bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of time to adjuvant chemotherapy (AC) on survival in colorectal cancer (CRC): A systematic review and meta-analysis.
Authors: Biagi J. J. , Raphael M. , King W. D. , Kong W. , Mackillop W. J. , Booth C. 
Published: February 2017

364 Background: The optimal timing from CRC surgery to initiation of AC is unknown. We report a systematic review and meta-analysis to determine the relationship between time to adjuvant chemotherapy (TTAC) and survival. Methods: A systematic review of literature was done to identify studies that described the relationship between TTAC and survival. Studies were only included if the distribution of relevant prognostic factors was adequately described, and either comparative groups were balanced or results adjusted for the prognostic factors. Hazard ratio (HR) and TTAC for overall survival (OS) and disease free survival (DFS) from each study were converted to a regression coefficient (β) and standard error (SE) corresponding to a continuous representation per 4 weeks of TTAC. The adjusted β from individual studies were combined using a fixed-effect model. Inverse-variance (1/SE2) was used to weight individual studies. The possible effect of publication bias was investigated using the trim and fill approach. Results: We identified 9 eligible studies involving 14,357 patients (4 published articles, 5 abstracts). Two studies were randomized trials and 7 were cohort studies. Six studies reported TTAC as a binary variable and 3 reported TTAC as ≥3 categories. An estimate of HR for OS was derived from all 9 studies and estimate for DFS was derived from 5 studies. Meta-analysis demonstrated that a 4-week increase in TTAC was associated with a significant decrease in both OS (HR = 1.12, 95% CI 1.09-1.15), and DFS (HR = 1.15, 95% CI 1.11-1.20). The analysis showed no significant heterogeneity among studies. These TTAC associations remained significant after analysis for potential publication bias, and when the analysis was repeated excluding the two studies of largest weight. Conclusions: This study demonstrates a 12% increase in the risk of death for each 4 week of delay in the start of AC for CRC. These findings indicate the need for clinicians and health systems managers to take the steps necessary to keep TTAC as short as reasonably achievable. In addition, our results suggest there may be some benefit to AC after a 3-month TTAC delay. No significant financial relationships to disclose.
A randomized, phase I/II trial of AMG 102 or AMG 479 in combination with panitumumab (pmab) compared with pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): Safety and efficacy results.
Authors: Van Cutsem E. , Eng C. , Tabernero J. , Nowara E. , Swieboda-Sadlej A. , Tebbutt N. C. , Mitchell E. P. , Davidenko I. , Chen L. , Smethurst D. 
Published: February 2017

366 Background: Pmab is a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb) approved as monotherapy for pts with mCRC. AMG 102 and AMG 479 are investigational, fully human mAbs against hepatocyte growth factor (HGF) and insulin-like growth factor receptor 1 (IGF1R), respectively. This 3-part study evaluated the safety and efficacy of AMG 102 or AMG 479 in combination with pmab. Methods: Part 1 was a phase 1b, open-label, dose-finding study to determine a tolerable dose of AMG 102 in combination with pmab. Part 2 was a phase II, randomized, blinded, placebo-controlled trial that explored pmab + the dose of AMG 102 selected in Part 1 vs pmab + AMG 479 vs pmab + placebo. Part 3 is a 2-arm randomized extension study for pts who developed disease progression (PD) or intolerability to pmab + placebo in part 2. Eligible pts were ≥ 18 years old with WT KRAS mCRC and ECOG PS 0/1. In part 1, all pts received 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W IV until PD or intolerability. The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). The primary endpoint for part 2 is objective response rate (ORR). Results: In part 1, no DLTs were reported for the first 6 DLT-evaluable pts. A total of 11 pts were enrolled in part 1 prior to the decision to use the 10 mg/kg Q2W AMG 102 dose in part 2; 5 pts were men; mean (range) age was 56 (37-75) yrs; ECOG 0/1 was 55%/45%. Grade 3 treatment-related adverse events (AEs) were acneiform dermatitis or rash (55%), paronychia (18%), infection (9%), capillary leak syndrome (9%), erythema (9%), nail disorder (9%), and pruritus (9%). There were no grade 4 or 5 treatment-related AEs. Serious AEs included acneiform dermatitis (n = 1), intestinal obstruction (n = 1), cerebrovascular accident (n = 1), capillary leak syndrome (n = 1), and anemia/general health deterioration (n = 1). One pt died on study from PD. In part 2, 142 pts received at least one dose of study drug; enrollment is complete, and data analyses are ongoing. Conclusions: In part 1, 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W was well tolerated. Primary efficacy results from part 2, including ORR and progression-free survival, will be presented. [Table: see text]
The impact of Asian race on colorectal cancer screening (CRCS).
Authors: Homayoon B. , Shahidi N. C. , Cheung W. Y. 
Published: February 2017

