bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3836: A tracking and feedback registry to reduce disparities in breast cancer care
Authors: Bickell Nina , Shastri Kruti , Fei Kezhen , Oluwole Soji , Godfrey Henry , Srinivasan Anitha , Hiotis Karen , Guth Amber 
Published: May 2019

Abstract
Background: Despite the existence of effective adjuvant treatment for early stage breast cancer, women do not always receive it, particularly, minority women. Primary treatment for breast cancer, surgery and varying combinations of radio-, chemo- and hormonal therapy, is delivered by different specialists and is often fragmented. Underuse of post-surgical adjuvant treatment occurs more commonly among women who do not see a medical oncologist despite surgeons’ referral request. To reduce underuse of adjuvant treatment due to failed connections, we tracked and fedback to surgeons information about whether their newly diagnosed breast cancer patients connected with an oncologist.
Methods: We compared oncology referral rates and underuse among pre-intervention (N=677) and intervention (N=300) patients undergoing breast cancer surgery at 6 NYC hospitals. All surgeons consented to the intervention. Each surgeon chose an office person to verify eligibility and identify patient’s oncology referrals. Patients identified upcoming oncology appointment sites and times. Following scheduled visits, oncologists were called to verify patients’ connection & these data were fedback to surgeons & their office staff. Six months later, we abstracted in- & outpatient charts. We compared rates of: completed oncology consultations and underuse of radiotherapy after breast conserving surgery, of chemotherapy for ER negative and hormonal therapy for ER positive tumors &gt;1cm between pre- and intervention women with newly diagnosed early-stage breast cancer.
Results: There was a significant increase in oncology consultations completed (83% to 97%; p&lt;0.0001) and decrease in underuse of adjuvant treatment (21% to 14%; p&lt;0.001); specifically, underuse of chemotherapy (22% to 11%; p=0.05) and hormonal therapy (20% to 8%; p=0.0004) declined. Among black and Hispanic women, underuse of radiotherapy significantly decreased (23% to 10%; p=0.02). Multivariate models, adjusting for clustering by hospital, patient age, race, stage and insurance, found the intervention increased rates of oncology consultation (OR=5.33; 95%CI: 2.68-10.60), and reduced adjuvant underuse (OR= 0.62; 95%CI: 0.42-0.93). Minority race was no longer a risk factor for an oncology consultation (OR=1.20; 95%CI: 0.69-2.08) or underuse of adjuvant therapy (OR= 1.13; 95%CI: 0.73-1.75).
Conclusions: A tracking and feedback registry which closes the referral loop between surgeons and oncologists appears to improve rates of medical oncology consultation, reduces rates of adjuvant treatment underuse and eliminates the racial disparity in treatment.
Abstract 4179: Promising clinical activity of a NAB paclitaxel plus gemcitabine combination in a disease-specific phase I trial in patients with advanced pancreatic cancer
Authors: Von Hoff Daniel D. , Borad Mitesh , Ramanathan Ramesh K. , Smith Lon S. , Drengler Ronald L. , Wood Tina E. , Laheru Daniel , Hidalgo Manuel 
Published: May 2019

Abstract
Patients (pts) with pancreatic cancer have very poor survival. A substantial percentage of pancreatic cancers have increased expression of SPARC (Secreted Protein And Rich in Cysteine) (Guweidhi et al., Annals of Surgery, 2005; 242: 224-234,Von Hoff et al., J Clin Oncol 2006; 24(18s): 138, Infante et al., J Clin Oncol 2007; 25 (3): 319.) Increased SPARC expression has been correlated with improved response to nanoparticle albumin-bound paclitaxel(nab-paclitaxel) due to a SPARC-albumin interaction (Trieu et al., New Targets in Delivery System for Diagnosis and Treatment (SKCC), 2007; abstract 53). Based on this observation, SPARC may play a role in selectively concentrating nab-paclitaxel in pancreatic tumors. Therefore a disease specific modified phase I trial of nab-paclitaxel + gemcitabine in pts with advanced pancreatic cancer was performed. Tumor samples were obtained for SPARC evaluation and CA19-9 levels were monitored as a drop in CA19-9 has been correlated with improved survival.
