bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral nelfinavir before and during radiation therapy for rectal cancer: Changes in tumor perfusion and correlation between tissue and radiological markers of response.
Authors: Hill Esme J. , Enescu Monica , West Nicholas , Franklin Jamie M. , Chu Kwun-Ye , Li Jun , Whittington Deborah , Macgregor Thomas P. , Ashraf Shazad , Blesing Claire , Mukherjee Somnath , Betts Margaret , Slater Andrew , Anderson Ewan M. , Brown Gina , Schnabel Julia A. , Partridge Mike , Quirke Philip , Sharma Ricky A. 
Published: February 2017

491 Background: Nelfinavir, an inhibitor of AKT in the PI3-kinase pathway, is a radiosensitizer which increases tumor blood flow and reduces hypoxia in preclinical models. We conducted a pilot study of nelfinavir before and during hypofractionated pelvic radiotherapy (RT) in patients with rectal cancer to evaluate the safety of the combination, changes in tumor perfusion and a tissue biomarker of radiosensitization, tumor cell density (TCD). Methods: Eight patients with T3-4 N1-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Safety was evaluated by CTCAE v 4.0. Dynamic contrast enhanced (DCE) CT and MRI scans were performed pre-treatment, after 7 days nelfinavir and prior to last fraction of RT. TCD was performed in biopsies taken pre-treatment and 7 days post-radiotherapy (West N et al. Br J Cancer. 2010, 102; 1519-23). Radiological response and tumor regression grade (TRG) was assessed on MRI 8 weeks from end of RT (Patel UB et al. J Clin Oncol. 2011, 29:3753-60). Results: This was the first clinical trial to combine nelfinavir with hypofractionated RT. There were 3 grade 3 adverse events (diarrhea, rash, lymphopenia). After 7 days of nelfinavir, there was a 40% increase in mean Ktrans on DCE-MRI (p = 0.029, paired t test). On DCE-CT, there was a 30% increase in mean blood flow from before RT to the last day of RT (p = 0.028). The median TCD in biopsies decreased from 41.2% (IQR = 23.5, 53.0%) at baseline to 9.2% (IQR = 2.8, 18.2%) after RT (p = 0.007, paired t test). By RECIST criteria, 3/8 patients treated had complete radiological responses and 4/8 had partial responses. TRG was associated with the magnitude of decrease in TCD measured in paired biopsies for individual patients (p = 0.029, Fisher’s Exact Test). Conclusions: These data suggest that the radiosensitizing drug, nelfinavir, can increase blood flow to rectal cancer when given prior to RT. Nelfinavir added to hypofractionated pelvic radiotherapy has acceptable toxicity and is associated with radiological and tissue biomarker responses. Funded by Oxford NIHR BRC, OCIC, Yorkshire Cancer Research, Oxford and Leeds ECMCs. Clinical trial information: 2010-020621-40.
The impact of low-frequency KRAS mutations on the efficacy of anti-EGFR antibody for patients with metastatic colorectal cancer.
Authors: Hikosaka Tomomi , Yamazaki Kentaro , Hamauchi Satoshi , Tsushima Takahiro , Yokota Tomoya , Todaka Akiko , Machida Nozomu , Fukutomi Akira , Onozawa Yusuke , Yasui Hirofumi 
Published: February 2017

496 Background: The benefit of anti-EGFR antibody is limited to metastatic colorectal cancer with KRAS wild-type (WT). However, some KRAS WT patients have low-frequency KRAS mutation (low MT) by pyrosequencing. Recently, it is reported that the efficacy of anti-EGFR antibody on these patients was inferior to no KRAS mutation patients (no MT) (D. Tougeron et al, Ann Oncol. 2013). Methods: Patients were categorized as low MT or no MT according to pyrosequencing cut-off point, and we evaluated anticancer effect of anti-EGFR antibody in each group. Results: A total of 358 patients were analyzed KRAS genotype by pyrosequencing between April 2010 and February 2013 in Shizuoka Cancer Center. 217 (60.6%) patients were KRAS WT of the total, and 93 (42.9%) were low MT, while 124 (57.1%) were no MT among them. 51 of low MT and 53 of no MT patients were treated by anti-EGFR antibody therapy, and response rate (RR) were 41% (CR/PR/SD/PD 1/20/17/13) and 32% (CR/PR/SD/PD 0/17/21/15), median progression-free survival (PFS) were 164 days and 170 days, respectively. 15 of low MT and 11 of no MT patients received anti-EGFR antibody monotherapy, and RR were 33% (CR/PR/SD/PD 0/5/7/3) and 19% (CR/PR/SD/PD 0/1/4/9), PFS were 184 days and 91 days, respectively. 27 patients in both groups were refractory or intolerance to 5-FU/L-OHP/CPT-11, and RR were 37% (CR/PR/SD/PD 0/10/9/8) and 19% (CR/PR/SD/PD 0/5/13/9), PFS were 132 days and 140 days, respectively. In univariate and multivariate analysis, there was no difference of anticancer effect between low MT and no MT. Conclusions: Unlike the previous report, patients with low-frequency KRAS mutations also benefited from anti-EGFR antibody therapy. However, some other biomarkers such as NRAS, BRAF, PIK3CA might affect these results. Now we are evaluating the effect of these candidate biomarkers on these results, and we will report the update data in this meeting.
GPX3 as a predictive biomarker in gastrointestinal malignancies.
Authors: Pelosof Lorraine Cheryl , Yerram Sashidhar R. , Yanagisawa Breann , Azad Nilofer Saba , Herman James Gordon 
Published: February 2017

