bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data.
Authors: Kafatos George , Lowe Kimberly , Jenkins-Anderson Sophie , Garawin Tamer , Traugottová Zuzana , Bilalis Antonios , Molnár Edit , Wieruszewska-Kowalczyk Karolina , Niepel Daniela , van Krieken J. Han ,   on behalf of the RAS Prevalence Research Project (RPRP) Group
Published: February 2017

513 Background: Guidelines for prescribing anti-EGFR therapy for metastatic colorectal cancer (mCRC) require prior testing to confirm RAS (exons 2, 3, 4 of KRAS and NRAS) wild-type status in Europe and the USA. There is limited published evidence reporting the prevalence of RAS mutations in patients with mCRC in a real-world setting. The aim of this study was to use data from a range of real-world sources to obtain RAS mutation prevalence estimates for different geographic regions. Methods: Aggregated RAS mutation prevalence data were collected from 13 sources, including individual pathology centers (n = 7), mCRC registries (n = 3), and Amgen-sponsored studies (n = 3). Data sources included in this study originated in Europe (n = 10), the Middle East (n = 2), and South America (n = 1). A meta-analysis of all collected data was carried out to investigate the effect of heterogeneity amongst the data sources and obtain pooled RAS prevalence estimates for each, using a mixed regression model. Results: Aggregate data from 4322 patients with mCRC were included in the pooled meta-analysis. The overall RAS mutation prevalence across all data sources was estimated to be 43.5% (95% CI: 41.5–45.5%). RAS mutation prevalence varied between data sources, ranging from low estimates of 33.7% (95% CI: 28.4–39.3%) for a Middle Eastern pathology dataset, and 34.6% (95% CI: 27.7–42.1%) for a Middle Eastern mCRC registry, to the highest estimates of 53.6% (95% CI: 43.2–63.8%) and 54.1% (95% CI: 51.7–56.5%) in two European pathology centers, in the Czech Republic and Poland, respectively. Conclusions: This is one of the first studies to carry out a large pooled analysis of RAS mutation prevalence, based on real-world data. There was a high degree of heterogeneity between the sources included, possibly due to the types of data source, patient selection criteria, geographic location, or differences in laboratory testing methods. The estimated RAS mutation prevalence reported here is lower than that in a recent pooled analysis of past clinical trials, which reported an overall prevalence of 55.5% (95% CI: 53.9–57.9%) (Peeters M, et al. Eur J Cancer 2015;51:1704–13). Further investigations are required to explain the disparity in these findings.
Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.
Authors: Khushman Moh'd M. , Hosein Peter Joel , Cameron Daniel , Clarkson David Roland , Butler Thomas Wayne , Vu Mary A. , Norden Carole Wiseman , Baliem Wilma , Jones Vanessa , Bhadkamkar Sanjyot , Nelson Cindy , Lee Frances , Singh Ajay , Taylor William R. 
Published: February 2017

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.
Updated analysis: Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802)—Sub-group analysis by KRAS Exon2 status.
Authors: Nakamura Michio , Yuki Satoshi , Sawada Kentaro , Oba Ayane , Sato Atsushi , Kato Takashi , Meguro Takashi , Ehira Nobuyuki , Tateyama Miki , Hatanaka Kazuteru , Eto Kazunori , Okuda Hiroyuki , Kobayashi Yoshimitsu , Muto Osamu , Abe Masakazu , Kato Kanji , Kudo Mineo , Miyashita Kencho , Sakata Yuh , Komatsu Yoshito 
Published: February 2017

522 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study that investigated 115 patients (pts) treated with 1st line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS and OS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for KRAS. Sixty-two pts (62.6%) had KRAS wild-type (wt) and 37 pts (37.4%) had mutation (mt). The pts characteristics between those with wt and with mt were generally balanced except for PS 0 (91.9% in wt, 75.7% in mt; p = 0.036) and lung metastasis (33.9% in wt, 62.2% in mt; p = 0.007). RR was 70.0% in wt versus 65.7% in mt. Adverse events related to BV were almost balanced except for bleeding (any grade) (30.6% in wt, 13.5% in mt; p = 0.088). The median PFS and OS was 9.9 and 26.8 months in wt versus 7.9 and 17.5 months in mt (PFS ; HR 1.519, p = 0.064 and OS ; HR 1.944, p = 0.005). In Cox multivariate analysis, KRAS mt showed significantly shorter PFS and OS (PFS ; HR 1.637, p = 0.045 and OS ; HR 2.132, p = 0.005). Conclusions: In this cohort, depending on the KRAS Exon2 mutational status, severe adverse events were no significant difference. The multivariate analysis showed that PFS and OS were significantly longer in the KRAS Exon2 wild-type patients. So, KRAS Exon2 mutational status can be a predictive and prognostic marker in bevacizumab combined 1st line chemotherapy. Clinical trial information: UMIN000018935.
Prospective observational study for the impact of short-term periodic intravenous steroid premedication for gastrointestinal cancer chemotherapy on bone metabolism.
Authors: Ishiguro Atsushi , Nakamura Michio , Muranaka Tetsuhito , Yuki Satoshi , Murai Taichi , Matsuda Chika , Oba Ayane , Itaya Kazufumi , Shigesawa Taku , Koike Yuta , Fujita Yomo , Endo Ayana , Tsukuda Yoko , Ono Yuji , Kudo Takahiko , Nagasaka Atsushi , Nishikawa Shuji , Komatsu Yoshito 
Published: February 2017

