger age in the riFOLFOXIRI-first group. The regorafenib-first group had better overall survival (13.8 vs. 10.7 mo, P=0.038), whereas patients in the riFOLFOXIRI-first group had a better partial response rate (P=0.005) but a higher rate of discontinuation due to adverse effects (P=0.004) and cross-over to regorafenib (P

To compare the cost-performance between planned short-course radiation and upfront concurrent chemoradiation on metastatic rectal cancer. A total of 75 patients with metastatic rectal cancer who underwent planned short-course radiation or upfront concurrent chemoradiation were enrolled. The Kaplan-Meier method was used to compute the survival rates. The χ2 test was used to compare baseline characteristics. The Cox proportional hazards model was applied to determine the prognostic influence of clinicopathological factors. The planned short-course radiation is superior to upfront concurrent chemoradiation in overall survival for the patients with metastatic rectal cancer (34.8 vs. 20.2 months, P = 0.010). The planned short-course radiation was an independent prognostic factor (P = 0.009, HR (95% CI) = 0.319(0.135–0.752)). The efficacy of radiation on downstaging was similar between planned short-course radiation and upfront concurrent chemoradiation. The total cost of concurrent chemoradiation is 4.52-fold more expensive than that of short-course radiation (340,142 vs. 75,106 NT dollars, respectively). Based on the impressive cost-performance of planned short-course radiation compared with upfront concurrent chemoradiation (better OS, modest downstaging and lower cost), planned short-course radiation should be the preferred radiation approach for managing metastatic rectal cancer.

Background Three-dimensional (3D) laparoscopy was developed to overcome the drawbacks of two-dimensional (2D) laparoscopy, namely lack of depth perception. However, the benefit of 3D laparoscopy in colorectal surgery is inconclusive. Here, we compare the 3-year follow-up outcomes of 3D and 2D laparoscopic colectomy. Patients and methods A total of 91 consecutive patients who underwent either 3D or 2D laparoscopy colectomy from October 2015 to November 2017 by a single surgical team for colon cancer were enrolled. Data were collected from a prospectively constructed database, including clinico-pathological features and operative parameters. The pathological results, recurrence, survival and systemic treatment were collected from the Taiwan Cancer Database. Results There were 47 patients in the 3D group and 44 in the 2D group. There were no significant differences in characteristics of patients, operation data, pathological results, complications, operative time, blood loss or the number of lymph node harvested between the two groups. In addition, disease-free survival and overall survival were equal between the two groups. Conclusions This is the first long-term result of a 3D laparoscopic colectomy. In our 3-year follow-up, there was no difference in long-term outcomes between 2D and 3D laparoscopy for colorectal surgery in an experienced centre.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan–kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness.

Background: Few reports have investigated genetic alterations between patients with early and late recurrence following curative surgery for colorectal cancer (CRC). Methods: A total of 1227 stage I–III CRC patients who underwent curative resection were included retrospectively. Among them, 236 patients had tumor recurrence: 139 had early (&lt, 2 years after surgery) and 97 had late (≥2 years after surgery) recurrence. Clinicopathological features and genetic alterations were compared between the two groups. Results: Compared to those with late recurrence, patients with early recurrence were more likely to have advanced pathological node (N) categories, tumor, node, metastasis (TNM) stages, adjuvant chemotherapy treatment, liver metastases, APC mutations, and worse five-year overall survival rates. Patients with right-sided colon cancer were more likely to develop early recurrence than were those with left-sided colon cancer or rectal cancer. Regarding rectal cancer, patients with early recurrence were more likely to be at advanced pathological N categories and TNM stages than those with late recurrence. Multivariate analysis revealed old age, early recurrence, multiple-site recurrence, and BRAF and NRAS mutations to be independent prognostic factors. Conclusion: CRC patients with early recurrence have a worse OS rate and more APC mutations than those with late recurrence.

Background We present our initial single-centre experience with Senhance surgical robot-assisted colorectal surgery and examine its safety and feasibility. Methods From June 2019 to December 2019, patients who underwent Senhance surgical robot-assisted colorectal surgery in our hospital were retrospectively analysed. We focused on the short-term outcomes. Results In total, 46 patients were enrolled in the study. Colorectal cancer was the most common indication for surgery (39 patients). The median total operation time was 283 min, and the median blood loss was 50 cc. Meanwhile, the median number of harvested lymph nodes was 20. Elderly age, advanced American Society of Anaesthesiologists stage, and right-sided colon surgery were associated with the occurrence of complications greater than grade III. Conclusion Our findings demonstrate the feasibility and safety of the Senhance surgical robotic system in colorectal surgery. Care should be taken regarding the indications and patient selection.

BackgroundThe prognosis of mucinous adenocarcinoma (MAC) and non-mucinous adenocarcinoma (NMAC) in colorectal cancer (CRC) is controversial, and the molecular differences between them are unclear.MethodsBetween 2000 and 2010, a total of 1,483 CRC patients were included. Among them, 73 patients (4.9%) were diagnosed with MAC. The clinicopathological features and genetic alterations were compared between MAC and NMAC.ResultsAfter propensity score matching to balance age and sex between MAC and NMAC patients, 292 CRC patients (73 MAC and 219 NMAC) were enrolled in the analysis at a 1:3 ratio. In right-sided colon cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, and advanced T category and tumor, node, metastasis (TNM) stage, chemotherapy, and a similar 5-year overall survival (OS) rate compared with patients with NMAC. In left-sided colon cancer and rectal cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, lymphovascular invasion, advanced T and N categories and TNM stages, chemotherapy, and a worse 5-year OS rate than patients with NMAC. Regarding genetic alterations, for NMAC, right-sided colon cancer had more BRAF mutations than left-sided colon cancer and rectal cancer. For MAC, right-sided colon cancer was associated with more microsatellite instability-high tumors and more AKT1 mutations than left-sided colon cancer and rectal cancer.ConclusionThe genetic alterations are distinct between MAC and NMAC in CRC. Tumor location may have an impact on genetic alterations and patient prognosis in MAC and NMAC.

Background Laparoscopic surgery has become a well-established technique for management of various surgical problems. A more efficient training methods are of upmost importance for current surgery residents. Methods This is a prospective, randomized, 3-arm trial to compare the training efficient of the naked-eye box trainer, training box games and conventional video-based box trainer in training laparoscopic suturing skill. Results The three training models were well acceptable and all could improve the acquisition of laparoscopic suturing and knotting skill in novices. The completion time was 604 ± 298 s in the box trainer games, 617 ± 335 s in the naked-eye training module, and 491 ± 334 s in the video-based box trainer (p = 0.322). Using the structured procedure-specific checklist, there was no significant difference in scores between these three groups (p = 0.977). Conclusions Naked-eye box trainer and training box games produce similar training effect as the conventional video-based box trainer. The naked-eye box trainer may serve as a convenient way for novice trainees to acquire laparoscopic suturing technique skills before video-based simulation.

