bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT): The British Columbia Cancer Agency (BCCA) mCRC score.
Authors: Gresham Gillian , Cheung Winson Y. , Chan Matthew , Kim Jason , Renouf Daniel John 
Published: February 2017

419 Background: Median OS of mCRC is 2 years, but the prognosis of individual pts can be highly variable. Our study objective was to develop a scoring system to improve the prognostication of mCRC pts at baseline assessment. Methods: Pts diagnosed with mCRC from 2006 to 2008, referred to 1 of 5 regional cancer centers in British Columbia, and received CT were reviewed. Pts with ECOG >3 were excluded due to their uniform poor prognosis. Univariate analyses were performed on baseline variables and those significantly associated with prognosis were included in a multivariate stepwise selection. Each significant factor was given a weighted score (range 1-5) based on the regression coefficients. Patients were assigned a composite risk score (range 0-15) based on their baseline variables, and then separated into quartiles for OS using cut-point analysis and Kaplan-Meier methods. Validation was conducted with the bootstrap technique. C-index statistic was 0.75, which indicated good discrimination. Results: A total of 505 mCRC pts were included: median age 63 (range 22-86), 58% male, 75% ECOG 0-1, 58% colon primary, 34% >1 metastatic site, and 46% smokers. Median pre-treatment CEA was 16.8 ng/ml. In this cohort, 64% were metastatic at presentation, 81% underwent primary tumor resection, 23% received prior adjuvant CT, and 72% were treated with palliative CT. ECOG 2-3 (HR 3.1, 95%CI 2.4-4.2), no primary resection (HR 2.3, 95%CI 1.6-3.3), colon primary (HR 1.6, 95%CI 1.2-2.1), >1 metastatic site (HR 1.6, 95%CI 1.2-2.1), CEA level >4 ng/ml (HR 1.2, 0.8-1.6), male (HR 1.2, 95%CI 0.8-1.6), and smoker (HR 1.4, 95%CI 1.0-1.8) were significant in the multivariate model and assigned points corresponding to their effect size. Median OS varied significantly depending on the composite risk score (Table). Conclusions: In this population-based analysis, the BCCA mCRC score was a simple method that used baseline variables to improve the prognostication of mCRC pts. This model requires external validation. [Table: see text]
The role of NF-κB pathway in cancer inflammation of esophageal squamous carcinoma.
Authors: Tzao Ching , Cheng Li-Yuan , Chang Chien-Chih , Sun Guang-Huan 
Published: February 2017

42 Background: Chronic inflammation plays an important role in tumorigenesis and tumor progression in human cancers. We aim to investigate the role of NF-kB in cancer inflammation of esophageal squamous cell carcinoma (ESCC). Methods: To generate M2-polarized macrophages, cells of human U937 monocyte cell line were treated with phorbol myristate acetate (PMA, 50 ng/ml) for 6 hours, and then cultured with PMA plus Th2 cytokines, IL-4 (20 ng/ml) and IL-13 (20 ng/ml), for another 18 hours. M2 phenotype was verified by flow cytometry and by cytokine profiling using enzyme-linked immunosorbent assay (ELISA). After co-culture with M2 macrophages, transcription nuclear factor-kB (NF-kB) activity was measured using quantitative polymerase chain reaction (Q-PCR), followed by reconfirmation with Western blot analysis for IkBα in KYSE-170 and -510 ESCC cell lines (kindly provided by Dr. Yutaka Shimada at Kyoto University, Japan). A selective inhibitor to NF-kB, Bay11-7082, was used to treat ESCC cell lines co-cultured with M2 macrophages, followed by cell proliferation, migration, invasion assays and vascular endothelial growth factor (VEGF) secretion by ELISA. The effect of Bay11-7082 (5 mg/kg) against growth of ESCC tumor was tested in xenografted tumors. Results: PMA plus Th2 cytokines treatment promoted differentiation of U937 cells into M2 macrophages. When treated with Bay11-7082, proliferation, migration, invasion and induction of VEGF expression was significantly inhibited in M2 macrophage co-cultured ESCC cells with a down-regulation of IkBα expression. Tumor growth was significantly increased in M2 macrophage co-cultured ESCC cells compared to that of the non-co-cultured controls, which was significantly retarded by treatment with Bay11-7082. Conclusions: NF-kB pathway was activated in ESCC cell lines co-cultured with M2 macrophages with an increase in cell proliferation, cell motility and angiogenic factor in vitro and tumor growth in vivo, which were significantly suppressed by a NF-kB inhibitor, Bay11-7082. These results suggest a role of M2 macrophage in promoting aggressiveness of ESCC cells, possibly through an activation of NF-kB pathway that may serve as a potential therapeutic target for ESCC.
Deepness of response: A quantitative analysis of its impact on post-progression survival time after first-line treatment in patients with mCRC.
Authors: Mansmann Ulrich Robert , Sartorius Ute , Laubender Ruediger Paul , Giessen Clemens Albrecht , Esser Regina , Heinemann Volker 
Published: February 2017

