bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phospholipid ether analogs for the detection of colorectal cancers.
Authors: Deming Dustin A. , Maher Molly , Leystra Alyssa A. , Grudzinski Joe , Clipson Linda , Albrecht Dawn , Washington Mary Kay , Matkowskyj Kristina , Pazoles Christopher J. , Hall Lance T. , Lubner Sam Joseph , Weichert Jamey , Halberg Richard B. 
Published: February 2017

486 Background: The treatment of pts with localized colorectal cancer (CRC) depends on the resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and regional lymph nodes is needed. Novelos, Inc. has developed a new phospholipid ether analog therapeutic and diagnostic platform. Molecules from this platform have shown to preferentially accumulate in multiple cancer types. CLR1502 is a near-infrared fluorescent labeled phospholipid ether analog, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer or a therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in human metastatic CRC. Methods: Mice with loss of APC and a constitutively active PI3K in the distal small intestine and colon develop multiple intestinal tumors ranging from benign adenomas to locally advanced adenocarcinomas. These mice were injected intravenously with CLR1502. At necropsy 96 hours after injection, the intestine was removed and tumors were analyzed using a Spectrum IVIS Caliper Life Science Imager and Fluobeam Handheld Imager. The intensity of the fluorescent signal was correlated with the histological characteristics for each individual intestinal tumor. In addition, SPECT imaging with 131I-CLR404 was performed as part of a clinical trial in patients with advanced solid tumors. Results: Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76E+10 vs 3.27E+9 respectively, p=0.027). Metastatic spread to the mesentery and mesenteric lymph nodes was detected with near-infrared fluorescent imaging. Similarly, 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Conclusions: CLR1502 and 124/131I-CLR1404 hold great promise for enhancing our ability to treat CRC. CLR1502 may enhance our ability to properly resect CRCs through better localization of the primary tumor and improve staging through the identification of involved lymph nodes. 124/131I-CLR1404 has the advantage of detecting distant disease.
Phosphodiesterase 10, a novel target in colon cancer.
Authors: Russo Suzanne , Li Nan , Lee Kevin , Xi Yaguang , Zhu Bing , Gary Bernard , Ramirez Veronica , Gurpinar Evrim , Canzeroni Joshua , Fajardo Alexandra , Sigler Sara , Piazza John T. , Chen Xi , Andrews Joel , Li Yonghe , Eberhardt Brian , Yet Larry , Keeton Adam , Grizzle William E. , Piazza Gary 
Published: February 2017

503 Background: Elevation of intracellular cGMP is known to inhibit tumor proliferation and induce apoptosis, although the phosphodiesterase (PDE) isozymes that regulate cGMP levels in tumor cells have not been well studied. We report first evidence that PDE10 is elevated in colon tumors compared with normal colon and suggest that PDE10 inhibitors can be used for the treatment or prevention of colon cancer. Methods: PDE10 protein and mRNA levels were measured in human colon tumor cells (HT29, HCT116, SW480, Caco2), normal colonocytes (NCM460), human clinical samples, and ApcMin/+ mouse model. Two chemically distinct PDE10 selective inhibitors, PQ-10 and Pf-2545920, were tested against the cell lines. The NCI-60 panel of human tumor cell lines was also screened against Pf-2545920 to identify potential differences in sensitivity among histologically diverse tumor types. We also performed siRNA knockdown studies in colonocytes and tumor cell lines. To determine the effect of the PDE10 siRNA knockdown on cyclic nucleotide hydrolysis, whole cell lysates from transfected cells were assayed for PDE activity using cGMP or cAMP as substrates. Results: PDE10 levels were low in normal colonocytes (NCM460) and elevated in tumor cell lines. Similarly, PDE10 was elevated human clinical specimens and the ApcMin+/ mouse model compared with normal mucosa. PDE10 inhibitors and siRNA selectively inhibited colonic tumor growth while stable knockdown inhibited colony formation and increased doubling time. Pf-2545920 also supressed growth of all cell lines within the NCI-60 panel. In comparison with lysates from vector control cells, transfection with PDE10 siRNA reduced cGMP hydrolysis by ~35% in both HCT116 and HT29 cell lines, but did not affect cGMP hydrolysis in colonocytes; siRNA did not significantly affect cAMP degradation in all 3 cell lines. Conclusions: PDE10 plays a role in colon tumorgenesis whereby inhibitors can selectively suppress tumor cell growth. The mechanism by which PDE10 inhibition affects growth appears to involve activation of cGMP/PKG signalling. PDE10 represents a novel anticancer target for the treament and prevention of colon cancer.
Prescribing preferences (PPrefs) of U.S.-based medical oncologists (MOs) for choice of therapy after failure of first-line FOLFOX plus bevacizumab (FFB) in patients with metastatic colorectal cancer (MCC).
Authors: Bendell Johanna C. , Britton Susan L. , Lankford Maria , Buettner Arden , Green Mark R. , Neely Douglas , Scharf Mitchell 
Published: February 2017