Background Perineal wound complications are a long-lasting issue for abdominoperineal resection (APR) patients. Complication rates as high as 60% have been reported, with the most common complication being delayed perineal wound healing. The aim of this study was to identify risk factors for delayed perineal wound healing and its impact on prolonged hospital stay. Methods We included low rectal tumor patients who underwent APR at a referral medical center from April 2002 to December 2017; a total of 229 patients were included. The basic characteristics and surgical outcomes of the patients were analyzed to identify risk factors for delayed perineal wound healing (> 30 days after APR) and prolonged hospital stay (post-APR hospital stay > 14 days). Results All patients received primary closure for their perineal wound. The majority of patients were diagnosed with adenocarcinoma (N = 213, 93.1%). In the univariate analysis, patients with hypoalbuminemia (albumin P = 0.001), which was an independent risk factor in the multivariable analysis (OR 2.962, 95% CI 1.437–6.102, P = 0.003). Patients with delayed wound healing also had a significantly increased risk of prolonged hospital stay (OR 6.404, 95% CI 3.508–11.694, P < 0.001). Conclusions Hypoalbuminemia was an independent risk factor for delayed wound healing, which consequently led to a prolonged hospital stay. Further clinical trials are needed to reduce the incidence of delayed perineal wound healing by correcting albumin levels or nutritional status before APR.

Objective: Mutation spectra in colorectal cancer with metastasis and its response to chemotherapy. Summary of Background Data: No molecular markers are available for selecting the optimal chemotherapeutic regimen (irinotecan or oxaliplatin) for metastatic colorectal cancer (mCRC). Methods: We enrolled 161 mCRC patients who underwent surgery for their primary tumors at Taipei Veterans General Hospital from 2004 to 2010. The prevalence of gene mutations was measured and correlated with responses to different cytotoxic agents. Results: We detected 1,836 mutations in 12 genes. KRAS mutants affected 44.3% of the tumors. The rate of good response was insignificantly higher for patients with KRAS mutant tumors who received oxaliplatin-based chemotherapy compared with patients with KRAS wild-type tumors (65.6% versus 47.0%; P = 0.15). For patients who received irinotecan-based chemotherapy, the rate of good response was similar in patients with wild-type (55.0%; n = 11) and those with KRAS mutant tumors (54.5%; n = 12; P = 1). In patients with KRAS mutant tumors treated with an oxaliplatin-based regimen, the overall survival was 38.5 months (95% CI: 26.6–50.5 months), which was insignificantly better than that for patients treated with an irinotecan-based regimen (30.4 months; 95% CI: 15.8–45.1 months; P = 0.206). Conclusions: Our data could not come to the conclusion that patient with KRAS mutation mCRC may have better response with oxaliplatin-based first-line chemotherapy. Further study is needed to confirm the relationship between gene mutation and chemotherapy response.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p &lt, 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.

Objectives Patients with systemic lupus erythematosus are considered vulnerable to infective endocarditis and prophylactic antibiotics are recommended before an invasive dental procedure. However, the evidence is insufficient. This nationwide population-based study evaluated the risk and related factors of infective endocarditis in systemic lupus erythematosus. Methods We identified 12,102 systemic lupus erythematosus patients from the National Health Insurance research-oriented database, and compared the incidence rate of infective endocarditis with that among 48,408 non-systemic lupus erythematosus controls. A Cox multivariable proportional hazards model was employed to evaluate the risk of infective endocarditis in the systemic lupus erythematosus cohort. Results After a mean follow-up of more than six years, the systemic lupus erythematosus cohort had a significantly higher incidence rate of infective endocarditis (42.58 vs 4.32 per 100,000 person-years, incidence rate ratio = 9.86, p Conclusions A higher risk of infective endocarditis was observed in systemic lupus erythematosus patients. Risk factors for infective endocarditis in the systemic lupus erythematosus cohort included heart disease, chronic kidney disease, steroid pulse therapy within 30 days, and a recent invasive dental procedure within 30 days.

To figure out the relationship between the tumor marker clearance rate during the treatment period and the disease prognosis. Carcinoembryonic antigen (CEA) is a glycoprotein that has been widely used as a tumor marker in colorectal cancer for more than 30 years. This study evaluated the role of the CEA clearance rate during treatment and determined its relationship with chemotherapy regimens, increased metastasectomy rate, and overall survival. The medical records of 442 metastatic colorectal cancer patients whose primary tumors were treated with surgery followed by systemic therapy at a single center from 2000 to 2012 were reviewed. The CEA clearance rate was calculated as a change in CEA after 6 courses of therapy divided by the treatment period [(posttherapy CEA – pretherapy CEA)/days between therapy], and classified into 4 groups for further evaluation. The CEA clearance rate during treatment of stage IV colorectal cancer was significantly correlated with different chemotherapy regimens (P < 0.01); pretreatment CEA level (P < 0.01); tumor differentiation (P < 0.01); increased metastasectomy rate (P = .02); and overall survival (P < 0.01). The CEA clearance rate during systemic therapy could evaluate patient treatment responses more precisely than traditionally rising or falling CEA levels, and may predict disease prognosis.

Patients with stage II colorectal cancer (CRC) have a higher risk of recurrence when they have certain risk factors, including clinical and pathological patterns. However, as the prognostic role of molecular patterns for stage II disease is still unclear, this study aimed to investigate it.A total of 509 patients with stage II CRC were enrolled, and all clinical, pathological, and molecular data were collected. Molecular patterns included microsatellite instability (MSI); elevated microsatellite alterations at selected tetranucleotides (EMAST) status; and expression of RAS/RAF genes, genes of the APC pathway, and other gene mutations. The endpoints were oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), local recurrence (LR), and distant recurrence (DR). Cox regression analysis was used.Numerous molecular patterns influenced the oncological outcomes on univariate analysis, but no variable reached significance in LR. On multivariate analysis, a mucinous component (MC) 50% (P 0.01) was significant for OS and CSS. Lymphovascular invasion (LVI; P 0.01), MC 50% (P 0.01), and EMAST-H (P = 0.02) significantly influenced DFS, whereas LVI (P 0.01), MC 50% (P 0.01), and TP53 mutation (P = 0.02) were significant for DR.In this study, MSI, EMAST, and RAS/RAF alterations did not influence the oncological outcomes. Overall, LVI and MC were two significant prognostic factors for DFS and DR. Thus, the histopathology, rather than the genes, plays a major role in the prognosis of patients with stage II CRC.

Purpose: The incidence, pathogenesis, molecular pathways, and outcomes of colorectal cancer vary depending on the location of the tumor. This study aimed to compare the difference in tumor characteristics and the outcome between right-sided colon cancer and left-sided colorectal cancer (LCRC). Materials and methods: A total of 1503 patients with colorectal cancer who underwent surgery at the Taipei Veterans General Hospital between 2000 and 2010 were enrolled in this study. Right-sided colon cancer was defined as cancers in the cecum, ascending colon, and transverse colon, while LCRC was defined as cancers in the splenic flexure colon, descending colon, sigmoid colon, and rectum. The endpoint was overall survival. The mutations were detected via polymerase chain reaction and MASS array. The prognostic value was determined using the log-rank test and the Cox regression analysis. Results: A total of 407 and 1096 cases were classified as right-sided colon cancer and LCRC, respectively. Compared to patients with LCRC, those with right-sided colon cancer had more mucinous type cancer (7.4% vs. 3.5%), poorly differentiated tumor (11.5% vs. 3.6%), and advanced tumor-node-metastasis stage. The risk for peritoneal tumor seeding was higher in the right-sided colon cancer group (12.8% vs. 5.7%). Overall survival was better in LCRC than in right-sided colon cancer ( P=0.036). Conclusions: In our study, right-sided colon cancer had a more advanced tumor stage, a higher risk of peritoneal metastasis, and a poorer outcome than LCRC. Moreover, right-sided colon cancer had more gene mutations in BRAF, KRAS, SMAD4, TGF-β, PIK3CA, PTEN, AKT1, and high microsatellite instability.