523 Background: Although intravenous glucocorticoid (GC) premedication (GCP) before chemotherapy (CTx) are frequently used to prevent nausea and vomiting for continuing comfortable CTx, the side effects of intermittent GCs on bone health have not yet been reported. So we designed a multicenter, prospective, observational study to evaluate the impact of periodic GCP on bone metabolism in gastrointestinal cancer (GIC) patients (pts). Methods: The eligibility criteria were as the follows: (i) histologically proven GIC. ; (ii) The duration of periodical GCP is weekly, biweekly, and triweekly. More over 4 weeks GC free intervals is not permissible. ; (iii) age over 20. The primary endpoint was to investigate the variations of bone mineral densities (BMD) at lumbar spine measured by dual energy x-ray absorptiometry (DEXA) and bone turnover biomarkers, cross-linked N-telopeptide of type I collagen (NTX) and bone alkaline phosphatase (BAP), between baseline (BL) and 16 weeks after starting CTx (16w). Results: From June 2013 to April 2015, 98 pts were enrolled. Two pts were not proven as GIC histologically. One patient (pt) was not measured on baseline DEXA. One pt was taken bisphosphonates already on BL point. Four pts were not administered CTx or GCP, and 16 pts were not measured BMD on 16w due to several reasons such as pts refusal, discontinuation of CTx, death and so on (74 pts were full analysis set). In 55 pts (74.3 % of FAS), the levels of BMD at 16w were decreased compared with BL and the average amount of BMD reduction rate was 5.83 % (-38.8 % to 31.1 %). Although no significant difference was found in the level of NTX between BL and 16w (p = 0.118), there was the significant increase of BAP level statistically (p = 0.006). There were also significant correlations between percent change in BMD and NTX, BMD and BAP, NTX and BAP (p = 0.037, 0.029, and 0.003, respectively). Conclusions: We found that periodic GCP in GIC pts caused the reduction of BMD and some influences for bone turnover. These results indicate that GCP might generate more serious osteoporosis of GIC pts during CTx. Further studies are necessary to illustrate the need to prevent GC induced osteoporosis in using GCP. Clinical trial information: 000011054.
RAS testing awareness amongst oncologists and panitumumab prescription for metastatic colorectal cancer: A European physician survey and medical records review.
Authors: Trojan Jorg , Kafatos George , Bennett James , Demonty Gaston , Downey Gerry , Mineur Laurent , Tomasek Jiri , Rouleau Etienne , Fabian Pavel , De Maglio Giovanna , Garcia Alfonso Pilar , Aprile Giuseppe , van Krieken J. Han 
Published: February 2017

530 Background: Patients with metastatic colorectal cancer (mCRC) must have a confirmed RAS wild-type status before starting panitumumab (pmab). Two studies, a physician survey and a medical records review (MRR), were carried out to evaluate physician awareness of the need for biomarker testing in mCRC. Methods: Both studies were carried out in three rounds. Rounds 1 and 2 (2012–14) examined KRAS testing only as they were completed before guidelines changed, and have been published previously. Round 3 (2014–15), reported here, was performed after guidelines changed and covered full RAS testing. Participants were from nine European countries:France, Germany, Italy, Spain, the Czech Republic, the Netherlands, Belgium, Denmark, and Sweden. For the survey, oncologists who had prescribed pmab to mCRC patients in the previous 6 months were interviewed by telephone using a standard questionnaire.For the MRR,oncologists were asked to provide clinical information extracted from their patients’ medical records. Results: 152 oncologists and 131 patients’ records were included in Round 3 of the physician survey and the MMR, respectively, compared with 301 oncologists and 306 records in Rounds 1 and 2. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly reported that pmab should be prescribed in RAS wild-type mCRC only, compared with 99.0% (n = 298) in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients had a confirmed RAS or KRAS wild-type status prior to initiation of pmab. Of those patients, 83.2% (n = 109) were tested for RAS status and 16.8% (n = 22) were tested for KRAS status only. Conclusions: Round 3 of the survey demonstrated a high level of knowledge amongst oncologists about the need for RAS testing in mCRC. The MRR supported these findings, showing that this knowledge is being applied to clinical practice. Comparisons between Round 3 and Rounds 1 and 2 show that physician awareness and adherence to prescribing guidelines remained high over time, despite recommendations changing with RAS testing replacing KRAS testing.
Impact of infectious complications on long-term survival following colorectal cancer surgery.
Authors: Mokdad Ali , Hirsch Hannah , Nassour Ibrahim , Borja Nicholas , Balch Glen C. , Polanco Patricio 
Published: February 2017