In this study, pts with advanced pancreatic cancer with no prior chemotherapy except as a radiation sensitizer received nab-paclitaxel + gemcitabine on days 1, 8, 15 every 28 days with a starting dose of 100 mg/m2 and 1000 mg/m2 respectively. Subsequent dose escalations of nab-paclitaxel were planned at 125 and 150mg/m2.
To date, 20 pts have been recruited for this study. All of the pts received nab-paclitaxel 100mg/m2 + gemcitabine 1000 mg/m2. 18/20 patients completed at least one cycle of treatment and were considered evaluable. Independent review of the patient’s measurable disease on CAT and PET scans is ongoing with many of the patients continuing to have radiographic regression of disease. 17/18 evaluable subjects had paired CA19-9 levels available for analysis. Clinical activity has been demonstrated by CA19-9 reduction of greater than 20% from baseline in 82% (14/17pts) and more than 70% from baseline in 59% (10/17 pts). A decrease of CA19-9 of at least 20% has been associated with improvement in patient survival (AH Ko et al., BJC 2005; 93, 195-199, Park BB et al., Cancer Chemother Pharmacol 2007 Sep; 60 (4): 489-94, and Boeck S et al., Oncology 2006; 70 (4): 255-64).
The most common Grade 3/4 adverse event (AE) was neutropenia (n=3, 2, respectively). Other grade 3 AEs include febrile neutropenia (1), fatigue (1) and hyperglycemia (1). In addition, 2 cases of grade 2 anemia and 2 cases of thrombocytopenia were observed.
Based on these results, the combination of nab-paclitaxel and gemcitabine in pancreatic cancer warrants further study. Dose escalation to cohort 2 is proceeding. When the MTD is determined, that cohort will be expanded. The optimum dose as determined in this study will be used in a larger, randomized phase II/III study.
Abstract 4740: Selective ablation of metastatic disease with integrin ανβ3 targeted nanoparticle drug delivery
Authors: Majeti Bharat K , Murphy Eric A , Barnes Leo , Makale Milan , Lutu-Fuga Kimberly , Weis Sara , Bouvet Michael , Wrasidlo Wolfgang , Cheresh David A 
Published: May 2019

Abstract
Angiogenic blood vessels found within growing tumors express high levels of integrin ανβ3 while mature vessels fail to express this integrin. Based on this we developed a ανβ3-targeted nanoparticle (NP) in an attempt to selectively deliver therapeutics to the tumor neovasculature. A cyclic peptide ligand (cRGDfK) coupled to a phospholipid and incorporated into a nanoparticle demonstrated specific binding to ανβ3 on cultured endothelial cells. To characterize the in vivo targeting capacity of these NPs, we monitored NP accumulation using intravital microscopy of tumor neovasculature. A dorsal skin-fold window chamber implanted with GFP-labeled melanoma cells lacking integrin ανβ3 were imaged at various times after NP injection into the bloodstream. By 5h post injection, the cRGDfK NPs targeted the neovasculature at the angiogenic tips adjacent to the tumor margin, whereas untargeted (cRADfK) NPs failed to bind. After establishing in vivo targeting, these ανβ3-targeted NPs were loaded with doxorubicin via an ammonium phosphate gradient for therapeutic studies. The cRGD-Dox particles disrupted angiogenesis in the mouse matrigel model leaving only small fragments of disrupted vessels within the FGF loaded plugs. Next, we utilized an orthotopic pancreatic cancer model to study the ability of the NPs to target the vasculature of both primary pancreatic tumors as well as metastatic sites including the hepatic hilar lymph node and mesenteric lymph nodes. cRGD-Dox particles injected systemically at 1 mg/kg produced a profound anti-metastatic effect while only marginally influencing the pre-established primary tumor within the pancreas. This is much improved compared to the free doxorubicin treatments in which 1 mg/kg of free doxorubicin had no effect and 15 mg/kg of free doxorubicin was required for a similar therapeutic effect in this orthotopic model. Animals treated with 15 mg/kg of free doxorubicin lost over 20% of their body weight within 7 days, whereas no decrease in body weight was observed in the cRGD-Dox treated animals, confirming the reduction in overall toxicity. Histology confirmed that the cRGD-Dox particles induced apoptosis in regions co-localized with β3 expressing tumor vasculature. Additionally, we tested the cRGD-Dox particles in an orthotopic renal cell carcinoma model. Similar to the pancreatic carcinoma, the cRGD-Dox particles had a slight effect on primary tumor growth but greatly reduced metastasis to several sites including the pancreas, liver, spleen, and diaphragm. These findings reveal that ανβ3 targeted NP drug delivery may preferentially disrupt newly forming metastatic lesions by delivery of chemotherapeutic agents to sites of active angiogenesis in which the endothelium expresses high levels of ανβ3.