To investigate the associations between programmed cell death ligand-1 (PD-L1) on tumor cells (TCs) or PD-L1 on tumor-infiltrating immune cells (TIICs) and the microsatellite instability (MSI) status in colorectal cancer (CRC). In total, 238 CRC patients were enrolled. PD-L1 expression and MSI status were studied by immunohistochemical staining and polymerase chain reaction. The χ2 test was used to compare characteristics. The Kaplan–Meier method was used for survival analysis. Cox proportional hazards models were used to determine the prognostic influence of clinicopathological factors. Eighteen patients (7.6%) were had MSI-high (MSI-H) CRC. The number of patients with PD-L1 expression on TCs, stromal TIICs and intraepithelial TIICs was 13 (5.5%), 64 (26.9%) and 45 (18.9%), respectively. The MSI-H phenotype was significantly associated with younger age, right sidedness, mucinous component, high grade, stromal TIICs expressing PD-L1 (P = 0.042) and intraepithelial TIICs expressing PD-L1 (P

// Chieh-Sheng Lu, 1, 2, 3 , Jen-Kou Lin 5, 6 , Wei-Shone Chen 5, 6 , Tzu-Chen Lin 5, 6 , Jeng-Kai Jiang 5, 6 , Shung-Haur Yang 5, 6 , Huann-Sheng Wang 5, 6 , Shih-Ching Chang 5, 6 , Yuan-Tzu Lan 5, 6 , Chun-Chi Lin 5, 6 , Hung-Hsin Lin 5, 6 , Hao-Wei Teng 3, 4, 5 1 Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan 2 Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 3 Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan 4 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 5 School of Medicine, National Yang-Ming University, Taipei, Taiwan 6 Division of Colon and Rectum Surgery, Department of Surgery, Taipei Veterans General Hospital & National Yang-Ming University, Taipei, Taiwan Correspondence to: Hao-Wei Teng, email: hwteng1971@gmail.com Keywords: intraperitoneal injection, ziv-aflibercept, metastatic colorectal cancer, serum ascites albumin gradient Received: May 22, 2016 Accepted: November 12, 2016 Published: November 24, 2016 ABSTRACT Ascites related to metastatic colorectal cancer (mCRC) reduces patient survival and quality of life, and systemic chemotherapy is largely ineffective for managing ascites. Here, we examined the clinical efficacy of intraperitoneal (IP) ziv-aflibercept for managing refractory ascites in 15 mCRC patients who did not respond to standard chemotherapy. Fifty or 100 mg of ziv-aflibercept in 100 mL of saline solution were infused through a pigtail catheter and retained for 24 h. When the ascites drainage volumes were subsequently monitored, 73.3% of patients showed an objective response (OR) to IP ziv-aflibercept treatment. Patients with low Eastern Cooperative Oncology Group (ECOG) performance status or with serum ascites albumin gradients (SAAG) less than 1.1 g/dL had better responses to treatment, and 4 patients with SAAG less than 1.1 g/dL showed rapid objective responses (rOR). These findings indicate that intraperitoneal ziv-aflibercept therapy may be a highly effective means of treating refractory ascites in mCRC patients, and that SAAG may be predictive of a rapid response to this treatment.

Introduction Left- and right-sided colon cancers were significantly different in epidemiologic, clinical and histological parameters. However, the impact of primary tumor location in metastatic colon cancer treated with front-line targeted triplet regimens is unclear, particularly in Asian populations. Methods A total of 121 patients with KRAS exon 2 codon 12/13 wild-type metastatic colon cancer were enrolled between January 2007 and December 2013. All patients received one target agent, such as cetuximab or bevacizumab, as a front-line targeted triplet regimen. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Results In cetuximab group, left-sided metastatic colon cancer was superior to right-sided metastatic colon cancer in objective response rate (70.1% vs 33.3%, P = 0.024), progression-free survival (15.0 vs 5.3 months, P

The use of multidisciplinary teams (MDTs), which address colorectal cancer treatment planning through weekly regular group meetings, was begun in October 2007. We analyzed and compared the outcomes of colorectal cancer patients with metastatic disease before and after the era of MDTs. From 2001 to 2010, 1075 patients who presented with stage IV disease and were treated in Taipei Veterans General Hospital were enrolled in the study. Among these patients, 439 (40.8 %) were diagnosed after MDTs had been established. The percentage of patients receiving surgical treatment for metastatic disease was calculated and compared before and after MDTs were established, and the survival rate was compared using a log-rank test, with a significance of P

Background:The risk of psoriasis in diabetic patients has rarely been explored.Objectives:This study aimed to investigate the association between dipeptidyl peptidase-4 (DPP4) inhibitors and the risk of psoriasis in type 2 diabetes mellitus (T2DM) patients.Methods:We conducted a population-based propensity score-matched cohort study on the basis of Taiwan’s National Health Insurance Research Database that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and sulfonylurea (sulfonylurea plus metformin). Psoriasis (PSO) was identified with ≥2 diagnoses. Diabetes complications severity index (DCSI) was calculated. A total of 22721 DPP4 initiator and 227684 sulfonylurea initiator were identified. A 1:10 matched-pair cohort based on propensity score(PS) was created. PS-stratified Cox proportional hazards models compared the risk of PSO in DPP4i versus sulfonylurea initiator within 2 years, controlling for potential confounders.Results:After propensity score matching, 9962 patients with T2DM starting DPP4i combination therapy and 39848 starting sulfonylurea combination therapy were selected. The incidence rate of PSO was lower in DPP4i group (188/100000 person- years) than in sulfonylurea group (467/100000 person-years). Risks of incident psoriasis were significantly lower in the DPP4i group versus sulfonylurea with the PS-stratified HR of 0.422 (95% CI 0.273 to 0.716).Conclusion:DPP4i plus metformin was associated with a reduced risk of psoriasis than sulfonylurea plus metformin. These findings merit further investigation.Disclosure of Interests:None declared

Objective The objective of this paper is to analyze the clinical features, outcomes, mortality risk factors, and all-cause mortalities of invasive aspergillosis (IA) in patients with systemic lupus erythematosus (SLE). Methods Medical records were reviewed to identify SLE patients with IA from January 2006 to June 2017, at Taipei Veterans General Hospital, Taiwan. A total of 6714 SLE patients were included. Clinical/laboratory parameters and treatment outcomes were analyzed. Results Four patients (19.0%) had definite and 17 had probable (81.0%) IA. Seven patients (33.3%) survived and 14 died (66.7%). Concurrently, there were 19 pneumonias (90.5%), 17 cases of other infections (81.0%), eight bacteremia (38.1%), nine cytomegalovirus (CMV, 42.7%) and six Candida (28.6%) infections. In all 55 blood cultures, 38 (69.1%) yielded gram-negative bacilli, of which carbapenem-resistant A. baumannii accounted for eight (21.1%); 17 (30.9%) yielded gram-positive cocci, of which methicillin-resistant S. aureus accounted for six (35.3%); and vancomycin-resistant Enterococcus accounted for four (23.5%). Daily steroid dose ≥ 20 mg (hazard ratio (HR) 2.00), recent pulse steroid therapy (HR 2.80), azathioprine (HR 2.00), rituximab (HR 2.00), plasmapheresis (HR 2.00), acute respiratory distress syndrome (HR 2.00), concurrent infections (HR 5.667) and CMV viremia (HR 1.75) were higher in the fatality group. All p values were less than 0.05. Septic shock ( n = 7, 50% in the fatality group) is the most common cause of mortality. Conclusions High daily steroid dosing, recent pulse steroid therapy, azathioprine, rituximab, concurrent infections, and CMV viremia were mortality risk factors for IA in SLE.