499 Background: Epigenetic heterogeneity within colorectal and pancreatic tumors influences their sensitivity to individual chemotherapy agents. Glutathione peroxidase 3 (GPX3), part of the cellular antioxidant system, is associated with platinum resistance in multiple tumor types. We explored the role of GPX3 methylation in colorectal (CRC) and pancreatic tumor cells’ sensitivity to platinum agents. Methods: Methylation-specific PCR (MSP) and quantitative real-time polymerase chain reaction (qPCR) were used to examine the promoter methylation status and expression level, respectively, of GPX3 in primary tumor xenografts and cell lines. Cell proliferation assays were used to measure cells’ sensitivity to cisplatin and oxaliplatin and short hairpin RNA (shRNA) was used to silence GPX3 in these cells. Results: We examined GPX3 promoter hypermethylation in colorectal and pancreatic primary tumor xenografts. GPX3 was methylated in 25% of colorectal cancer primary tumor xenografts tested and 50% of pancreatic cancer primary tumor xenografts tested; methylation correlated with decreased/absent expression in these samples. Additionally, GPX3 is methylated in 6 out of 9 colorectal cancer cell lines tested and cell lines with methylated GPX3 had significantly decreased GPX3 expression. Importantly, the cisplatin IC50 for the cell lines with methylated GPX3 was 4-fold lower (median 4.5 mM) compared to those lines with unmethylated GPX3 (median 20 mM) and oxaliplatin demonstrates a similar trend with the IC50 of the highly GPX3-expressing line CaCO2 being approximately two-fold that of the fully-methylated line HCT116. Underlying the importance of methylation, azacitidine treatment resulted in GPX3 re-expression in HCT116 cells with sensitivity to oxaliplatin decreasing as would be expected. Currently, we are using shRNA to silence GPX3 in CRC lines to directly test its role in platinum sensitivity; preliminary results demonstrate an approximately two-fold decrease in oxaliplatin IC50 when GPX3 expression is decreased in GPX3-expressing cells. Conclusions: Epigenetically silenced GPX3 may serve as a predictive biomarker for platinum sensitivity in CRC and pancreatic tumor cells.
Use of genetic variants in c-MET to predict clinical outcome in localized gastric cancer (GC) patients (pts) treated with surgery.
Authors: Sunakawa Yu , Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Azuma Mizutomo , Ning Yan , Stintzing Sebastian , Stremitzer Stefan , Yamauchi Shinichi , Sebio Ana , Volz Nico Benjamin , El-khoueiry Rita , Koizumi Wasaburo , Watanabe Masahiko , Lenz Heinz-Josef 
Published: February 2017