427 Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy +/- monoclonal antibodies has prognostic value for PFS and OS. "Deepness of response (DpR)" is a new efficacy outcome measure that could explain the impact of tumor shrinkage on long-term survival outcome. If shrinkage takes place DpR is the percentage of tumor shrinkage observed at the nadir compared to baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can quantify the tumor load at distinct time points. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows us to relate DpR to individual post-progression survival (PPS) time. Methods: Based on the data from 2 randomized trials (CRYSTAL, n=1198; OPUS, n=337), 4 treatment regimens (FOLFIRI +/- cetuximab and FOLFOX4 +/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and to relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. Proper scoring rules were used to assess whether the LD-based or the volume-based approach allowed a better prediction of individual prognosis. Results: Results are reported for the CRYSTAL study using LD-based measures for 663 pts with KRAS wild-type tumors and imaging data. The 348 pts treated with FOLFIRI alone had a mean DpR of 35.52% (Interquartile range [IR]:12.09%, 59.86%), minimum DpR -80%. The 315 pts treated with FOLFIRI + cetuximab had a mean DpR of 50.07% (IR: 22.87%, 79.55%) and a minimum DpR of -49%. The DpR was significantly different between the 2 groups (p<0.00001). Individual DpR is a significant prognostic factor for PPS time in both the LD-based (p=0.0023) and volume-based (p=0.0003) models. Proper scoring rules provided evidence of a more precise estimation of individual PPS time based on volume algorithm-measured DpR. Results of the OPUS study will be presented. Conclusions: Our results emphasize the value of the variable DpR as a new efficacy outcome measure for clinical trials. The tumor-shrinking capacity of cetuximab was shown to be associated with its ability to prolong PPS.
Plasma concentrations of 5-FU and creatinine clearance as predictive markers for severe toxicities of capecitabine in patients with colorectal cancer.
Authors: Makihara Katsuya , Mishima Hideyuki , Azuma Sayaka , Miyagi Kazuyo , Komori Katsuya , Hasegawa Hiroko , Yasui Masayoshi , Ikenaga Masakazu , Tsujinaka Toshimasa 
Published: February 2017