Background The incidence, site distribution, and mortality rates of patients with colorectal cancer differ according to gender. We investigated gene mutations in colorectal patients and wanted to examine gender-specific differences. Methods A total of 1505 patients who underwent surgical intervention for colorectal cancer were recruited from March 2000 to January 2010 at Taipei Veterans’ General Hospital and investigated for gene mutations in K-ras, N-ras, H-ras, BRAF, loss of 18q, APC, p53, SMAD4, TGF-β, PIK3CA, PTEN, FBXW7, AKT1, and MSI. Results There were significant differences between male and female patients in terms of tumor location (p

Background HCQ is an antimalarial drug that is widely prescribed for the treatment of Sjogren syndrome. Glucocorticoids may alter glucose metabolism and contribute to diabetes mellitus. Treatment for primary Sjogren syndrome (SS) sometimes requires glucocorticoids that may worsen glucose homoeostasis. HCQ can reduce diabetes risk in SLE and RA. Objectives This study aimed to investigate the association of HCQ use and diabetes mellitus risk in primary SS patients. Methods This nationwide, population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. In the period 2002–13, 7311 newly diagnosed primary SS patients were identified after excluding those with a previous diagnosis of RA, SLE or diabetes mellitus. The propensity score matched 4874 patients with at least 6 month hydroxychloroquine exposure after diagnosis and 2437 patients without. Incidence of diabetes mellitus was identified as a new diagnostic code using a diabetes mellitus-specific medication. Results Four hundred and ninety-seven newly diagnosed diabetes mellitus patients were identified among primary SS patients (4874 had taken HCQ and 2437 had never taken HCQ), with an average follow-up period of 4.9 years. Compared with patients without HCQ treatment, the hazard ratio (HR) of diabetes mellitus in patients taking HCQ at a cumulative dose ≥175 g was reduced [HR 0.60 (95% CI: 0.45 to 0.80), p Conclusions This propensity score matched analysis of Taiwanese patients with primary SS found that use of HCQ is associated with reduced risk of incident diabetes mellitus in a dose-dependent manner. High-dose glucocorticoids increase the risk of diabetes, which can be decreased by concomitant HCQ use. Disclosure of Interest None declared

Background Sjogren’s syndrome is an autoimmune disease that involves several organs. In the latest classification criteria, salivary minor gland is one of the major factor contributing to the diagnosis. Ultrasonography is a non-invasive, easy accessible tool in evaluation the contour and structure of salivary glands, which have been shown to have efficacy in monitoring the disease status of Sjogren’s syndrome as well as in diagnosis the disease. Otherwise, salivary flow rate is another component of classification criteria, and its association with disease activity remains to be elucidated. Objectives To investigate the efficacy of salivary gland ultrasonography and salivary flow rate in patients with Sjogren’s syndrome and Sicca symptoms. Methods Total 97 patients of primary or secondary Sjogren’s syndrome, and patients with sicca symptoms were enrolled. Ultrasonography was performed at parotid and submandibular glands with 13–16MHz linear probe. Each gland was scored from 0 to 4. Minor salivary gland biopsy results were examined by pathologist with Chisholm-Mason grade. Unstimulated salivary flow rate was recorded first, and stimulated salivary flow rate was tested after 5 min of sugar-free chewing gum stimulation. Patients‘ symptoms were recorded by ESSPRI questionnaires. Results Total 56 primary Sjogren’s Syndrome, 10 secondary Sjogren’s Syndrome, and 31 patients with sicca symptoms were enrolled. Significant correlations were noted between unstimulated salivary flow rate and minor gland biopsy (p=0.029), stimulated salivary flow rate and biopsy (p=0.006), salivary gland ultrasonography and minor gland biopsy (p Conclusions Both salivary gland ultrasonography and salivary flow rate correlated with the severity of salivary minor gland biopsy. The stimulated salivary flow rate had better correlations with the biopsy result than unstimulated flow, and it also correlated with patients’ self-reported dryness symptoms. Salivary gland ultrasonography had correlations with symptoms of patient. These non-invasive methods may play roles in evaluation of the disease activity. Disclosure of Interest None declared

To investigate the clinicopathological features and prognostic significance of the BRAFV600E mutation in Asian patients with colorectal cancer. We retrospectively reviewed the medical records of 1969 patients with colorectal cancer admitted to Taipei Veterans General Hospital for surgical treatment between 2000 and 2013. The measured endpoint was overall survival after surgery. The prognostic value of the BRAFV600E mutation was analyzed using the log-rank test and Cox regression analysis. The BRAFV600E mutation was detected in 106 (5.4%) patients and associated with female gender, abnormal cancer antigen (CA)19-9 at diagnosis, microsatellite status, right-sided primary tumors, mucinous histology, poor differentiation, and lymphovascular invasion. Metastatic patterns were more common in non-regional lymph node metastasis (20.8 vs. 7.4%, p = 0.06) and peritoneal seeding (41. vs. 21.2%, p = 0.04). Mutations were not prognostic in the overall survival of the entire study group but only in specific patients: age

Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship between ER stress-related ATF signaling and CIP2A. We found that CIP2A expression was positively correlated with ATF6 expression by analyzing publicly available RNA sequence data of patients with colorectal cancer (The Cancer Genome Atlas, TCGA). In addition, we demonstrated that tunicamycin-induced ER stress in vitro upregulated ATF6 and CIP2A. Mechanistically, we found that ATF6 directly bound to the CIP2A promoter and induced CIP2A gene expression, which contributed to colon cancer cell survival. Furthermore, knockdown of CIP2A reduced the viability of cells under ER stress. Most importantly, immunohistochemical analysis of a tissue microarray from a colon cancer patient cohort showed that higher expression levels of ATF6 and CIP2A were associated with a trend toward poor prognosis. Taken together, our results show that ER stress-related ATF6 upregulates CIP2A and contributes to the prognosis of colon cancer. Targeting CIP2A may disrupt ER stress-mediated colon cancer cell survival and thus improve the prognosis of patients with colon cancer.

