bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT095: The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody
Authors: Dominguez George A. , Condamine Thomas , Mony Sridevi , Hashimoto Ayumi , Wang Fang , Liu Qin , Forero Andres , Bendell Johanna C. , Witt Robert , Hockstein Neil , Kumar Prasanna , Gabrilovich Dmitry I. 
Published: July 2017

Abstract
The goal of this current study was to clinically test the hypothesis that by targeting TRAIL-R2, myeloid-derived suppressor cells (MDSCs) can be selectively eliminated. MDSC) are one of the major contributors to immune suppression in cancer. We previously demonstrated in a preclinical study that MDSCs are sensitive to a TRAIL receptor 2 (TRAIL-R2) agonist. The TRAIL-R2 agonistic antibody (DS-8273a; provided by Daiichi Sankyo, Inc.) was tested in 16 patients with advanced solid cancers or lymphomas enrolled in a phase 1 trial. The antibody (24 mg/kg) was administered IV once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated using flow cytometry and immunohistochemistry. Overall, the treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Furthermore, treatment with DS-8273a resulted in reduction of the elevated numbers of MDSC in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSC rebounded back to the pre-treatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells with decreases in MDSC levels inversely correlating with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSC in 50% of the patients who were able to provide pre- and on-treatment biopsies. In conclusion, targeting TRAIL-R2 using DS-8273a resulted in a temporary elimination of MDSCs without affecting mature myeloid or lymphoid cells, and these data support further use of this antibody in combination with current immmunotherapies of cancer.
Citation Format: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna C. Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich. The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT095. doi:10.1158/1538-7445.AM2017-CT095
Abstract CT103: A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results)
Authors: Greenwood Bernadette Marie , Feller John F. , May Stuart T. , Jones Wes , Winkel Axel 
Published: July 2017

Abstract
Purpose: In the United States alone, new prostate cancer cases for 2016 were estimated at 180,890 and deaths at 26,120. Focal therapies for low risk and intermediate risk localized prostate cancer are increasingly being explored. Additionally, new treatments for patients with biochemical recurrence of prostate cancer are also under investigation. Our objective is to investigate the safety and feasibility of using outpatient MR-guided laser focal therapy for MR visible prostate cancer utilizing a transrectal approach for laser applicator placement and therapy delivery in an outpatient setting.
Method and Materials: All MRI-guided therapy was delivered using a 1.5 Tesla MRI system for both image acquisition and real-time thermometry. Commercially available hardware and software were used for image analysis and interventional planning. Laser therapy was delivered using a 15W, 980 nm diode laser applicator with fiber-cooling catheter introduced transrectally using a commercially available MRI-compatible introducer system.
Results: 80 men were treated. 112 cancer foci were treated. Total procedure time was between 1.5 and four hours MRI volume of coagulation necrosis ranged from 0.57 to 22.93 cc. No serious adverse events or morbidity were reported. 17 treatment regions were positive at six months biopsy, consistent with residual or recurrent cancer 26% of subjects 18% of treated regions.We observed a 40% decrease in mean PSA at 1 year post therapy and no statistically significant change in IPSS and SHIM scores at 6 months post-treatment.
Conclusion: Our data indicate that outpatient, transrectally delivered MRI-guided laser focal therapy for prostate cancer is both safe and feasible.
Clinical Relevance/Application: In the current climate of cost-reduction and emphasis on minimally-invasive treatment of cancer, focal treatment of prostate cancer may be an attractive option. The precise energy delivery under MRI-guidance may have favorable results for cost control and quality of life without eliminating the possibility of whole-gland treatment in the patient’s future.
Citation Format: Bernadette Marie Greenwood, John F. Feller, Stuart T. May, Wes Jones, Axel Winkel. A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2017-CT103
Abstract CT112: Use of targeted sequencing of cancer genome (cancer panel) to develop patient-centered therapeutic target based on molecular alternations: A pilot prospective study for 25 patients with refractory and metastatic cancer and treatment response
Authors: Kwon Chae Hwa , Seol Young Mi , Kim Young Keum , Choi Yuri , Won Yeo Jin , Park Do Youn 
Published: July 2017