50 Background: Dysregulation of the c-MET signaling pathway occurs in a wide range of human cancers including GC. Such derangements result from various molecular mechanisms, including mutations, amplification and overexpression of c-MET. Overexpression and amplification of c-MET have been correlated with poor clinical outcomes in pts with GC. However, the association between c-MET polymorphisms and prognosis in GC is not well defined. We examined the prognostic impact of c-MET polymorphisms on clinical outcomes in pts with localized GC treated with surgery. Methods: One-hundred and sixty-one Japanese pts were included, with localized GC (stage Ib-IV) treated with surgery alone (n=58), or surgery plus adjuvant therapy (n=103) between 2002 and 2010. Median follow up was 4 years. Genomic DNA was extracted from the pts’ blood or tissue. Six functionally significant c-MET SNPs (rs1621, rs40239, rs41736, rs41739, rs184953, rs10234854) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with disease free survival (DFS) and overall survival (OS) by uni- and multivariate analyses, adjusting for age, sex, stage and type of adjuvant therapy. Results: The MET rs40239 variant was associated with favorable clinical outcomes. Univariate analysis showed pts with any G (AG/GG) allele had significantly longer DFS and OS compared to those with the AA genotype (HR: 0.43; 95% CI: 0.25-0.74; P=0.001, HR: 0.47; 95% CI: 0.27-0.81; P=0.006, log-rank test, respectively); this remained significant upon multivariate analysis (HR: 0.48; 95% CI: 0.27-0.83; P=0.009, HR: 0.50; 95% CI: 0.28-0.88; P=0.017, respectively). In the subgroup analysis by gender, men, but not women, with the AG/GG genotypes maintained a DFS and OS benefit. Conclusions: Our results show for the first time that the c-MET polymorphism, rs40239, may serve as a prognostic marker in pts with localized GC treated with surgery. There also appears to be a gender-related difference in the impact on clinical outcome by genetic variants of c-MET. Prospective validation of this study is warranted.
Ultra-high-quality sequencing assay for comprehensive genetic panel analysis of tumor-derived circulating cell-free DNA in colorectal cancer patients.
Authors: Lee Jeeyun , Mortimer Stefanie , Mei Gangwu , Sebisanovic Dragan , Siew LaiMun , Eltoukhy Helmy , Talasaz AmirAli 
Published: February 2017

504 Background: Current approaches based on invasive biopsy genetic analysis can fail to capture an accurate picture of the real-time cancer profile due to limited spatial window of biopsy into residual disease throughout the body. Moreover, tumor rebiopsy has significant challenges to be widely used in practice for serial monitoring of disease progression or acquired resistance. Analysis of circulating tumor nucleic acids (ctDNA), on the other hand, presents a new tool for the monitoring and treatment of cancer. However, due to high-quality false positives in current NGS assays, the majority of studies on ctDNA have been limited to hotspot analyses, and typically only involve patients where ctDNA fractions are high (>1-5%). Methods: We have developed a differentiated sequencing assay, Digital Sequencing Technology (DST) that enables detection of rare genomic abnormalities with ultra high-specificity and sensitivity. Our assay is able to eliminate the error and distortion created by sample-prep and sequencing processes in standard NGS workflows and produce near-perfect representations of all rare variants. Results: We have shown that in sequencing a comprehensive cancer panel of 80kbp in 0.1% cancer cell line titration samples, standard Illumina SBS generates many high-quality false positive variant calls in the range of 0.05-5%, while our assay resulted in highly sensitive and completely error-free variant calls across the entire panel. We then profiled ctDNA and matched primary tumor samples in more than 50 plasma samples collected from metastatic colorectal cancer patients. We found mutations in ctDNA with allele frequencies in the range of 0.05-40%. We established the concordance of ctDNA mutations with different clones within primary tumors. We further investigated the potential clinical usefulness of discordant mutants based on the treatment history of each patient. Conclusions: This work indicates the remarkable potential of using our assay in deep analysis of ctDNA, thereby allowing researchers and clinicians to comprehensively and non-invasively monitor the genetic dimension of cancer throughout the body.
Identification of hypoxanthine and phosphoenolpyruvic acid as serum markers associated with chemoradiotherapy response in locally advanced rectal cancer.
Authors: Kim Min-Jeong , Yoo Byong Chul , Yeo Seung-Gu 
Published: February 2017

507 Background: Patients show variable responses to chemoradiotherapy (CRT), generally performed before surgery for locally advanced rectal cancer (LARC). We aimed to identify molecular markers predictive of CRT responses by analyzing low-mass ions (LMIs) in serum of LARC patients. Methods: LMIs (<1000 m/z) in serum obtained before CRT from 73 LARC (cT3–4) patients were profiled using matrix-assisted laser desorption/ionization mass spectrometry. LMIs with higher weighting factors in discriminating CRT responses were selected using principal components analysis and discriminant analysis. Selected LMIs were identified using the Human Metabolome Database. The concentrations of identified LMIs were determined by colorimetric enzyme assay, and compared according to post-CRT pathological stage (ypStage) or Dworak’s tumor regression grade (TRG). Results: The nine highest-ranking LMIs were selected. Among them, two LMIs with 137.08 and 169.04 m/z were identified as hypoxanthine (HX) and phosphoenolpyruvic acid (PEP), respectively. The HX concentration was higher in patients with ypStage 0-I compared with ypStage II-IV (p = 0.034) or ypStage III-IV (p = 0.030); a similar difference was observed between TRG IV-III and TRG 1 (p = 0.035). In contrast, the concentration of PEP was significantly lower in TRG 4-3 compared to TRG 2-1 (p = 0.012), and a lower PEP level was also found in ypStage 0 compared to ypStage I-IV, with marginal significance (p = 0.061). Conclusions: This study demonstrated that pretreatment serum concentrations of HX and PEP, identified using LMI profiling, may be useful for predicting the CRT response of LARC.
Impact of KRAS on outcomes of patients with unresectable colorectal liver metastases (CRLM).
Authors: Ang Celina , Gewirtz Alexandra N. , Chou Joanne F. , Capanu Marinela , Vakiani Efsevia , Kemeny Nancy E. 
Published: February 2017