Recent studies suggest that aberrant DNA methylation might occur early and commonly in colorectal tumorigenesis. In 111 normal subjects, the mean LINE-1 methylation level of peripheral blood was 81.0 ± 5.7%. Of 143 colorectal cancer (CRC) patients, the mean level of LINE-1 methylation was 60.5 ± 12.5%. We defined below 60% as cut-off value of LINE-1 hypomethylation, and 93 cases (65.0%) had LINE-1 hypomethylation in the tumor tissue. LINE-1 hypomethylation was not associated with any other clinical features. There was a trend that LINE-1 hypomethylation tumors were associated with advanced disease, but it did not reach statistical significance. There was no significant association between mutations of 12 genes, MSI-high, EMAST, and LINE-1 hypomethylation level. The median follow-up was 61.2 months. Five-year disease-free survival (DFS) and overall survival curves of patients with LINE-1 hypomethylation tumors were significantly lower than those of patients with normal LINE-1 methylation tumors (p = 0.032 and 0.001, respectively). Multivariate analysis showed that only TNM staging was an independent prognostic factor for CRC patients including DFS and overall survival (OS). LINE-1 did not impact patients' outcomes in multivariate analysis including DFS and OS. In conclusion, LINE-1 hypomethylation is marginally related to advanced stage CRC and impacts patients' outcomes in univariate analysis.

Background and objectives 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. Methods The study population comprised 1,492 retrospectively collected stages I–IV colorectal cancer specimens. Tissue was obtained between 2000 and 2010 at a single hospital. We analyzed 61 hot spots using MALDI–TOF mass spectrometry for nucleic acid analysis. Results Mutations were found in the RAS pathway in 47.3% of patients and in the PI3K pathway in 14.3% of patients, with 9.2% of patients carrying mutations in both pathways. Both the RAS and PI3K pathway mutations were significantly associated with proximal tumors, mucinous tumors, and microsatellite instability. Tumors carrying a RAS pathway mutation exhibited a higher frequency of lung and peritoneal metastasis than did tumors with a wild-type gene (P = 0.025 and 0.009, respectively). NRAS gene mutation was significantly associated with lung metastasis (P = 0.001). Conclusions Somatic mutations in the RAS pathway of the primary tumor in colorectal cancer can influence patterns of metastasis and recurrence. J. Surg. Oncol. 2015 111:905–910. © 2014 Wiley Periodicals, Inc.

Carcinoembryonic antigen (CEA) is widely used as a tumor marker in colorectal cancer (CRC). This study aimed to evaluate the role of the degree of change in CEA levels during the treatment period and found that the degree of change highly correlated with disease survival and Response Evaluation Criteria in Solid Tumors (RECIST) criteria in evaluating therapy response. A total of 447 metastatic CRC patients treated with surgery of the primary tumor followed by systemic therapy at a single center from the year 2000 through 2011 were reviewed. The degree of change in CEA levels was expressed as the CEA ratio (post-CEA/pre-CEA) and classified into four groups during the treatment period for further evaluation. The imaging change of the same population was also compared with the CEA ratio during the treatment period. The CEA ratio was significantly correlated with different chemotherapy regimens (p

Purpose This study aimed to determine the prognostic value of mutations in the tumor suppressor gene FBXW7 for clinical outcomes in colorectal cancer (CRC). Methods Between January 2000 and December 2009, FBXW7 mutations in tumor tissues from 1,519 CRC patients at Taipei Veterans General Hospital were assessed using a MassArray system. We compared the clinicopathological variables and prognosis between the wild-type and mutant tumor tissue groups. Results FBXW7 mutations were present in 114/1,519 CRC patients (7.5%). In stage I/II CRC patients, mutant FBXW7 was more common than wild-type FBXW7 (62.3% vs. 50.8%). CRC patients with FBXW7 mutations did not differ significantly in their 5-year overall survival (OS). Stage I/II CRC patients with FBXW7 mutations had lower OS, but this difference was not significant (71.6% vs. 78.2%). Among FBXW7 tumors, S582L was the most frequent mutation type (19.3%), followed by R465H (16.6%), R505C (14.9%) and R479Q (14.9%). Subgroup analysis of FBXW7 mutants showed that R465H/R465C/R479Q had better 5-year OS than other mutant types (76.9% vs. 56.0%; p=0.012). Conclusions There was no strong association between patient prognosis and FBXW7 mutations in our large-scale study.

In patients with systemic lupus erythematosus (SLE), low bone mineral density (BMD) is associated with increased age, prolonged disease, low body mass index (BMI), and overlap with rheumatoid arthritis (RA). Elevated fibroblast growth factor (FGF)-23 in cyclosporine A (CsA) users with SLE are associated with decreased active vitamin D and osteocalcin.The objective of this study was to investigate the steroid and CsA effect on bone metabolism and serum FGF-23 in SLE patients.Seventy-two SLE patients and 10 age- and sex-matched healthy individuals underwent blood tests for bone metabolic biomarkers and FGF-23, and lumbar spine dual-energy X-ray absorptiometry for BMD.Comparisons between patients and controls were made in premenopausal women/men younger than 50 years and postmenopausal women/men older than 50 years separately. SLE patients had more frequent low Z-score (≤-2.0, 8.5 vs. 0%), osteopenia (-2.5T-score-1.0, 52 vs. 50%), and osteoporosis (T-score≤-2.5, 12 vs. 0%), than the healthy age-compatible counterparts. BMD was significantly lower in patients with advanced age, longer disease duration, lower BMI, and overlap with RA (all p0.05 by multiple linear regression analyses). Serum FGF-23 was significantly higher and 1,25-dihydroxyvitamin D (1,25(OH)2D3) lower in SLE patients treated with glucocorticoid and CsA than in those not taking both of them (p=0.027 and 0.002, respectively). The cumulative dose of glucocorticoid was inversely correlated with serum intact parathyroid hormone (r=-0.299, p=0.011), C-terminal telopeptide of type I collagen (r=-0.581, p0.001), and osteocalcin (r=-0.648, p0.001). FGF-23 and the cumulative dose of CsA were positively correlated (r=0.38, p=0.001) and both were negatively correlated with 1,25(OH)2D3 (r=-0.266, p=0.016 and r=-0.55, p0.001) and osteocalcin (r=-0.234, p=0.034 and r=-0.274, p=0.02).SLE patients treated with glucocorticoid and CsA exhibited markedly decreased bone turnover. Those taking CsA had higher serum FGF-23 associated with suppression of 1,25(OH)2D3 and bone formation. Such high-risk patients necessitate regular screening of osteoporosis.

Adjuvant chemotherapy use in stage II colorectal cancer (CRC) is debated. We evaluated the prognostic significance of clinicopathological features recommended by most guidelines for identifying high-risk stage II CRC and adjuvant chemotherapeutic response.We enrolled 1,039 stage II CRC patients who underwent curative surgery at Taipei Veterans General Hospital from January 2005 to December 2010. Seventy-seven patients who received radiotherapy were excluded. The endpoint was disease-free survival.Of 962 patients, 37 had stage T4 tumors; 50, lymphovascular invasion; 39, poor differentiation; 249, preoperative carcinoembryonic antigen (CEA) levels5 ng/mL; and 53 underwent emergent operations. One hundred ninety-four patients received 5-fluorouracil-based adjuvant chemotherapy. During a median follow-up period of 60.2 months, recurrence developed in 110 patients (11.4 %). The 5-year disease-free survival (DFS) was 87.6 %. In multivariate analysis, preoperative CEA5 ng/ml (p = 0.001), emergent operation for obstruction/perforation (p = 0.008), lymphovascular invasion (p = 0.014), and T4 disease (p = 0.030) were significantly associated with poor DFS. High-risk stage II patients (n = 484) benefited from adjuvant chemotherapy (5-year DFS with and without adjuvant chemotherapy, 87.3 vs. 78.9 %; p = 0.028).Adjuvant chemotherapy improved DFS in high-risk stage II CRC patients, but not in low-risk patients.