Abstract 4997: Prospective identification, tracking, and targeting of cancer-initiating cells in breast cancer and glioma via low proteasome activity
Authors: Vlashi Erina , Kim Kwanhgee , Della Donna Lorenza , McDonald Tyson , Lagadec Chann , McBride William H , Frank Pajonk 
Published: May 2019

Abstract
Cancer initiating cells (CICs) in breast cancer and glioma are resistant to radiation and chemotherapy. Complete elimination of these cells from the tumor mass determines therapeutic success. Thus, prospective identification of this cell population is key to developing novel targeting strategies for CICs. The current surface marker combinations employed in identifying CICs have several shortcomings. Here we report a novel marker for CICs that allows identification, tracking, and targeting of CICs in-vitro and in-vivo.
Proteasome activities of human (U87 and U87viii) and murine (GL261) glioma cells, as well as human (MCF-7 and MDA-MB-231) and murine (67NR) breast cancer cells were analyzed using fluorogenic peptide substrates. Stable cell lines were generated with retroviruses coding for fusion proteins of ZsGreen and the degron of murine ornithine decarboxylase (ODC), or in combimation with thymidine kinase (TK). Accumulation of ZsGreen was monitored by fluorescence microscopy and flow cytometry. Self-renewal capacity was assessed in sphere forming assays, and tumorgenicity was determined by injection of sorted tumor cells into nude mice.
Cell populations enriched for CICs demonstrated significantly reduced activities of the 26S proteasome and showed differential expression of proteasome subunits. Accumulation of ZsGreen corresponded with the CD24-/low/CD44+ phenotype in MCF-7 cells, and glioma ZsGreen-positive cells expressed high levels of the stem cell marker, nestin. Cells with low proteasome function exhibited a 5-fold increased sphere forming capacity, and 3-log increased tumorgenicity.
Histologically, ZsGreen-positive U87 cells resided in a perivascular niche, and stained negative for Ki67. Optical in-vivo imaging revealed a significant increase in the number of ZsGreen-positive cells after treatment with sublethal doses of radiation. Fractionated sublethal irradiation of these xenografts caused induction of jagged-1 and notch-1 expression, and induced Ki67 expression in the zsGreen-positive population. Treatment of TK-ZsGreenODC-expressing U87 cells with ganciclovir eliminated cells with low proteasome activity, and subsequently prevented sphere formation in-vitro, and caused complete regression of tumors in-vivo.
We conclude that low proteasome activity is a unique characteristic of CICs. Cell lines infected with reporter constructs for proteasome activity can be utilized to identify CICs and track their response to cancer treatments. Most importantly, this feature of CICs can be exploited as a specific target for selective elimination of CICs, leading to improved tumor control.
Abstract LB-242: Aberrant crypt foci (ACF) are not surrogate biomarkers of sporadic adenoma prevention with celecoxib: Results from the Adenoma Prevention with Celecoxib (APC) trial
Authors: Cho Nancy L , Redston Mark , Zauber Ann G. , Carothers Adelaide M , Hornick Jason L , Wilton Andrew , Sontag Stephen , Nishioka Norman , Giardiello Frances , Saltzman John R , Gostout Chris , Eagle Craig J , Hawk Ernest T. , Bertagnolli Monica M 
Published: May 2019

Abstract
Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients enrolled in the Adenoma Prevention with Celecoxib (APC) Trial to determine whether the presence of ACF in the rectum correlated with that of adenomas in the entire large intestine. Participants were randomized to placebo (n=17), celecoxib 200 mg bid (n=15), or celecoxib 400 mg bid (n=13). Magnification chromoendoscopy (MCE) was performed to identify and biopsy ACF within the rectum at baseline and after 8-12 months of medication use. A total of 670 ACF were identified in 45 patients, and 70 of these were examined histologically. All of the ACF examined were non-dysplastic. Analysis showed no differences in ACF number between baseline and post-treatment studies (8.3±1.0 vs. 6.3±1.1) and no modulation by treatment (celecoxib vs placebo; p=0.77). Immunohistochemical studies showed that ACF contained cells exhibiting increased proliferation, but lacked other features of neoplasia such as increased Cox-2 expression and microvascular density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, estrogen receptor (ERα) or MGMT. Of the secondary markers assessed at baseline, only SMAD4 expression correlated with post-treatment adenoma recurrence. Taken together, these data showed that non-dysplastic ACF are not accurate surrogate endpoint biomarkers of colorectal adenoma risk or NSAID chemoprevention response.