531 Background: Colorectal cancer surgery is associated with significant postoperative morbidity, which may have long-term implications on patient outcomes. We hypothesize that operative complications following surgery for colorectal cancer are associated with increased recurrence and worse survival. Methods: Using a prospectively maintained database, we reviewed patients with colorectal cancer that underwent a curative resection from 2008 to 2015. Patients were categorized by presence of any complication within 90 days from surgery and by type of complication, infectious and non-infectious. We compared clinical, pathological, and perioperative data using t-test, chi-squared test, and ANOVA. We compared overall (OS) and recurrence free survival (RFS) using Kaplan Meier and log-rank test. Multivariable Cox regression was used to compare mortality and recurrence. Results: Two hundred and twenty-nine patients underwent 104 colon and 125 rectal cancer resections (20 pelvic exenterations, 83 low anterior and 17 abdominoperineal resections) were followed for a median of 23 months. Fifty percent were completed minimally invasively. Postoperative complications occurred in 52%; 19% had a major complication (Clavien-Dindo 3-4). Postoperative complications were more likely to occur in open (61% vs. 38%, p < 0.01) and rectal operations (63% vs. 42%, p = 0.02). On multivariable analysis, OS and RFS were not statistically different in patients with complications. Patients with infectious complications had worse 3-year survival when compared to patients with non-infectious complications and without complications (58%,69%,76%, p = 0.04). Recurrence at 3 years was also significantly different among the three groups (p = 0.03). Infectious complications remained associated with worse overall survival (HR 1.8; 95% CI 1.02,3.26) and recurrence free survival (HR 1.9; 95% CI 1.06,3.39) after adjusting for patient, tumor, and perioperative data. Conclusions: Infectious complications following colorectal cancer surgery are associated with worse OS and RFS independent of tumor stage, type of surgery, and technique. Current research is ongoing to explore possible etiologies of this association.
Defective mismatch repair (dMMR) status as a predictive biomarker in Chinese patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab (BV) + chemotherapy.
Authors: Ling Jiayu , Chen Dianke , Zhang Jianwei , Zhong Lixing , Cai Yue , Deng Yanhong 
Published: February 2017

537 Background: Monoclonal antibody bevacizumab targeting the vascular endothelial growth factor has become the standard treatment of metastatic colorectal cancer(mCRC) and has led to modest but significant improvements in patient outcomes. Given the modest gains there is a pressing need for predictive factors to better identify patients who would benefit from this target therapy. Methods: We performed retrospective study of 94 Chinese pts with mCRC who received BV combining chemotherapy, whose MMR protein (MLH1, MSH2, MSH6, PMS2) expression was analyzed. Overall survival (OS) was recorded. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of clinical factors on OS in the cohort. Results: A total of 94 pts (male/female, 58/37; median age, 51.0 years (range 20.0-79.0); synchronous/metachronous metastasis, 70/24; primary lesion resected/unresected 69/25) were enrolled in this study from October 2010 to March 2014. Median OS of the full cohort was 24.5 months (95% CI, 21.2-28.0 months). Of 94 pts, 70 pts were evaluable for MMR. Seven pts (10.0%) had dMMR and 63 pts (90.0%) had pMMR. The pts characteristics between those with dMMR and pMMR were different in age younger than 65 years (100% in dMMR, 69.0% in pMMR; p = 0.08) and synchronous metastasis (100% in dMMR, 75.0% in pMMR; p = 0.13). The median OS was 36.3 months in dMMR versus 21.6 months in pMMR (p = 0.056), and dMMR versus pMMR in bev treating CRC pts was associated with marginal significantly better OS (HR = 0.143; 95%CI, 0.02-1.05; P = 0.056). This association was consistent with that in a multivariable analysis. Also, we found a statistically significant interaction between MMR status and synchronous metastasis (Pinteraction = 0.041). Primary lesion resection was significantly associated with superior OS and was dependent of clinical variables or MMR status. (HRadjusted= 0.43 95% CI 0.20-0.95 P = 0.036 ). Conclusions: MMR status and primary lesion resection status may be predictive factors to better identify patients who would benefit from bevacizumab therapy in Chinese mCRC.
Expression of P4H9-detecting molecule on spindle-shaped fibroblasts to indicate malignant phenotype of colorectal cancer.
Authors: Yokoyama Shozo , Ieda Junji , Yamamoto Naoyuki , Mitani Yasuyuki , Takifuji Katsunari , Hotta Tsukasa , Matsuda Kenji , Watanabe Takashi , Iwamoto Hiromitsu , Deguchi Masaaki , Yamaue Hiroki 
Published: February 2017