510 Background: In patients with resected CRLM, mutant (MUT) KRAS may confer a worse prognosis than wild-type (WT) KRAS (Karagkounis et al., ASCO 2012, abs 3616; Kemeny et al., ASCO 2013, abs 3609). We analyzed the impact of KRAS on the outcomes of patients with unresectable CRLM treated with hepatic arterial infusion (HAI) + systemic chemotherapy. Methods: Median overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan Meier methods. The log rank test was used to examine the association of patient demographics and disease-related factors including KRAS mutation status with OS and PFS. Cox proportion hazards model was used to examine the association of liver resection with survival outcomes by treating liver resection as a time dependent covariate. Results: Of 93 patients: 59 male, 34 female; 77 Caucasian, 16 non-Caucasian; 66 were age < 60 years, 27 were age > 60 years; 70 were KRAS WT and 23 were KRAS MUT; 59 had chemotherapy pre-HAI pump placement and 53 subsequently underwent liver resection. Median PFS and OS were 13.3 months and 45.7 months, respectively. Age, sex and race were not associated with PFS or OS. Univariate analysis of the impact of KRAS, pre-HAI chemotherapy, and subsequent liver resection on PFS and OS is presented in the Table. Multivariate analysis including important variables did not change outcome. Conclusions: In patients with unresectable CRLM treated with HAI and systemic chemotherapy, overall survival tended to be improved in KRAS WT vs MUT patients. [Table: see text]
Planned interim analysis of phase II study of sorafenib and capecitabine (SorCape) in previously treated metastatic colorectal cancer (mCRC): NCT01471353.
Authors: George Thomas J. , Ivey Alison Marguerite , Daily Karen Colleen , Dang Long H. , Watson Scott , Granicz Renee , McEwan Margaret A. , Scian Joanna , Lu Xiaomin , Iqbal Atif , Tan Sanda , Zendejas Ivan , Allegra Carmen Joseph 
Published: February 2017

548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. A similar TKI, regorafenib, has efficacy as monotherapy in advanced mCRC. Demonstrating activity of this compound class with standard cytotoxic therapy represents a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2 PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 29 of 43 planned pts have received therapy and the first 26 are included in this planned interim analysis. Baseline pt demographics are in the Table. Most frequently observed adverse events (any AE) included HTN (15%), diarrhea (35%), fatigue (65%) and HFS (91%). 19 pts (73%) had a grade 3 AE (12/19 were HFS). There were no grade 4 or 5 toxicities. 11/25 (44%) evaluable pts have radiographic stable disease. With a median f/u of 6.2 mo, interim PFS is 4.4m. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Planned interim PFS data appears promising in this refractory mCRC population. Molecular correlatives for predictors of response are being analyzed. Clinical trial information: NCT01471353. [Table: see text]
A phase I study of etirinotecan pegol in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.
Authors: Krishnamurthi Smitha S. , Chadha Manpreet , Rodal Mary Beth , Weiss Glen J. , Bokar Joseph A. , Jameson Gayle S. , Mast Catherine Patricia , Zhao Carol , Waluch Bridget , Hoch Ute , Hannah Alison , Dowlati Afshin , Meropol Neal J. , Ramanathan Ramesh K. 
Published: February 2017