428 Background: Pharmacokinetically guided dose adjustment of 5-fluorouracil (5-FU) are available but management of capecitabine has not been established. Patients with renal impairment often experience severe adverse events. The aim of this study is to assess the relationship between plasma concentration of 5FU, metabolites after administration of capecitabine, renal function and adverse events. Methods: Plasma concentration–time data for capecitabine, 5’-DFUR, 5’-DFCR and 5-FU were analyzed by blood samples within 60–180 min after administration of capecitabine on day 8 in colorectal cancer patients receiving capecitabine based regimen (capecitabine with or without oxaliplatin and bevacizumab). Concentrations of 5-FU were analized by a nanoparticle antibody-based immunoassay for 5-FU(My 5-FUR assay). Correlation between the peak concentration of capecitabine metabolites (Cmax) or creatinine clearance (Ccr) and toxicity (grade 3–4 diarrhea, grade 2-3 hand–foot syndrome and grade 3–4 anorexia) were assessed. When parameter of correlation exists, logistic regression analysis was done. ROC (receiver operating characteristic) analysis was conducted to explore the cut off value of the parameter associated with severe adverse events. Results: A total of 42 patients were analyzed. The Cmax of 5’-DFUR, 5-FU and Ccr were significantly correlated with the incidence of severe adverse events. Cmax of 5-FU (p = 0.015) and Ccr (p = 0.016) were also independent parameters. According to the ROC analysis, severe adverse events were observed in the patients whose Cmax of 5-FU was higher than 295 ng/mL and Ccr was lower than 64.8 mL/min. Conclusions: Plasma concentration of 5-FU and renal function are good predictive markers of adverse events after capecitabine administration. These results would lead to the appropreate indivisual dosage adjustment of capecitabine.
Tumor cancer stem cell genetic profile as predictor of relapse in stage II and III radically resected colon cancer patients.
Authors: Giampieri Riccardo , Scartozzi Mario , Loretelli Cristian , Mandolesi Alessandra , Bittoni Alessandro , Faloppi Luca , Bianconi Maristella , Bearzi Italo , Cascinu Stefano 
Published: February 2017

429 Background: Although disease stage is the most relevant factor influencing treatment choice in locally advanced radically resected colon cancer, it is not uncommon to observe disease relapse in patients with apparent low risk stage that are usually excluded from an adjuvant therapy. On the contrary we also know that some patients with high risk stage are not likely to relapse, independently from medical treatment received. Preclinical data suggested that cancer stem cells may influence the biological behaviour of many solid tumours including colorectal cancer, we then tested a panel of genetic markers of stemness in resected Dukes stage B and C colorectal cancer patients in order to define a prognostic profile. Methods: We performed k-means unsupervised clustering (K=2) using the mRNA expression data of 66 genes. The algorithm divided the patients into two groups (A and B). Most patients clustered in a manner consistent with relapse free survival, defined as the time between primary surgery and first radiological sign of metastatic involvement or patients death, whichever came first. Results: A total of 62 patients were analysed (36, 58% stage II and 26, 41% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and B. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Interestingly, even if group A had a worse outcome in terms of risk of relapse, an higher proportion of stage II patients could be found in this group (83%) when compared with the group B (52%). Among tested genes, those with the highest capability in determining allocation into one of the two groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. Conclusions: This analysis supports the idea that, other than (or maybe more than) stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients. Our findings may also be relevant for new treatment strategies targeting tumour stem cells genetic profile.
Microenvironment and cytokines in pseudomyxoma peritonei.
Authors: Lohani Kush Raj , Shetty Shreya Jagadish , Judge Sean J. , Venkatesh Govindarajan , Thomas Peter , Loggie Brian W. 
Published: February 2017