381 Background: While research shows that African Americans and Hispanics frequently receive less CRCS than Whites, few studies have focused on CRCS among Asians. The aims of the current analysis were to 1) compare CRCS between Asians and Whites in a large U.S. population, 2) evaluate for other clinical predictors of CRCS, and 3) examine the impact of health insurance coverage, place of birth and English proficiency on potential racial disparities. Methods: From the 2007 California Health Interview Survey, we identified all Asian (N=2,108) and White (N=23,237) average-risk respondents aged ≥50 years who were eligible for CRCS. Logistic regression was performed to evaluate for differences in CRCS between Asians and Whites. We used stratified and interaction analyses to examine whether associations between race and CRCS were modified by insurance status (insured vs uninsured), birthplace (U.S. vs non-U.S.) or language skills (good vs poor English), while controlling for other confounders. Results: Baseline characteristics were similar between Asians and Whites: mean age was 64 years in both groups; 45% and 47% were male; and 47% and 50% were employed, respectively. Only 58% of Asians and 66% of Whites reported undergoing up-to-date CRCS (p<0.001). In multivariate analyses, female gender and those living in rural areas were less likely to receive CRCS (OR 0.84, 95%CI 0.76-0.93, p=0.001 and OR 0.88, 95%CI 0.81-0.98, p=0.015, respectively).When compared to Whites, Asians also had decreased odds of CRCS (OR 0.82, 95%CI 0.71-0.95, p=0.008), even after adjusting for confounders such as education and income. Stratified analyses revealed that this disparity existed mainly in the insured (OR 0.83, 95%CI 0.72-0.96, p=0.014), but not in the uninsured (OR 0.94, 95%CI 0.43-2.06, p=0.873). The relationship between race and CRCS was not modified by place of birth or English proficiency. Conclusions: Despite its ability to reduce mortality, CRCS is suboptimal in our U.S. population-based cohort of Asians when compared to Whites. The racial disparity was more evident within the insured subset, suggesting that factors unrelated to healthcare access, such as patient preference, physician discretion or patient-physician rapport, may be more important drivers of CRCS among Asians. No significant financial relationships to disclose.
Effect of probiotic treatment on the transition from chronic colonic inflammation to dysplasia and cancer.
Authors: Appleyard C. B. , Cruz M. L. , Passalacqua I. , Isidro A. A. , Isidro R. A. 
Published: February 2017

385 Background: Effective prevention of colitis-associated cancer still needs to be achieved. There is evidence that the microflora plays an important role in the progression of chronic inflammation to neoplastic transformation, so the aim of this study was to evaluate the potential efficacy of the probiotic VSL#3 in preventing this transition. Methods: Chronic colitis was induced in male Sprague Dawley rats by the administration of trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol ic), followed six weeks later by reactivation with TNBS (5 mg/kg iv) for 3 days. To induce colitis-associated dysplasia and cancer the animals then received TNBS (iv) twice a week for ten weeks. One group of rats received the probiotic in drinking water (VSL#3; ∼5 billion cfu /100 gram body weight) from 1 week prior to initial colitis induction until the time of sacrifice (n = 22-23/group). After sacrifice the colons were removed and analyzed for total macroscopic damage, microscopic damage and presence of dysplasia or cancer. Tissue and serum samples were analyzed for cell proliferation and apoptosis, angiogenic factors and presence of alkaline sphingomyelinase. Results: Those animals receiving the probiotic had significantly less macroscopic and microscopic damage than the vehicle treated-controls in all areas of the colon (p < 0.05). Pathological analysis revealed that 29% of the vehicle treated animals developed carcinoma, which was confined to the proximal region. None of the probiotic treated animals developed carcinoma. Treatment with the probiotic caused a significant shift to a less severe diagnosis with no high-grade dysplasia found in either the proximal or midcolon. Treatment with the probiotic reduced crypt cell proliferation by 22% as assessed by measurement of BrdU incorporation in comparison with the vehicle treated group. Levels of the antiangiogenic factor angiostatin were higher in the probiotic treated animals (5-fold), as were serum levels of alkaline sphingomyelinase (2-fold). Conclusions: Treatment with the probiotic VSL#3 can delay the transition of chronic inflammation to dysplasia and cancer via effects on processes such as modulation of cell proliferation and angiogenesis. No significant financial relationships to disclose.
Effect of Kampo medicine Juzen-taiho-to on adverse events induced by cetuximab.
Authors: Morimoto S. , Shimada M. , Kurita N. , Iwata T. , Nishioka M. , Yoshikawa K. , Miyatani T. , Mikami C. , Kashihara H. 
Published: February 2017