550 Background: Etirinotecan pegol (EP; NKTR-102) is the first long-acting topoisomerase I inhibitor designed to concentrate and provide continuous tumor exposure. This study was designed to identify the recommended dose of EP in combination with 5-fluorouracil (5FU; 400/2400 mg/m2 by bolus, then 46-hour infusion) and leucovorin (LV; 400 mg/m2). Methods: Patients (pts) were enrolled in a standard 3+3 design. Initially, pts received all 3 agents every 2 weeks (schedule A). Due to higher SN38 exposure with the triplet compared to single-agent EP in the 25 mg/m2dose cohort, the schedule was modified to deliver all 3 agents for the first 4 doses at 2-week intervals; 5FU/LV continued at 2-week and EP at 4-week intervals thereafter (Schedule B). The protocol enrolled adults with an advanced malignancy; pts had ECOG 0 or 1 with adequate organ function. Results: 26 pts were enrolled in 5 cohorts: median age 63 (44-80); male:female 12:14; median prior regimens 3.5 (1-9). Schedule A: 25 mg/m2 (n=8, 6 evaluable for toxicity) and 50 mg/m2 (n=3). Schedule B: 50 mg/m2 (n=3), 75 mg/m2 (n=6) and 100 mg/m2 (n=6). DLTs: Grade (G) 3 abdominal pain following the infusion (1 pt; 25 mg/m2); G3 nausea/dehydration and G4 neutropenia (NTP) >3 days (2 pts; 100 mg/m2). 5 pts at a dose of 75 mg/m2 had a dose delay due to NTP or diarrhea in the first 2 months. Common G3+ toxicity at 75 mg/m2: NTP (50%), diarrhea and lymphopenia (both 33%). At >50 mg/m2EP, SN38 exposure was comparable to that previously observed after single-agent EP. 5-FU exposure: comparable to prior reports. Two pts (ovarian, gall bladder) had a PR; 11 additional pts had stable disease >6months (3 NSCL 6M-9M; 3 CRC 6-8M; esophageal 7M, desmoplastic round cell sarcoma and pheochromocytoma 6M) or tumor marker response (pancreatic pt who had received prior irinotecan 93%, 9M; breast 82%, 5M). ORR or SD>6M was observed in 8 of the 12 patients in the two highest dose levels. Conclusions: 75 mg/m2 EP with 5FU/LV (Schedule B) shows promising clinical activity with an acceptable safety profile. The combination warrants further clinical testing. Single-agent EP is currently being studied in a phase 3 trial in breast cancer compared to physician’s choice (n=852).
The role of adjuvant radiation therapy in T4 nonrectal colon cancers.
Authors: Pail Orrin , Spieler Benjamin , Samueli Benzion , Shacham-Shmueli Einat , Gutman Mordechai , Zmora Oded , Venturero Moris , Golan Talia , Goldstein Jeffrey , Symon Zvi , Lawrence Yaacov Richard 
Published: February 2017

553 Background: The standard treatment for non-metastatic locally advanced (T4M0) non-rectal colon cancer is surgical resection followed by adjuvant chemotherapy. There is strong rational for the use of post-operative radiation therapy (RT) in T4 tumors since negative margins are difficult to obtain. Despite promising single institutional studies, a phase III clinical trial closed early due to poor accrual. The efficacy of adjuvant RT in these patients remains unknown. We hypothesized that patients at lower risk of micro-metastases would benefit most from aggressive local treatment. Methods: Cases were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Inclusion criteria: T4-anyN-M0 non-rectal colon cancers, diagnosed between 1988 and 2010. Exclusion criteria: rectal tumors and cases lacking staging information. Endpoints: overall survival (OS) and cancer-specific survival. Analyses were based on the Kaplan-Meier method and Cox proportional hazard model. Results: A total of 36,260 patients with T4 colon cancer were identified. Due to changes in the use of systemic adjuvant therapies, an initial analysis was performed to determine effect of adjuvant RT by year of diagnosis. Prior to 2003, adjuvant RT provided no significant improvement in OS. However, between 2003 and 2010, adjuvant RT improved OS by 8 months, from 48 to 56 months (HR: 0.83, p = 0.001). Within this latter period, adjuvant RT improved OS in three subsets of the population: in patients without nodal involvement (N0) (HR: 0.79, p = 0.009); in patients with primary tumor in the sigmoid colon (HR: 0.79, p=0.007); in patients with primary tumor size of 6cm or greater (HR: 0.74, p < 0.001). On multivariate analysis, the following categories remained significant: N stage, tumor grade, year of diagnosis, gender, primary site, and radiation therapy. Conclusions: Some patients with T4 non-rectal colon cancer appear to benefit from adjuvant RT after surgical resection of the primary tumor, especially node-negative tumors located within the sigmoid colon, larger than 6cm in diameter. This benefit has become more evident since the introduction of more effective adjuvant chemotherapy. Our conclusions require verification in a prospective study.