533 Background: Phase III trials have tested biologic (bio) agents (bevacizumab [bev], anti-EGFR antibodies, ziv aflibercept [ziv]) plus chemotherapy (CT) vs. CT alone after failure of first-line therapy in patients given CT + bev first line. Several have shown improvements in progression-free and overall survival (OS) with the CT + bio approach, but it is not clear how these therapies are being used in the “real life” setting. Methods: Since 3/2013 PPrefs for this setting among 276 MOs were studied using a validated, proprietary, live, case-based market research tool. A core scenario and variations based on KRAS status and first-line therapy outcome were tested (S1, S2, S3, S4). PPref data acquired using blinded audience response technology. All sources of research support were blinded. Core scenario: 49 yr old female with cecal mass, liver/lung metastases, confirmed wt KRAS for S1-3, given FFB first line. S1: FFB x 16 wks → excellent PR → 5FU bev X 16 wks → progressive disease [PD]; S2: FFB x 16 wks → excellent PR → bev alone x 16 wks → PD; S3: FFB → stable disease [SD] x 5 months as best response [BR] → PD; 4) Here changed to mutKRAS; FFB x 8 wks → PD as BR. Results: Findings shown below (Table). Conclusions: In scenarios with wt KRAS, first-line response to FFB, a majority plan bev again second line. If BR to FFB is SD in WT KRAS, anti-EGFR antibody-based therapy is used more often. In S 1-3, ziv is the PPref of 7 - 14% of MOs studied. With mutKRAS and PD as BR to FFB, use of an antiangiogenic + second-line CT is preferred by > 80%, nearly equally split between bev and ziv. Recent phase III trial data showing OS benefits are reflected in current MOs first failure PPrefs. [Table: see text]
Ziv-aflibercept in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety data from the global aflibercept safety and quality-of-life program (ASQoP and AFEQT studies) in patients ≥65.
Authors: Bordonaro Roberto , Sobrero Alberto F. , Frassineti Luca , Ciuffreda Libero , Aprile Giuseppe , Thomas Anne L. , Moore Yan , Zilocchi Chiara , Dochy Emmanuelle , Taïeb Julien , Ferry David Raymond 
Published: February 2017

545 Background: The prespecified analysis of patients ≥65 years of age in the VELOUR study demonstrated a safety profile similar to that of ziv-aflibercept (Z) (known as aflibercept outside the United States) plus FOLFIRI in the overall VELOUR study. Results from VELOUR supported the initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of two clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) to capture QoL and safety data from a target population similar to that of VELOUR in a real-life setting. We report early safety data from this interim analysis for patients ≥65 y. Methods: ASQoP and AFEQT are single-arm, open-label trials evaluating safety and QoL of Z in mCRC patients previously treated with an oxaliplatin-containing regimen. Eligible patients received Z (4 mg/kg) q2wks on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/patient decision. Initial starting doses and subsequent dose modifications are at the treating physician’s discretion. The percentage of patients ≥65 y with grade (G) 3/4 adverse events (AEs) in the combined safety population of ASQoP and AFEQT are compared with that of the prespecified analysis in patients ≥65 y from VELOUR. Results: At data cut-off, the safety population comprised 116 patients with at least 1 completed cycle of treatment; 53 (45.7%) were ≥65 y. At least 1 G3/4 AE was experienced by 64.2% of patients vs 89.3% in VELOUR. Most reported G3/4 AEs were G3. There were no reports of G4 hypertension, diarrhea, stomatitis, or proteinuria. Conclusions: Thisinterim safety analysis from ASQoP and AFEQT in patients ≥65 y has identified no new safety signals. The early interim analysis provides additional safety data and suggests an acceptable toxicity profile in this real-life setting. Clinical trial information: NCT01571284. [Table: see text]
Potential predictive markers of chemotherapy for advanced gastric cancer: Biomarker study in GC0301/TOP-002, randomized phase III study of irinotecan plus S-1 versus S-1.
Authors: Sugimoto Naotoshi , Tsuburaya Akira , Kawabata Ryohei , Nishikawa Kazuhiro , Imamoto Haruhiko , Tsujinaka Toshimasa , Esaki Taito , Horita Yosuke , Kimura Yutaka , Fujiya Tsuneaki , Takayama Osamu , Oono Ryo , Yabusaki Hiroshi , Taguri Masataka , Morita Satoshi , Koizumi Wasaburo , Tan Patrick , Ninomiya Motoki , Furukawa Hiroshi , Sasako Mitsuru ,   JGCA
Published: February 2017