Background and Objectives Regional lymph nodes (LNs) are believed to be a first-line barrier against tumor metastasis. However, it remains unclear whether underlying genetic factors exist and affect LN metastasis risk. We therefore evaluated inherited risk variants using single nucleotide polymorphisms (SNPs) in pathological T3 colorectal cancer patients in the absence or presence of LN metastasis. Methods The study population comprised 629 retrospectively collected colorectal cancer samples between 2000 and 2009 in a single hospital, including 273 patients with LN metastasis and 355 control subjects without LN metastasis. We analyzed 87 SNPs in genes that are associated with susceptibility to carcinogenesis or metastasis in colorectal or other cancers. Results Only 11 SNPs were found to have significant genotype distribution differences between the cases and controls. The average number of risk alleles carried by patients with LN metastasis was 7 (6.6 ± 1.4; range 2–10), which was significantly higher than the 6 risk alleles that were carried on average by patients without LN metastasis (6.0 ± 1.6; range 0–10; P

Background Carcinoembryonic antigen (CEA) is the most widely used tumor marker for colorectal cancer. This study aimed to investigate the role of CEA reduction ratio after preoperative chemoradiotherapy (CRT). Methods We enrolled 284 patients who underwent preoperative CRT followed by radical surgical resection. Patients were divided into 3 groups: serum CEA levels before CRT (pre-CRT CEA) less than 5 ng/mL (group 1); pre-CRT CEA of 5 ng/mL or more with CEA reduction ratio of 50% or more (group 2); and pre-CRT CEA of 5 ng/mL or more with CEA reduction ratio less than 50% (group 3). Results The 5-year disease-free survival (DFS) rate was not different between groups 1 (71.8%) and 2 (69.4%) but was significantly lower in group 3 (49.5%). CEA group, lymph node status after CRT (ypN) stage, and histologic type were independent prognostic factors for DFS on multivariate analysis. Conclusions CEA reduction ratio might be an independent prognostic factor for DFS in rectal cancer patients treated with preoperative CRT and radical surgery.

Background This study aimed to establish a correlation between MSI, KRAS mutations, and BRAFV600E in colon cancer and to investigate the prognostic effect. Methods Colon cancer patients who underwent surgical intervention were enrolled. MSI status was identified by genotyping, and the mutational statuses of KRAS and BRAF were determined by MassARRAY, targeting 22 mutations. The clinicopathological differences and correlations between these factors were analyzed. Results Among 1,063 patients, tumors with MSI-H were significantly associated with BRAFV600E (P = 0.001). KRAS and BRAF mutations were mutually exclusive (P = 0.001). Patients with MSI-H tumors had significantly improved overall survival compared with patients that had microsatellite instability-low/stable (MSI-L/MSS) tumors (hazard ratio 0.686: 95% confidence interval: 0.479–1.162, P = 0.040). In addition, the BRAFV600E mutation was a poor prognostic factor in tumors with MSI-L/MSS (P = 0.020). KRAS mutations were not prognostic factors, but sub-group analysis demonstrated that mutations in KRAS codon 12 were associated with significantly worse survival than wild-type KRAS, mutations in KRAS codon 13, or mutations elsewhere. Conclusions MSI and the BRAFV600E mutation have a prognostic impact in colon cancer. Variable KRAS mutations may have different effects on colon cancers; further studies are needed to verify these results. J. Surg. Oncol. 2014; 110:451–457. © 2014 Wiley Periodicals, Inc.

We aimed to compare the treatment efficacy of cetuximab versus bevacizumab in combination with either irinotecan-based or oxaliplatin-based regimens (targeted triplet) as the first-line treatment for patients with metastatic colorectal cancer. Between April 2005 and March 2012, patients (n = 158) diagnosed with metastatic colorectal cancer after at least four courses of first-line bevacizumab-based (n = 95) or cetuximab-based triplet (n = 63) were retrospectively analyzed. The KRAS genotypes were sequenced for all patients. The Kaplan–Meier method was used for survival analysis, and Cox proportional hazards models were used for univariate and multivariate analyses. Cetuximab-based triplet was associated with a higher objective response rate (66.0 vs. 47.2 %, p = 0.037) and a higher conversion rate to resectability (39.7 vs. 20.0 %, p = 0.007) compared to bevacizumab-based triplet. Compared with bevacizumab-based triplet, cetuximab-based triplet significantly increased progression-free survival in patients with measurable metastatic colorectal cancer who achieved objective tumor response (responders) (median 13.1 vs. 10.5 months, p = 0.023), but no significant increase was observed for overall survival. After adjustment for group differences in baseline characteristics and combined chemotherapy agents, cetuximab-based triplet remained an independent determinant of progression-free survival in responders as compared with bevacizumab-based triplet. KRAS mutation was not a prognostic factor in patients with metastatic colorectal cancer. As compared with bevacizumab-based triplet, cetuximab-based triplet as the first-line treatment of metastatic colorectal cancer was associated with better progression-free survival in patients with measurable tumors who achieved objective tumor response to bio-chemotherapy.

Introduction. There is epidemiological evidence that Jia-Wei-Xiao-Yao-San (JWXYS) is the most common Chinese medicine decoction coprescribed with tamoxifen (Tam) when breast cancer is treated by hormonal therapy. However, whether there is interaction between JWXYS and Tam remains to be clarified. The aim of this study was to investigate the in vitro and in vivo effects of JWXYS on human breast cancer MCF-7 cells treated with Tam. Methods. In vitro cultured MCF-7 cells were cotreated with JWXYS and Tam. This was followed by MTT ([4,5-cimethylthiazol-2-yl]- 2,5-diphenyl tetrazolium bromide) assays and cell cycle analysis to assess cell proliferation; Western blot analysis was used to analyze the expression of various proteins involved in growth-related signal pathways. In addition, immunohistochemistry was used to detect autophagy among the cancer cells. In vivo analysis used female athymic nude mice implanted with MCF-7 cells; these mice were randomly assigned to 6 groups. All mice were killed humanely after 21 days of treatment; body weight, tumor volume, and tumor weight were then measured. Results. JWXYS was not cytotoxic to MCF-7 cells, based on the fact that there were no statistically significant changes between the JWXYS + Tam groups and the Tam-alone group in cell numbers, cell cycle progression, and cell proliferation signals, the latter including the expression levels of AKT, ERK, P38, p27(Kip1), and light chain (LC3)-I, II. Furthermore, using the MCF-7 xenograft mouse model, there were no significant changes between the JWXYS (1.3-3.9 gm/kg) + Tam groups and the Tam-alone group in terms of tumor weight and the protein expression levels of AKT, ERK, P38, and p27 (Kip1). However, there was a significant decrease in LC3-II protein expression with the low-dose JWXYS + Tam group but not with the middle- or high-dose JWXYS + Tam groups compared with the Tam-alone group. Conclusion. Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam. However, the presence of interference at the molecular level in relation to LC3-II expression provides important information and may affect treatment strategies when physicians have patients with estrogen receptor-α(+) or progesterone receptor(+) breast cancers.