396 Background: Cetuximab is now considered a standard treatment for advanced or unresectable colorectal cancer, unfortunately patients suffer a skin reaction as the main indication of the toxicity of cetuximab. It is recently reported that Kampo medicine (Goshajinkigan) is considered to be an effective agent for the neuropathy of oxaliplatin. Kampo medicine “Juzen-taiho-to” (TJ-48, Tsumura CO. Ltd.), which consists of 10 component herbs, is known as a tonic agent which improves the general systemic condition of cancer patients by reducing the adverse effects of chemotherapy, radiation therapy, and surgical treatment and to inhibit metastases. The aim of this study was to clarify the efficacy of TJ-48 for adverse events associated with cetuximab therapy. Methods: From 2009, cetuximab was administered initially at a dose of 400 mg/m2 followed by weekly infusions at 250 mg/m2 to 20 patients with non-resectable or recurrent colorectal cancer. Eighteen patients received oral administration of 7.5 g/day of TJ-48 (TJ-48 group) every day in the first course and 7 patients did not receive TJ-48 (Control group). Adverse events were evaluated for every course according to CTCAE version 3.0. Results: There was no statistically significant difference between the two groups based on any of patient characteristics. No patients complained of persistent Grade 3 infusion reaction. The percentage of Grade 2 or more skin reactions in each course tended to be lower in the TJ-48 group compared with the Control group (TJ-48 group 34% vs control group 57%). Incidence of Grade 2 anorexia in the TJ-48 group was significantly lower than in the Control group (TJ-48 group 34% vs control group 71%, p=0.03). There were no differences regarding tumor response between the two groups. Conclusions: TJ-48 is useful to prevent anorexia in non-resectable or recurrent colorectal cancer patients treated with cetuximab regimen. [Table: see text]
Association of PTEN loss and local recurrence in stage II-III colon cancer.
Authors: Jiang Z. , Mehta T. R. , You Y. N. , Chang G. J. , Eng C. , Overman M. J. , Maru D. , Hamilton S. R. , Kopetz S. 
Published: February 2017