539 Background: Cancer cells and fibroblasts are coordinated for cancer progression. Our previous study has shown that P4H9, produced by epitope for b2 integrin, detected a molecule on fibroblasts in mammary fat pad mouse model in response to Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressing cancer cells. P4H9 detecting molecule (PDM) expression appeared to be associated with myofibroblast differentiation. The aim of the present study is to investigate whether PDM express on fibroblast and cancer cells in clinical tissue samples, and whether PDM expressing cells in colorectal cancer tissue are correlated with clinicopathological features of patients with colorectal cancer. Methods: Immunohistochemistry were conducted with P4H9 on clinical tissue samples from 156 patients with colorectal cancer. The risk factors for metastases and survival were calculated for clinical implication of PDM expressing spindle shaped fibroblasts. Immunofluorescence with P4H9 were performed on CCD-18Co fibroblasts and colorectal cancer cell lines, HT29 and HCT116. Results: Multivariate analysis showed that PDM expressing spindle shaped fibroblasts was an independent risk factor for lymph node metastasis, hematogenous metastasis, and short survival. Kaplan-Meier survival curve presented that PDM expressing spindle shaped fibroblasts was associated with shorter survival time (p< 0.0001). PDM expressing spindle shaped fibroblasts is associated with metastasis and shorter survival of the patients with colorectal cancer. Immunofluorescence showed that PDM expressed on CCD-18Co fibroblasts and colorectal cancer cell lines, HCT116 with fibroblast like morphology. Conclusions: PDM expressing spindle shaped fibroblasts may play a role to bring out malignant phenotype of colorectal cancer. PDM may be a new biomarker and a novel therapeutic target for patients with colorectal cancer.
Esophageal cancer in young patients: Is aggressive treatment associated with better outcomes?
Authors: Glaser Alexander D , Cameron Miles , Almhanna Khaldoun , Hoffe Sarah E. , Fontaine Jacques , Frakes Jessica M. , Pimiento Jose Mario 
Published: February 2017

54 Background: Recent studies suggest that survival in young patients with esophageal cancer (EC) is worse than their older counterpart, secondary theoretically to more aggressive disease and late stage at diagnosis. The aim of this study is to compare stage at diagnosis, patterns of treatment and outcomes of young patients with EC at Moffitt Cancer Center (MCC). Methods: Patients with EC treated surgically between 1996 and 2014 at MCC were recorded at an IRB approved database. We divided the patients into two cohorts, those younger or older than 50 years of age. Demographics, pre-treatment clinical data, therapeutic courses and treatment outcomes were analyzed. We compared clinical variables and defined p < 0.05 as statistically significant. Overall survival was examined using the Kaplan-Meier method. Results: Of the 816 patients treated surgically for EC 86 (10.5%) were < 50 years old. The majority of patients were male 622(85.2%) vs. 67(77.9%) in the younger group (p =.084). Of the 816 patients, 569 had pre-treatment staging information available. Pre-treatment clinical staging for the older and younger cohorts was, Stage0/TIS = 13(2.2%) vs. 1(1.4%); Stage I = 90(15.3%) vs. 6(8.3%); Stage IIA = 119(20.3%) vs. 16(22.2%); Stage IIB = 88(15.0%) vs. 8(11.1%); Stage III = 269(46%) vs. 40(55%); Stage IV = 8(1.4%) vs. 1(1.3%)(p =.44). Younger patients were more likely to receive neoadjuvant therapy (75.6% vs.62.1%)(p =.013), and also neoadjuvant combined with adjuvant therapy, 24(41.4%) compared to 48(12.1%) in the older cohort (p =.001). Pathological complete response (pCR) rate was higher in older patients (43.2% vs 32%)(p =.204); Median survival was higher in younger cohort 64.3 vs. 56.4 months. Neither of these were statically significant (p =.516). Conclusions: This retrospective study with several variables only included surgical patients. In our experience, younger age was not associated with late stage presentation. Younger patients were more likely to be treated with neoadjuvant therapy, and despite similar pathologic response rates they were more likely to receive adjuvant therapy. Although younger patients received more aggressive treatment, their overall survival did not differ from their older counterparts.