This study investigated the herb–drug interaction of xanthorrhizol and tamoxifen in human breast cancer cells. Using MCF-7 cell line as an in vitro model, the herb–drug interaction between xanthorrhizol and tamoxifen was measured by MTT assay, luciferase reporter assay, and cell cycle analysis. The effects of xanthorrhizol on growth/autophagy related signaling were determined by immunostaining, western blotting, and real time RT-PCR. Additionally, the in vivo effect of xanthorrhizol and tamoxifen on athymic nude mice implanted with MCF-7 cells was evaluated. When MCF-7 cells were co-treated with tamoxifen and xanthorrhizol, there were no significant changes in terms of cell number, luciferase activity, percentage S-phase cells and LC3-II expression. However, using the MCF-7 implanted nude mice model, it was possible to detect significantly increased tumor volumes, a larger tumor size, and increased protein expression of P38 and P27(Kip1) in the xanthorrhizol + tamoxifen group compared to the tamoxifen-alone group. It can be concluded that while there is no significant herb–drug interaction between xanthorrhizol and tamoxifen in vitro, there is such an interaction in tumor-bearing mice, which provides important information that affects breast cancer treatment translational research. Keywords:: breast cancer, tamoxifen, interaction, xanthorrhizol

The aim of this study was to determine the impact of the circumferential resection margin on the outcomes of patients with rectal cancer undergoing total mesorectal excision.Medical records from July 2004 to June 2008 were prospectively reviewed, and 348 patients who underwent potentially curative surgery for rectal cancer were identified. The influence of the circumferential resection margin on local recurrence, distant metastasis, and 5-year cancer-specific survival was assessed.Of 348 patients, 13 (3.7%) had positive circumferential resection margins. During a median follow-up period of 58.0 months, 8 patients (2.3%) had local recurrence and 53 (15.2%) developed distant metastases. Local recurrence rates and distant metastasis rates in patients with positive circumferential resection margins were 15.4% and 61.5%, respectively, significantly higher than in those with negative circumferential resection margins (1.8% and 13.4%, respectively) (P.001). The 5-year cancer-specific survival rates were 75.8% and 0% for patients with tumors having negative and positive circumferential resection margins, respectively (P.001).A circumferential resection margin of ≤1 mm adversely affects cancer-specific survival, local recurrence, and distant metastasis.

Objective In recent trends, patients with breast cancer seek integrative medical treatment when receiving either hormonal (tamoxifen [Tam]) or target (trastuzumab) therapy. Our previous in vitro studies demonstrated that the Chinese medicine Si-Wu-Tang (SWT) stimulates MCF-7 cell growth via activation of estrogen receptor α and human epidermal growth factor receptor 2 (HER2) signaling. The present study demonstrates herb-drug interference with cell proliferation in tumor-bearing mice treated with SWT and Tam in vivo and with proliferation capacity in breast cancer cells treated with SWT and trastuzumab in vitro. Methods To assess in vivo SWT + Tam interference, we randomly separated female MCF-7-implanted athymic nude mice into five groups, namely, vehicle (n = 11), estradiol (n = 8), SWT (n = 8), Tam (n = 11), and SWT + Tam (n = 8). All mice were killed after 21 days of treatment. Body weight, uterine weight, tumor volume, and tumor weight were measured. To assess in vitro SWT-trastuzumab interference, we cotreated BT-474 and SK-BR-3 breast cancer cells with SWT and trastuzumab. This was followed by (4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and cell cycle analysis to measure cell proliferation and by Western blot analysis to analyze protein expression in growth-related signal pathways. Results SWT reversed Tam-induced antiproliferative effects on tumor weight and tumor volume and increased estrogen receptor α and N-cadherin expression in the SWT + Tam-treated group compared with the Tam-treated group. Furthermore, SWT reversed trastuzumab-induced antiproliferative activity in HER2 cell lines (SK-BR-3 and BT-474) through increased phosphorylation of the cell cycle regulatory protein p27(Kip1) and possibly of the antiapoptosis protein P38. Conclusions Based on the in vivo and in vitro demonstration of herb-drug interference in breast cancer cells, we conclude that physicians should pay more attention to such interference when treating patients with receptor-positive (estrogen receptor-positive, progesterone receptor-positive, or HER2) breast cancers.

The prognosis for colorectal cancer (CRC) patients with unresectable metastases is dismal. This study compared outcomes of different metastatic treatments. We collected 653 CRC cases with unresectable metastases including 490 cases receiving primary tumor resection then chemotherapy (surgery group) and 163 patients receiving neoadjuvant chemotherapy then did or did not receive operations (chemotherapy (C/T) group) from 2004 to 2010. The statistical endpoint was overall survival from the date of diagnosis. In the C/T group, 124 (76 %) patients received an operation after 9.0 ± 6.2 months of chemotherapy, including 57 (34.9 %) patients with curative surgery. The C/T group had a higher proportion of T4 lesions (37.4 %) than the surgery group (26.9 %). Survival of the C/T group was longer than that of the surgery group (28.8 ± 8.8 vs. 24.3 ± 7.5 months; p = 0.043). Survival of 57 patients receiving curative surgery was 36.0 ± 6.3 months, which was significantly better than that of the 67 patients receiving palliative resection (25.2 ± 5.6, p

Purpose We retrospectively analyzed ABCG2 expression levels in patients with metastatic colorectal cancer (CRC) to investigate the interaction between ABCG2 expression and the tumor response to oxaliplatin and 5-fluorouracil (FOLFOX). Methods Forty-three patients with CRC with liver metastasis who received first-line FOLFOX treatment at our institution between 2008 and 2010 were enrolled. ABCG2 expression was assessed by immunohistochemistry. Tumor response was determined using the modified Response Evaluation Criteria in Solid Tumors criteria. Results At least 50% tumor shrinkage was observed in 16/43 patients (37.2%), including a complete response in 1 patient. According to the intensity of ABCG2 expression and the percentage of tumor cells expressing ABCG2, 21 tumors displayed high ABCG2 expression. Among these tumors, only 2 (9.5%) exhibited partial responses to FOLFOX; conversely, 63.6% of tumors with low ABCG2 expression (14/22) responded to FOLFOX. Primary and corresponding metastatic samples were available for 15 patients, and 13 of the metastatic tumors had higher ABCG2 expression than the corresponding primary tumors, but only 1 of these tumors responded to FOLFOX (7.7%). Conclusions ABCG2 expression is associated with the tumor response to FOLFOX in patients with metastatic CRC. ABCG2 may be a selective marker for the efficacy of FOLFOX in treating CRC.