Abstract
With the advent for technology of next generation sequencing, targeted sequencing is now becoming part of decision of chemotherapeutics in cancer patients, especially in refractory and metastatic cancer. We performed targeted sequencing to develop patient-centered trials to find therapeutic target based on molecular alternations. We used cancer panel for capturing of target region covering 83 cancer-related genes and validated it using 3 cases with ALK-fusion, ERBB2 amplification, or KRAS mutation. A total of 25 refractory metastatic cancer patients enrolled on this study so far. The majority of alterations were identified in ATM, FBXW7, NOTCH1, TP53, STK11, ARID1B, GNAS, FGFR3, SMAD4, and HNF1A. Among 25 patients, 12 had FDA-approved drug responsive or resistant alterations. However, targeted therapy was guided in 3 patients (12 %) on the basis of sequencing results because of lack of access to clinical trials, declining performance status and/or stable disease with previous treatment; crizotinib to ALK-EML4 fusion in malignancy of undefined origin (MUO) patient, pazopanib to FGFR amplification in malignant peripheral nerve sheath tumor (MPNST) patient, and everolimus to AKT3 amplification in uterine endometrial stromal sarcoma patient. All 3 patients showed partial response after targeted therapy. In addition, we identified KRAS codon 146 mutation (A146V), associated with resistance to anti-EGFR, in a cetuximab resistant colon cancer patient with wild-type KRAS exon 2 and 12 and EGFR. Taken together, this study suggests that identifying targets associated with response or resistance to specific targeted therapies using targeted sequencing can show great promise for improving the care of patients with refractory and metastatic cancer patients.
Citation Format: Chae Hwa Kwon, Young Mi Seol, Young Keum Kim, Yuri Choi, Yeo Jin Won, Do Youn Park. Use of targeted sequencing of cancer genome (cancer panel) to develop patient-centered therapeutic target based on molecular alternations: A pilot prospective study for 25 patients with refractory and metastatic cancer and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT112. doi:10.1158/1538-7445.AM2017-CT112
Abstract CT140: PINC trial: Preventing invasive breast neoplasia with chloroquine
Authors: Espina Virginia A. , Liotta Lance , Rassulova Svetlana , Gallimore Holly , Grant-Wisdom Thalia , Menezes Geetha , Nayer Hassan , Edmiston Kirsten 
Published: July 2017

Abstract
The PINC trial (NCT01023477) examined the dosage efficacy of oral chloroquine (CQ), an autophagy inhibitor, as a neoadjuvant therapy to reduce the volume, cause regression and decrease the recurrence of breast ductal carcinoma in situ (DCIS), for any grade or ER/PR/Her2 status. Study Objectives: Establish the safety of preventive doses of chloroquine in patients receiving external beam radiation. Elucidate functional molecular and cellular impacts of in vivo autophagy pathway treatment for DCIS. Study the impact of autophagy inhibitors on the MRI characteristics of DCIS lesions. Study the molecular cytogenetic profile of DCIS lesions before and after therapy. This trial implemented a general strategy to accelerate the pace of community-based translational research. Technology for providing immediate feedback on the therapeutic efficacy at the molecular level can be broadly extended to other trials. Methodology: 12 patients diagnosed with DCIS (any grade or ER/PR/Her2 status) were enrolled and randomly assigned to receive CQ at 250mg/week (n=5) or 500mg/week (n=7) for 4 weeks, followed by standard of care surgical therapy. MRI was performed before/after CQ treatment. DCIS spheroid forming cells were isolated and propagated from fresh human DCIS lesions. DCIS cells were characterized by organ culture, xenograft transplantation, molecular cytogenetics, and 59 cell signaling kinases were quantified by Reverse Phase Protein Microarrays.
Results: 12 patients completed 4 weeks of CQ treatment prior to surgical excision of their DCIS lesion, with 1 yr follow-up information. CQ treatment reduced PCNA proliferation index in DCIS lesions compared to untreated controls (p=0.001) and inhibited autophagic flux (LC3B positive puncta by IHC). CQ reduced the number of mammospheres in organoid culture without altering copy number variation. Xenograft transplants in NOD/SCID mouse mammary fat pads failed to generate tumors (n=4). 7/12 patients exhibited a reduction in lesion diameter by MRI, 3/12 patients exhibited no measurable change, and 2/12 had a slight increase. Calcium export channel protein (PMCA2) co-localized with 3+ HER2 positive DCIS lesions. Tumor infiltrating macrophages migrated into DCIS ducts following CQ therapy compared to controls (p=0.006). Conclusion: Oral chloroquine, as anti-autophagy therapy, generates a measurable reduction in proliferation of DCIS lesions and enhances immune cell migration into the duct.
Citation Format: Virginia A. Espina, Lance Liotta, Svetlana Rassulova, Holly Gallimore, Thalia Grant-Wisdom, Geetha Menezes, Hassan Nayer, Kirsten Edmiston. PINC trial: Preventing invasive breast neoplasia with chloroquine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT140. doi:10.1158/1538-7445.AM2017-CT140
Abstract CT144: Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312)
Authors: Cole Kristina A. , Reid Joel M. , Liu Xiaowei , Minard Charles G. , Maris John M. , Fox Elizabeth , Weigel Brenda J. 
Published: July 2017