Abstract LB-248: A single-institution prospective study evaluating the functional diffusion map (fDM) as an early imaging biomarker for overall survival in high-grade glioma
Authors: Ross Brian D , Hamstra Daniel A , Galban Craig J , Meyer Charles R , Johnson Timothy D , Sundgren Pia C , Tsien Christina , Junck Larry , Ross David J , Rehemtulla Alnawaz , Chenevert Thomas L , Lawrence Theodore S 
Published: May 2019

Abstract
Introduction: Standard assessment of radiologic response in patients with malignant glioma is traditionally carried out using T1 gadolinium-enhanced MRI at approximately 10 weeks following treatment initiation. Diffusion-weighted MRI of gliomas, analyzed by the functional diffusion map (fDM), may provide an early measure of response during treatment to predict patient survival (OS). Tumor cells restrict the random diffusion of water molecules within a tumor; therefore, diffusion will increase during successful therapy. The fDM imaging biomarker is a voxel-wise method for analysis of DW-MRI data providing for quantification of treatment-associated spatial alterations in tumor diffusion values earlier than radiologic response.
Methods: A prospective single-institution trial of early assessment of brain tumor response by MRI was performed early during radiation therapy. Sixty patients with high grade glioma undergoing radiation therapy were enrolled in an IRB-approved study of intra-treatment MRI 1, 3, and 10 weeks after the initiation of treatment. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at one-year. Log Rank and Cox Proportional Hazards models were utilized to assess OS.
Results: Measurable changes in diffusion MRI were observed as early as one week into treatment. The volume of tumor with increased diffusion as assessed by fDM 3 weeks after the start of therapy was the strongest predictor of patient survival at one year, with larger fDM predicting longer median survival [52.6 vs. 10.9 months, log-rank, P&lt;0.003, HR 2.7 (95% CI: 1.5-5.9)]. Radiologic response at 10 weeks was of similar prognostic value [log-rank, P&lt;0.0007, HR 2.9 (95% CI: 1.7-7.2)]. Pre-treatment age (&lt;50 vs. 50+, P&lt;0.007), pathologic grade (III vs. IV, P&lt;0.05), and the use of concurrent temozolomide (yes vs. no, P&lt;0.05) all predicted for increased survival on univariate analysis. On multivariate analysis only age (P&lt;0.03) and fDM (P&lt;0.04) retained prognostic significance for overall survival. Radiologic response and fDM agreed in their stratification for 75% of patients. However, a composite index of response including both fDM at 3 weeks and RR at 10 weeks provided a more robust predictor of patient survival and may help identify patients where RR does not correlate with clinical outcome.
Conclusions: Compared to conventional neuro-imaging, fDM provided an earlier assessment of equal predictive value during the course of treatment, providing the opportunity to individualize therapy. The combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.
Abstract LB-303: Berubicin, a brain tumor targeting anthracycline: Discovery and clinical evaluation
Authors: Priebe Waldemar , Madden Timothy , Conrad Charles A. 