399 Background: Activation of the PI3K/Akt signaling pathway by PIK3CA mutations has been associated with increased risk for local recurrence (LR) in rectal cancer patients (pts). We hypothesized that loss of expression of PTEN, a tumor suppressor gene and negative regulator of the PI3K/Akt pathway, may also be associated with increased rates of LR in colon cancer. Methods: We studied 156 pts with stage II-III colon cancer resected from 1/1990 to 12/2002, including pathology review, PTEN immunohistochemistry, microsatellite instability (MSI) status, 18q loss of heterozygosity (LOH) status and clinical follow-up. PTEN expression with a CLIA-compliant protocol (DAKO antibody) was determined in a tissue microarray with four cores from each tumor and with non-neoplastic mucosa. PTEN loss was defined as complete absence of expression in malignant epithelium with preserved expression of adjoining non-neoplastic tissue serving as a positive control. LR was defined as anastomotic or pericolic peritoneal disease. Results: 83 M and 73 F pts with median age of 63 were included, with median follow-up of 7.6 yrs. PTEN loss was identified in 26 (16.7%) pts. There were no significant differences in age, sex, T stage, N stage, tumor differentiation, tumor site, lymphovascular invasion (LVI), mucinous component, MSI status or 18q LOH between the PTEN-lost and PTEN-intact groups. The overall survival, relapse-free survival, and distant metastases rate were similar. However, PTEN loss was associated with higher rates of LR (15.4% vs. 4.6%, p = 0.041), and the time to LR was shorter for pts with PTEN loss in their tumor than in PTEN-intact pts (HR 3.3, p = 0.049 by log-rank). LR was associated with LVI, R-sided tumor, 18qLOH, and PTEN loss in univariate analysis. In a multivariate analysis, PTEN loss was associated with a 10.6 fold increased risk of LR (95% CI: 1.7-64.8, p = 0.011). Conclusions: PTEN loss is associated with a higher rate of and shorter time to LR after resection of colon cancer. This result is consistent with a prior report on the role of PI3K pathway in LR of rectal cancer and suggests that PTEN alteration is a prognostic indicator and that the PI3K/Akt pathway is a potential therapeutic target for these pts. No significant financial relationships to disclose.
Specific activity of cyclin dependent kinase 1 as a novel predictor of recurrence risk in stage II colon cancer.
Authors: Maak M. , Zeestraten E. , Shibayama M. , Schuster T. , Friess H. , Van De Velde C. J. , Ishihara H. , Rosenberg R. , Kuppen P. J. , Janssen K. 
Published: February 2017

402 Background: Altered cell cycle dynamics and check points are typical features of solid tumors, and cyclin dependent kinases (CDKs) play pivotal roles in these processes. Previously we have demonstrated that CDK-based analysis, composed of CDK1 and CDK2, is useful in the prediction of outcomes in early breast cancer patients (Ann Oncol. 19(1):68-72, 2008, Br J Cancer. 100(3):494-500, 2009). Clinically, there is a need for risk stratification in patients with stage II colon cancer who have a recurrence risk of 20 to 30%. Therefore we investigated the use of CDK-based analysis for recurrence prediction of stage II colon cancer patients. Methods: Fresh frozen tissue samples of 254 patients with histologically confirmed adenocarcinoma of the colon, UICC stage II, who received primary tumor resection in Munich (217 cases), and Leiden (37 cases) were used. Protein expression and activity of CDK1 and CDK2 were determined by in vitro assays as previously described. Specific activity (SA) of CDKs was calculated as kinase activity in relation to its corresponding mass concentration. Results: Development of distant metastasis was observed in 27 patients (10.6%) after a median follow up of 86 months. We found that predictive performance of CDK1SA, but not CDK2SA, for the metastasis was substantial and almost constant for long-term event prediction (average area under the curve (AUC) = 0.69). Tumor recurrence risk analysis in association with CDK1SA identified a low- (41% of population) and high- risk group (59%). Cox proportional hazard model analysis retained the CDK-based patient classification as an independent prognostic factor for distant metastases-free survival (low vs. high-risk group: Hazard ratio = 6.2, 95% CI: 1.45 to 26.9, p=0.0049). Clinical parameters such as grading, T-categories, age, and sex were excluded as confounding factors for CDK1SA-risk. Conclusions: CDK1SA allows stratification of different risk subgroups of stage II colon cancer patients. CDK1SA-based analysis is useful for predicting patients with high risk of distant recurrence, who should be treated with chemotherapy. No significant financial relationships to disclose.
Use of the XRCC1 single nucleotide polymorphism to predict pathologic complete response to neoadjuvant chemoradiation in stage II/III rectal cancer.
Authors: Duldulao M. P. , Li W. , Ho J. , Chen Z. , Lee W. , Kim J. , Garcia-Aguilar J. 
Published: February 2017