433 Background: Pseudomyxoma Peritonei (PMP), a peritoneal mucinous neoplasm of appendix origin, is associated with inflammation and fibrosis which is central to the disease biology. Here, we examine possible biomarkers or regulators of PMP biology in peritoneal tumor microenvironment and in serum. Methods: Ascites, peritoneal washings and serum were collected from PMP patients. Cytokines and C-reactive protein (CRP) levels were determined using Milliplex immunoassays. Immunohistochemistry (IHC) was performed on formalin-fixed tissue sections. Statistical analysis was performed by the Mann Whitney U test and Bivariate analysis. Results: Serum CRP was significantly elevated in PMP patients (n=29) versus controls (n=4) (0.124 vs 0.004 mg/dl, p = 0.003). CRP levels were lower in ascites (0.028 vs 0.124 mg/dl, p = 0.014), but correlated with serum levels (R = 0.65, p < 0.001). Cytokines typically elevated after infection or injury—TNF-α, IL-1α, IL-1β and γ INF—were not significantly elevated in PMP ascites; however, IL-6, IL-8, IP-10 and MCP-1 were consistently higher (p < 0.001) in PMP with ascites (n=29) when compared to control peritoneal washings (n=9). Both serum and ascites from 10 patients were evaluated for these four cytokines. Ascites levels were significantly elevated compared to their respective serum for IL-6 (1107 vs 3.18 pg/ml, p < 0.001), IL-8 (167 vs 1.59 pg/ml, p < 0.001), IP-10 (5454 vs 504 pg/ml, p < 0.001) and MCP-1 (2420 vs 234 pg/ml, p = 0.002) but the serum levels were not significantly elevated compared to controls (n=6) (p = 0.31, 0.2, 0.63, 0.37 respectively). IHC revealed staining for IL-6 and IL-8 in stromal cells and focal staining of tumor for IP-10 and MCP-1. Recombinant IL-6-treated LS174T cells (mucinous colon cancer cell line) showed increased proliferation (p<0.009) which was inhibited by anti-IL-6 antibodies (p<0.004). Conclusions: CRP, a liver-synthesized marker of systemic inflammation, is elevated in PMP, and may have clinical utility. The results support local synthesis for cytokines IL-6, IL-8, IP-10 and MCP-1 in the peritoneum. Interestingly, the pattern of cytokines appears to be distinct from those following injury or infection. Further studies may yield novel targets for future treatment.
Does conversion chemotherapy really improve survival in patients with colorectal liver metastases?
Authors: Kataoka Kozo , Kanazawa Akiyoshi , Iwamoto Shigeyoshi , Miyake Yasuhiro , Kato Takeshi , Nakajima Akio , Arimoto Akira , Kono Yukihiro 
Published: February 2017

435 Background: Recently, liver resection becomes possible by intensive chemotherapy, i.e. conversion chemotherapy, in patients with initially unresectable colorectal liver metastases (CLM). But the criteria for non-resectability varies one team to another, and there are few reports about the clinical benefit of conversion chemotherapy followed by liver resection. Methods: Our criteria for resectability of CLM depends on the size of remnant liver volume (>30%) and expected function after the removal of all metastases, regardress of number and size of CLM. From December 2007 to September 2011, 113 patients were diagnosed as CLM without extra-hepatic metastases and received chemotherapy. 47 patients were initially diagnosed as resectable and received hepatic resection after chemotherapy (resected group). 66 patients were initially diagnosed as unresectable, but 11 patients become resectable after chemotherapy (conversion group) and 55 patients remain unresectable in spite of chemotherapy (unresecetd group). We assessed the survival benefit between these 3 groups, retrospectively. Results: 110 patients received oxaliplatin-based regimen and 3 irrinotecan-based regimen. In coversion group, 8 patients received cetuximab containing regimen and 2 received bevacizumab containing regimen. 46 of 47 patients in resected group received R0 resection and 7 of 11 patients in conversion group. No serious postoperative complications were observed in resected and conversion group, but the incidence of a surgical site infection in conversion group was somewhat higher than in resected group. Median disease-free survival was significantly higher in the resected group than conversion group (16.73 months [95% CI: 7.80~25.47] and 3.83 months [95% CI: 0.35~7.31 months]) (P=0.031). And median overall survival (OS) was also higher in resected group, but not significant. In resected and conversion group, median OS was significantly higher than in unresected group. (52.20 vs 39.37 vs 20.57 months (p <0.001)). Conclusions: The recurrence rate was higher in coversion group, but conversion chemotherapy followed by hepatic resection seems to be promising and feasible strategy in initially unresectable CLM patients.
Correlation of production of IL-17 with immune suppression relating myeloid-derived suppressor cells (MDSC) and nutritional damages in patients with digestive system cancer.
Authors: Gonda Kenji , Shibata Masahiko , Yazawa Takashi , Yashima Rei , Kimura Takashi , Kenjo Akira , Nakamura Izumi , Ohki Shinji , Anazawa Takayuki , Tsuchiya Takao , Shimura Tatsuo , Koyama Yoshihisa , Gotoh Mitsukazu , Takenoshita Seiichi 
Published: February 2017