Published: May 2019

Abstract
Development of effective chemotherapeutic strategies to treat brain tumors has been limited in part by the inaccessibility of the CNS to pharmacological intervention. Topoisomerase II (topo II) overexpression has been well documented in human gliomas and is correlated to poor survival, but to date no effective topo II poison, capable of reaching the target tissue after systemic administration, has been developed. We hypothesized that the presence of ATP-binding cassette (ABC) transporters in the blood-brain barrier (BBB) might, in part, be responsible for limiting the CNS penetration of most anticancer drugs including topo II poisons like doxorubicin (DOX). To identify new agents effective in vivo against brain tumors, we have used our innovative modular design of DNA-binding agents to create unique libraries of potential topo II poisons. By systematically screening such libraries, we have identified highly apoptotic compounds that can circumvent P-gp and MRP1-mediated resistance mechanisms, suggesting that such compounds will be potent cytotoxins against gliomas, through their ability to cross the BBB.Synthesis and in vitro screening of a library of over 400 DNA binding agents in a panel of cells overexpressing P-gp and MRP1 led to identification of 10 compounds possessing the necessary characteristics from which the compound Berubicin (RTA744, WP744) was selected for detailed preclinical evaluation. Berubicin (BRB) is structurally related to the well-known anticancer drug DOX, but is significantly more apoptotic than DOX against multidrug-resistant tumor cell lines with the MDR1 and MRP1 phenotypes and can cross the BBB, achieving CNS and brain tumor concentrations exceeding that of plasma. Subsequent preclinical development led to IND and Phase I clinical studies in humans. In the first Phase I trial dose escalation of BRB proceeded according to an accelerated titration design, with single patient cohorts and 100% dose escalations until evidence of drug-related Grade 2 or greater toxicities were observed. The MTD of berubicin administered on a qd X 3 schedule was 7.5 mg/m2/day (22.5 mg/m2/cycle). Toxicities appear consistent with the anthracycline class, with no unexpected toxicities observed. Of interest no neurotoxicity or cardiotoxicity have been reported. Median time to progression in the Phase I study as of 5/21/ 2007 was 7.4 weeks with one complete response (CR), one partial response (PR)) and 7 minor response or stable disease patients, observed. Because of the unique biological characteristics of BRB (potent topo II poison, ability to cross BBB, activity against multidrug resistant tumors) and the results of Phase I clinical studies this agent is uniquely placed to become an effective therapeutic agent for the treatment of brain tumors.
Abstract LB-304: Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study of neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer
Authors: Willett Christopher G , Xu Lei , Duda Dan G , di Tomaso Emmanuelle , Boucher Yves , Lahdenranta Johanna , Ancukiewicz Marek , Bendell Johanna , Czito Brian , Blaszkowsky Lawrence , Clark Jeffrey , Jain Rakesh K 
Published: May 2019

Abstract
Background: A phase I/II study of neoadjuvant bevacizumab with 5-fluorouracil and radiation therapy in patients with locally advanced rectal cancer is underway to assess the clinical benefits of bevacizumab enhancement of chemo-radiation therapy.
Methods: 24 patients with endoscopic ultrasound or surface coil MRI staged T3/T4 non-metastatic rectal cancer were enrolled from 2001-2007. All patients completed 4 cycles of neoadjuvant therapy including: 1) bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 2) peripheral venous infusion 5-FU (225 mg/m2/24 hours) administration each treatment week of cycles 2 - 4; 3) external beam irradiation delivery (50.4 Gy in 28 fractions over 5.5 weeks); and 4) surgery 7 to 9 weeks after completion of all neoadjuvant therapy. Correlative studies are undertaken before and during the trial. We collected serial tumor biopsies, PET-FDG scans, and analyzed blood and urine for potential biomarkers.
Results: Histologic examination showed no residual primary cancer in 5 patients (ypT0). Of 19 patients with residual disease, microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 in 3 patients, ypT2 in 4 patients, ypT3-4 in 12 patients). Downstaging was seen in 12/22 tumors. Nine patients had microscopic nodal metastases. Bevacizumab alone and combined treatment were both associated with increased plasma VEGF, PlGF and SDF1alpha levels in analyzed patients (P&lt;0.01 at all 4 timepoints compared to baseline). Viable CECs were decreased by VEGF blockade at day 3 (P&lt;0.01 compared to baseline), and CEC levels correlated with histologic tumor response (T3 vs T0, p &lt;0.05). Laser-capture micro-dissection identified a set of genes changed by anti-VEGF therapy in cancer cells as well as in tumor-associated macrophages. Actuarial 4 year local control and disease-free are 100% and 88%, respectively.
Conclusions: Addition of bevacizumab at a dose of 5 mg/kg to standard chemo-radiation shows activity and the combined regimen yields promising results.