55 Background: Irinotecan plus S-1(IRI-S) achieved longer median survival than S-1 monotherapy and was well tolerated for patients with advanced gastric cancer (AGC) in GC0301/TOP-002, but it did not show significant superiority (Gastric Cancer 2011). According to subset analyses, IRI-S may have extra survival benefit in some group of patients, prompting to explore prognostic or predictive markers.We correlated expression of 5 genes related to DNA and anticancer drug metabolism (TS, DPD, Topo-I, ERCC1, TP) with outcome of patients in each arm. Methods: Paraffin-embedded primary tumor specimens before chemotherapy were available from 126 of 326 patients. mRNA expression in microdissected tumors was measured by real-time RT-PCR, and categorized into low and high using the median as a cut-off. Multivariate analysis for overall survival (OS) adjusting baseline factors, gene expression and treatment (S-1/IRI-S) was performed with a Cox regression model. Interaction tests were also carried out between gene expression and treatment. Results: Although baseline factors of the subjects were similar to the entire GC0301/TOP-002 trial, median survival seemed opposite; 13.1M for S-1 and 11.4M for IRI-S arm, p=0.192. 92 samples, 47 of S-1 and 50 of IRI-S arm, were assessable for 5 genes. Multivariate analyses showed that liver metastasis correlated with poor prognosis (HR, 2.73; 95% CI, 1.50-5.01; P=0.011), but no gene was significantly correlated with OS. There were interactions between the treatment effect for DPD and TP. HRs between high and low DPD were 3.02 in S-1 and 0.96 in IRI-S arm, p=0.012 for interaction; while those for TP were 2.98 in S-1 and 0.38 for IRI-S arm, p=0.002. In patients with low TS and high Topo-I (n=18), OS was 11.2M for S-1 and 18.6M for IRI-S arm, p=0.531. Conclusions: The correlative analyses suggest DPD and TP are predictive factor for the first-line treatment of AGC including S-1 and irinotecan. Combined biomarker analyses with the previous randomized phase III study including S-1 or irinotecan is warranted to verify these findings.
Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 metastatic colon cancer patients.
Authors: Hanna Nader , Woods Corinne , Zheng Zhiyuan , Onukwugha Ebere , Seal Brian S. , Mullins C. Daniel 
Published: February 2017