409 Background: The X-ray repair cross-complementing protein 1 (XRCC1) gene plays an important role in DNA damage repair; and the R194W and R399Q single nucleotide polymorphisms (SNPs) are associated with attenuated DNA repair activity. Our objective was to determine whether XRCC1 SNPs were associated with response to neoadjuvant chemoradiation therapy (CRT) in rectal cancer patients. Methods: We conducted a prospective multicenter phase II trial to investigate the effect of additional chemotherapy with a longer CRT-to-surgery interval on treatment response in patients with rectal cancer. Paired normal and rectal cancer tissues were prospectively collected from enrolled patients (n=110). DNA was extracted from normal rectal mucosa and analyzed for XRCC1 R194W and R399Q by polymerase chain reaction and sequencing. Each SNP was compared to response to CRT. Response to CRT was determined by a central pathologist. Results: Of the 110 patients, 25% (n=27) achieved a pathologic complete response (pCR). We examined the XRCC1 R194W SNP and observed that the allelic frequency of patients with the R/R genotype was 84% (n=92), the R/W genotype was 14% (n=16), the W/W genotype was 1% (n=2). By Fisher's Exact test, patients harboring either the R/W or W/W genotype, had a significantly higher rate of pCR compared to patients with the R/R genotype (44% vs. 21%, respectively; p=0.04). We then examined the R399Q SNP and observed that the allelic frequency of patients with the R/R genotype was 34% (n=37), the R/Q genotype was 49% (n=54), and the Q/Q genotype was 17% (n=19). In contrast, the detection of XRCC1 R399Q SNPs was not associated with pCR. Conclusions: We demonstrate that XRCC1 R194W SNP is associated with increased rate of pCR in our prospective multi-center trial. Although the detection of XRCC1 R399Q SNP is not associated with pCR, the detection of XRCC1 SNPs that predict treatment response may help identify patients who are unlikely to respond to CRT and therefore may potentially avoid treatment-associated morbidities. No significant financial relationships to disclose.
Detecting deficient DNA mismatch repair in stage II and III colon cancers.
Authors: Sinicrope F. , Benatti P. , Foster N. R. , Marsoni S. , Monges G. , Labianca R. , Yothers G. A. , Gallinger S. , Sargent D. J. 
Published: February 2017

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]
Use of serum CXCL16 to predict liver metastasis and prognosis in colorectal cancer patients.
Authors: Matsushita K. , Toiyama Y. , Tanaka K. , Yasuda H. , Saigusa S. , Fujikawa H. , Inoue Y. , Miki C. , Kageyama S. , Kusunoki M. 
Published: February 2017

424 Background: Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. In CRC, serum levels of CEA have become well-established prognostic indicators. However, it is not generally accepted as optimal in its prognostic power. The aim of this study was to identify novel and reliable serum prognostic markers. Methods: We performed cytokine array to identify novel prognostic serum marker, and CXCL16 was selected. To investigate the relationships between sCXCL16 and clinicopathological findings including survival, the serum levels of CXCL16 in 237 CRC patients and 20 normal volunteers were assessed by enzyme-linked immunosorbent assay. Furthermore, we investigated proliferation, invasion and wound healing assay to investigate the biological role of CXCL16 to colon cancer cell by recombinant CXCL16 exposing to HT-29. Results: The mean sCXCL16 concentration in patients was significantly higher than that in normal volunteers (p<0.0001). In addition, sCXCL16 levels increased significantly in accordance with the progression of UICC stage classification (p < 0.05). In clinicopathologic findings, sCXCL16 was significantly associated with the presence of lymph node (p=0.019) and the presence of liver metastases (p=0.011). Elevated sCXCL16 level demonstrated a significant association with poor survival, and was an independent risk factor for poor survival. Furthermore, sCXCL16 was an independent marker for predicting liver metastasis (logistic analysis; p=0.0015). In vitro, recombinant CXCL16 promoted epithelial mesencymal transition (EMT) phenotype characterized by impaired E-cadherin and induction of Vimentin. In addition, CXCL16 promoted cell growth, migration and invasion. Conclusions: Our data demonstrate that preoperative sCXCL16 level increased in colorectal cancer patients, and that sCXCL16 correlated with liver metastasis, and is an independent prognostic factor for overall survival. Elevated CXCL16 has been proposed as a useful predictive marker for liver metastasis and overall survival in CRC. In vitro, CXCL16/CXCR6 axis might play an importance role in mediating cell survival, migration and invasion by EMT in CRC cell. No significant financial relationships to disclose.