// Yuan-Tzu Lan 1, 2 , Ming-Huang Chen 3, 6 , Wen-Liang Fang 2, 4 , Chih-Cheng Hsieh 5, 6 , Chien-Hsing Lin 7 , Fang-Yu Jhang 4 , Shung-Haur Yang 1, 2 , Jen-Kou Lin 1, 2 , Wei-Shone Chen 1, 2 , Jeng-Kai Jiang 1, 2 , Pei-Ching Lin 6, 8 , Shih-Ching Chang 1, 2 1 Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 2 Department of Surgery, National Yang-Ming University, Taipei, Taiwan 3 Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan 4 Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 5 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 6 School of Medicine, National Yang-Ming University, Taipei, Taiwan 7 Genome Research Center, National Yang-Ming University, Taipei City, Taiwan 8 Department of Clinical Pathology, Yang-Ming Branch, Taipei City Hospital, Taipei, Taiwan Correspondence to: Pei-Ching Lin, email: b7901127@tmu.edu.tw Shih-Ching Chang, email: changsc@vghtpe.gov.tw Keywords: cfDNA, GI tract cancer, biomarker, carcinoembryonic antigen, response Received: September 08, 2016 Accepted: November 30, 2016 Published: December 07, 2016 ABSTRACT Background: Cell-free DNA (cfDNA) extracted from blood has become a clinically feasible biomarker in various types of cancer. However, the clinical significance of cfDNA in gastrointestinal (GI) tract cancer among Asian populations requires further investigation. Results: The median cfDNA copy number was highest in esophageal cancer, followed by colorectal cancer and gastric cancer, which were all significantly higher than those of healthy individuals. The cfDNA levels were higher in GI tract cancer, followed by those in carcinoma in situ and then healthy individuals ( P = 0.019). During the postoperative surveillance, the cfDNA level tended to be more sensitive than the carcinoembryonic antigen level in predicting recurrence. For recurrent gastric cancer, a persistently high cfDNA level and an increasing trend was observed after surgery. For stage IV colorectal cancer, dynamic changes in the cfDNA level were correlated with the responses to chemotherapy and surgery. Materials and Methods: Blood samples were collected from 95 healthy individuals and from 855 patients diagnosed with GI tract malignancy, including 98 with esophageal cancer, 428 with stomach cancer, 329 with colorectal cancer and 30 with carcinoma in situ . The copy numbers of extracted cfDNA were analyzed and compared among the different types of GI cancers. Conclusions: The cfDNA level can serve as a feasible biomarker for detecting tumors in GI tract cancer. The cfDNA level may play a role in predicting tumor responses to chemotherapy and surgery in colorectal cancer; tumor recurrence should be considered in gastric cancer with a persistently high cfDNA level after surgery.

// Hung-Hsin Lin 1, 2, * , Nien-Chih Wei 3, * , Teh-Ying Chou 4, 5 , Chun-Chi Lin 1, 2 , Yuan-Tsu Lan 1, 2 , Shin-Ching Chang 1, 2 , Huann-Sheng Wang 1, 2 , Shung-Haur Yang 1, 2 , Wei-Shone Chen 1, 2 , Tzu-Chen Lin 1, 2 , Jen-Kou Lin 1, 2 , Jeng-Kai Jiang 1, 2 1 Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan 2 Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan 3 Auspex Diagnostics, Taiwan 4 Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 5 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Jeng-Kai Jiang, email: jkjiang@vghtpe.gov.tw Keywords: recurrence, drug efficacy, microarray, colorectal cancer, personalized treatment Received: July 06, 2016 Accepted: January 06, 2017 Published: January 13, 2017 ABSTRACT We developed a series of models to predict the likelihood of recurrence and the response to chemotherapy for the personalized treatment of stage I and II colorectal cancer patients. A recurrence prediction model was developed from 235 stage I/II patients. The model successfully distinguished between high-risk and low-risk groups, with a hazard ratio of recurrence of 4.66 ( p < 0.0001). More importantly, the model was accurate for both stage I (hazard ratio = 5.87, p = 0.0006) and stage II (hazard ratio = 4.30, p < 0.0001) disease. This model performed much better than the Oncotype and ColoPrint commercial services in identifying patients at high risk for stage II recurrence. And unlike the commercial services, the robust model included recurrence prediction for stage I patients. As stage I/II CRC patients usually do not receive chemotherapy, we generated chemotherapy efficacy prediction models with data from 358 stage III patients. The predictions were highly accurate: the hazard ratio of recurrence for responders vs. non-responders was 4.13 for those treated with FOLFOX ( p < 0.0001), and 3.16 ( p = 0.0012) for those treated with fluorouracil. We have thus created a prognostic model that accurately identifies patients at high risk for recurrence, and the first accurate chemotherapy efficacy prediction model for individual patients. In the future, complete personalized treatment plans for stage I/II patients may be developed if the drug prediction models generated from stage III patients are verified to be effective for stage I and II patients in prospective studies.

Background: Metastatic malignancy occurs rarely in the colon or rectum. We presented 14 patients with colorectal metastasis (CRM). Methods: A retrospective review was conducted on a computerized colorectal tumor database at the Taipei Veterans General Hospital from January 2000 to June 2013. Results: The incidence of CRM was 0.19% (14 in 7,524 patients). There were 6 males and 8 females with a mean age of 66.9 ± 13.6 years. Origins of the CRM included lung cancers (n = 3), prostate cancers (n = 2), and others (n = 1, respectively). Clinical presentations were not specific and colonoscopic pictures were indistinguishable from primary colorectal cancers; 5 of the 9 biopsies identified metastasis. Eight patients had extracolonic metastasis and 6 patients had CRM only. Significantly better survival was observed in the CRM-only group (p = 0.037). The mean interval from the treatment of primary tumor to the diagnosis of CRM was 30.2 ± 49.0 months. The mean survival time after CRM was 24.9 ± 30.8 months. Conclusion: Clinical features and colonoscopic findings of CRM were indistinguishable from primary colorectal cancer. Histopathological review of the biopsy could be helpful in identifying the primary lesion. Surgical resection with curative intent provided longer survival in CRM-only patients.

To investigate the impact of concurrent chemoradiotherapy (CCRT) on stage IV rectum cancer. Between 2000 and 2011, 297 consecutive patients diagnosed with stage IV rectum cancer (synchronous metastasis) were enrolled. Cox proportional hazard analyses were used for prognostic factors determination, and the Kaplan–Meier method was used for survival analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matched patients for validation studies. In total, 63 patients received CCRT and 234 did not. The patients in the CCRT group were younger, had more low-lying lesions, and had more T4 lesions, lung metastases, metastasectomies, and oxaliplatin-based upfront chemotherapy. Before propensity-score matching, a younger age (HR = 0.662, P = 0.016), lower carcinoembryonic antigen (CEA) level (≤20 ng/ml) (HR = 0.531, P = 0.001), no metastasectomy (HR = 3.214, P

Background and Objectives 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. Methods Liver metastases specimens (n = 292) obtained from patients after liver metastasectomy were used to determine the KRAS/BRAF genotype. Associations between clinicopathological parameters and KRAS/BRAF genotype were identified by univariate and multivariate analyses using the Cox proportional hazards model. The impact of KRAS/BRAF genotype on survival was analyzed using the Kaplan–Meier method. Results The 5-year survival rate of the cohort was 55.8%. The KRAS and BRAF mutation rates were 38.0 and 2.1%, respectively. BRAF genotype, but not KRAS, was found to be an independent prognostic biomarker (HR = 5.181, P = 0.002) after adjustment for other significant confounding clinicopathological variates: Number of liver metastases (HR = 1.983, P = 0.009), concomitant extrahepatic disease (HR = 1.858, P = 0.014), and surgical margin (HR = 3.241, P