559 Background: The purpose of this study was to investigate the association between multiple chemotherapy/biologic treatment lines and survival among patients diagnosed with metastatic colon cancer (mCC). Methods: Patients aged 66 to 105 years old diagnosed with mCC between 2003 and 2007 were selected for analysis from the Surveillance, Epidemiology and End Results SEER-Medicare data to determine the association between chemotherapy/biologic treatment lines and survival. We examined the survival benefits using Cox proportional-hazards regressions with inverse probability weighting method to adjust for the probability of receiving treatment lines. Results: Patients with no chemotherapy/biologic treatment had an adjusted median survival time of 6.8 months. Each chemotherapy/biologic treatment line received was associated with longer adjusted median survival times: 11.9 months, 23.2 months and 26.4 months for receipt of first-line treatment only, second-line treatment and subsequent treatment, respectively. Colon cancer-specific mortality hazard ratios (HRs) were 0.637, 0.391 and 0.350 (p<0.001 for each) for first-line, second-line and subsequent treatments, respectively. Overall mortality hazard ratios were 0.604, 0.398 and 0.364 (p<0.001 for each) for first-line, second-line and subsequent treatments, respectively. Compared to receiving only first-line treatment, proceeding to second-line treatment was associated with longer colon cancer-specific survival (HR=0.614, p<0.001) and longer overall survival (HR=0.659, p<0.001). Patients with a low-graded tumor had longer colon cancer-specific and overall survival (HR=0.746, p<0.001; HR=0.762, p<0.001, respectively) and lived 5.6 months longer. Factors associated with shorter survival were a higher age category and being female. Conclusions: Among mCC patients who survived at least 3 months from diagnosis, each chemotherapy/biologic treatment line was independently associated with significantly longer survival. Proceeding from first-line to second-line therapy or having a low-graded tumor was also associated with longer survival. Proceeding from second-line third-line therapy showed neither benefit nor harm.
Tumor burden (TB) as a prognostic indicator in patients with metastatic colorectal cancer (mCRC).
Authors: Loh Kiley Wei Jen , Shapiro Jeremy David , Tran Ben , Wong Hui-Li , Wong Shu Fen , Richardson Gary Edward , Harold Michael , Gibbs Peter 
Published: February 2017

572 Background: At initial diagnosis of mCRC, accurate assessment of patient prognosis is critical to defining the optimal initial treatment strategy. While performance status (PS) and number of metastatic sites are presumed surrogates of TB, to date TB assessment has not been formally examined as a potential prognostic marker in mCRC, despite supportive evidence in other malignancies. Methods: We developed a CT-based scoring system for TB on mCRC patients from the TRACC (Treatment of Recurrent and Advanced Colon Cancer) database. Objective (size and number of metastases) and subjective (clinical judgment) scoring systems were used to separate patients into high, moderate, or low TB subsets. Subjective scoring was repeated by a blinded second assessor on a subset of cases. Clinicopathologic correlates with TB were then assessed, along with survival outcomes for each subset. Results: 151 patients were assessed, median age was 68 years and 51% were male. Using subjective scoring, 55 (36%), 33 (22%), and 63 (42%) were categorized to high, moderate, and low TB subsets. Concordance between assessors using subjective scoring for 30 selected cases was 80% (high), 60% (moderate), and 90% (low). Factors correlating with increasing TB (high vs. low) on objective scoring were PS (31 vs 5% ≥ 2, p = 0.0002), number of disease sites (57 vs 9% ≥2, p < 0.0001) and for patients with mCRC at presentation, reduced likelihood of primary CRC resection. Median overall survival was superior in low compared to high TB subsets for subjective (not reached vs. 15.9mths, p < 0.0001) and objective (not reached vs. 14.7mths, p < 0.0001) scores. Survival difference for low vs high TB were maintained on objective scoring even when patients with resectable metastases were excluded (22.7 vs. 11.9mths, p = 0.0017). Conclusions: TB measured subjectively or objectively is associated with overall survival in mCRC, and is a potential novel prognostic marker. Multi-variate analyses will be performed, and an independent validation cohort is being examined. As TB inversely correlated with primary resection for patients with mCRC at presentation, including TB assessment in further analyses of the survival impact of primary CRC resection is one potential application of this measure.
Liver-directed therapies for colorectal cancer liver metastasis (CLRM): A Surveillance, Epidemiology, and End Results (SEER)-Medicare analysis.
Authors: Beg Muhammad Shaalan , Adhami Faisal , Xuan Lei , Hodges Joseph , Meyer Jeffery , Halm Ethan , Pruitt Sandi 
Published: February 2017