437 Background: Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cellular mechanisms mediating this relationship remain unclear. Th17 cells, which produce the proinflammatory cytokine IL-17, have been recognized as one of the key factors in regulation of inflammatory bowel disease and rheumatoid arthritis. Methods: This study demonstrated that, in patients with digestive system cancers including 7 patients with esophageal, 14 with gastric, 20 with colorectal, 5 with hepatocellular, 7 with cholangiocellular, and 7 with pancreatic carcinomas, IL-17 production was correlated with MDSC level and with markers for nutritional impairment, immune suppression and chronic inflammation. Results: IL-17 production was significantly higher in patients with all types of digestive cancer than in normal volunteers. In addition, IL-17 production levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio, and significantly inversely correlated with cell mediated immune response indicators (lymphocyte PHA-blastogenesis and IL-12 production) and patients’ nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. Conclusions: These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism for disease progression through enhancement of immune suppression or cachexia. Controlling activation of Th17 cells may prove to be a valuable strategy for treatment of patients with gastrointestinal cancer.
Surgical practice patterns and long-term survival for early-stage rectal cancer.
Authors: Stitzenberg Karyn Beth , Penn Dolly , Sanoff Hanna Kelly , Meyers Michael O. 
Published: February 2017

459 Background: Local excision (LE) is considered a standard option only for patients with T1N0 rectal cancer and those who are medically unfit for proctectomy. The growing numbers of case series suggest that use of LE may be increasing. The objectives of this study are to characterize practice patterns for surgical management of rectal cancer and determine the comparative effectiveness of LE versus proctectomy for overall survival (OS) for Stage I rectal cancer. Methods: National Cancer Database data were used to identify all patients with rectal cancer diagnosed from 1998-2010. Patient and tumor characteristics associated with procedure type were examined. Kaplan-Meier plots and Cox proportional hazards models, controlling for patient and tumor characteristics and receipt of radiation (XRT), were used to compare OS for Stage I cases from 1998-2005. Results: 147,553 (50%) of 296,068 cases were excluded due to prior malignancy, non-invasive disease, distant metastases, failure to receive definitive surgery, treatment indicated to be palliative, or receipt of neoadjuvant therapy. 76,756 (69%) cases were treated with proctectomy and 34,697 (31%) with LE. Use of LE steadily increased from 23% in 1998 to 41% in 2010, p<0.001. LE was most commonly used for Stage I cases. Women, older patients, patients with less comorbidities, black patients, uninsured patients, and those with T1 tumors were more likely to receive LE than other Stage I patients. Socioeconomic status and rurality were not associated with use of LE. Adjuvant XRT was used for 12% of T1 tumors and 46% of T2 tumors after LE and 5% of T1 tumors and 12% of T2 tumors after proctectomy. For patients with T1N0 tumors, adjusted OS was associated with receipt of proctectomy (HR 0.83; 95%CI 0.77, 0.89) but not XRT. For patients with T2N0 tumors, adjusted OS was associated with both proctectomy and XRT: LE only HR 1.0; proctectomy only HR 0.70; LE+XRT HR 0.70; proctectomy+XRT HR 0.70. Conclusions: Use of LE for rectal cancer is increasing. LE alone is associated with poorer long-term OS than proctectomy. For patients with larger tumors, those that receive adjuvant XRT in addition to LE have significantly better OS than those who receive LE alone.
Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.
Authors: Bendell Johanna C. , Hart Lowell L. , Pant Shubham , Infante Jeffrey R. , Jones Suzanne Fields , Mohyuddin Adil , Murphy Patrick , Patton Jeffrey , Penley William Charles , Thompson Dana Shelton , Burris Howard A. 
Published: February 2017

475 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.