577 Background: Oligometastatic CLRM comprises a distinct subset of stage IV colorectal cancer. Liver directed therapies (LDT) including surgery, ablation, radiation, and transarterial chemotherapy/embolization have been shown to improve cancer outcomes in smaller series. We sought to evaluate utilization of LDT and their impact on survival in patients with CLRM in a population-based database. Methods: We analyzed linked SEER-Medicare data. Eligible patients were ≥ 66 years, diagnosed between 1992-2009, carry a code for secondary malignancy of the liver (ICD-9 197.7) and survived ≥ 30 days after diagnosis. LDT (yes vs. no) were defined by ICD-9 and CPT codes of surgery (hepatectomy), ablation (e.g. radiofrequency and cryoablation), radiation (e.g., stereotactic surgery and brachytherapy), and transarterial/embolization (e.g., radioembolization). Treatment and non-treatment groups were matched using a propensity score comprised of a comprehensive set of patient and tumor characteristics including: age, sex, race, marital status, Medicaid status, and tumor histology, grade, and location. Cox Proportional Hazard models were used to compare the impact of the LDT on overall survival among propensity-matched pairs of treated and untreated patients. Results: LDT were performed in 12.7% (n = 1,793) of all 14,150 patients. There were 13.7% of patients over 85 years. Females were 52.1% and 83 % White. Off all, 5.4% had surgery, 3.9% had ablation, 4.6% had radiation, and 1.6% had transarterial chemotherapy/embolization. Unadjusted 5 year overall-survival (OS) was 26.9% for those underdoing LDT vs. 7.5% who did not (HR = 0.44, (CI 0.41,0.46)). Cox modeling demonstrated a survival benefit for each LDT with HR of 0.36 (0.33,0.39) for surgery, 0.35 (0.32,0.39) for ablation, 0.78 (0.72, 0.85) for radiation and 0.42 (0.36,0.49) for transarterial/embolization. Conclusions: While use of LDT for CLRM in this national sample of Medicare patients were low, those who received treatment had markedly improved survival compared to matched patients who did not. Surgery and ablation were the most effective therapies. These findings require evaluation in a prospective clinical study.
Analysis of fiducials implanted during endoscopic ultrasound (EUS) for locally advanced rectal cancer patients receiving high-dose rate endorectal brachytherapy (Endo-HDR).
Authors: Moningi Shalini , Malayeri Ashkan , Gearhart Susan , Efron Jonathan , Wick Elizabeth C. , Azad Nilofer Saba , Diaz Luis A. , Armour Elwood , Le Yi , Shin Eun Ji , Herman Joseph M. 
Published: February 2017

655 Background: Rectal cancer affects over 40,000 patients in the US per year. The current standard of care for patients with localized rectal cancer is neoadjuvant radiation therapy with concurrent chemotherapy (NCRT) followed by surgery; however, it has shown no proven survival benefit for locally advanced rectal cancer patients. Preliminary results show that a short course of radiation therapy, using high-dose rate endorectal brachytherapy (Endo-HDR), may be as effective with less toxicity and delay to time of surgery. This requires the placement of fiducial markers, using an endoscopic ultrasound guided method (EUS), into the tumor for accurate source placement and treatment. Our aim is to compare three different types of fiducials in terms of visibility and migration. Methods: 12 patients with locally advanced rectal cancer that received Endo-HDR and EUS guided fiducial placement were retrospectively evaluated at JHH. Results: 12 patients underwent EUS guided placement of 42 fiducials. For 11 of our 12 patients, the mean number of fiducials placed per patient was 3.63 (SD 1.03) using a 19-gauge needle. One patient received 2 fiducials using a 22- gauge needle. Of the 12 patients that received fiducials, 3 received traditional fiducials (TF), 8 received segmented fiducials (SF) and 1 received foldable fiducials. All fiducials were clearly visible. The mean number of fiducials that detached from implanted site before surgery for patients with TFs was 0.667, and for patients with SFs was 0.875 (p=0.744). The median migration distance, as measured by interfiduciary distance, for segmented fiducials was significantly larger when compared to traditional fiducials (0.45 cm for SF compared to 0.1 cm for TF; p=0.049) Conclusions: SFs appear to be less stable, with regards to migration, in the rectum when compared to traditional fiducials in our patient population. These differences could be due to placement difficulty or operator dependent differences. Improvement in fiducial structure is required in order to help decrease migration and detachment and maximize visualization, which will lead to more accurate administration of Endo-HDR.