Abstract
Background: Inhibition of the WEE1 kinase by AZD1775 potentiates replicative stress induced by oncogenes or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. A pediatric phase I dose escalation study of AZD1775 in combination with irinotecan was completed within the COG DVL consortium.
Methods: Patients age 1-21 years with relapsed/refractory solid or CNS tumors were eligible. Both agents were administered orally once daily on days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of both agents. AZD1775 dose levels (DL) were 50 mg/m2 (DL1), 65 mg/m2 (DL 2 and 3), 85 mg/m2 (DL4) and 110 mg/m2 (DL5). Irinotecan, 70 mg/m2 day (DL 1-2), or 90 mg/m2/day (DL3-5), was administered with cefixime for diarrheal prophylaxis. Toxicity was graded according to CTCAE v4.0.
Results: Thirty-one eligible patients, median age 14 years (range 5-20) were enrolled; 29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), ependymoma (4), medulloblastoma (2) and CNS Ewings sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). Two patients experienced dose limiting toxicity, grade 3 diarrhea and dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 mg/m2).
Conclusion: This is the first pediatric clinical trial of AZD1775 in combination with chemotherapy. The maximum tolerated dose in children and adolescents with solid tumors was AZD1775 85 mg/m2/day in combination with irinotecan 90 mg/m2/day for five days every 21 days. Accrual is ongoing for a pediatric PK expansion, PD analysis and Phase 2 expansion in patients with neuroblastoma or medulloblastoma / CNS PNET. Clinical trial information: NCT02095132
Citation Format: Kristina A. Cole, Joel M. Reid, Xiaowei Liu, Charles G. Minard, John M. Maris, Elizabeth Fox, Brenda J. Weigel. Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT144. doi:10.1158/1538-7445.AM2017-CT144
Abstract LB-015: Dissecting TGF beta-induced lethal EMT in Kras-driven pancreatic cancer
Authors: Su Jie 
Published: July 2017

Abstract
Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a devastating malignancy with an extremely poor prognosis. New insights are urgently needed into the tumorigenesis process and the tumor suppression mechanisms of pancreatic cancer. Genetic alterations in PDAC occur in a temporal sequence, usually initiating with activating mutations of the KRAS (~95%), and progressing by loss of tumor suppressors, including INK4A/ARF, TP53 and SMAD4/DPC4. Our recent work reveals that in mouse KrasG12D-driven PDAC cells, TGFβ induces a robust epithelial-to-mesenchymal transition (EMT) response, which leads to cell apoptosis. To determine the KrasG12D-dependent mechanism of priming pancreatic epithelial cells to be sensitive to TGFβ-induced lethal EMT, we utilize systematic approaches to integrate the transcriptome profile and Smad2/3 binding patterns to the genome to identify candidate mediators that regulate TGFβ-induced lethal EMT. To identify TGFβ gene response changes mediated by KrasG12D, we perform RNA-Seq analysis of inducible Tet-On KrasG12D pancreatic epithelial cells (PECs) treating with TGFβ or SB505124. Systematic analyses reveal that mutant KrasG12D, but not KrasWT, enables robust TGFβ gene responses of Snai1, Has2, Has3 and IL11. The massive induction of these genes is crucial for TGFβ-induced lethal EMT. Smad2/3 ChIP-Seq analysis reveals that transcription factor binding motifs of Rreb1 are specially associated with these KrasG12D-enhanced Smad2/3 binding sites. Furthermore, depletion of Rreb1 greatly impairs TGFβ-induced apoptosis. In summary, oncogenic KrasG12D drives a cell state change and sensitizes premalignant PECs to respond to TGFβ-induced lethal EMT. This function switch of TGFβ is potentially mediated through Kras-activated Rreb1 as a specific DNA binding partner of Smads.
Citation Format: Jie Su. Mem. Dissecting TGF beta-induced lethal EMT in Kras-driven pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-015. doi:10.1158/1538-7445.AM2017-LB-015
Abstract LB-040: Application of clinical whole exome sequencing among larger scale advanced cancer patients in China
Authors: Xu Qiang , Wang Guan , Dai Chun , Chen Cheng , Xu Xiaoman , Wang Haining , Wu Angela , Wang Jiping 
Published: July 2017

Abstract
Background: Genomics-guided precision medicine has become a major paradigm shifting effort in cancer care globally to improve the outcome of cancer patients. More and more patients receive individualized cancer treatments based on their tumor-specific characteristics at both gene and genomic levels.
Methods: Over 1,000 cancer patients from more than 70 hospitals across 20 provinces in China were recruited into the project. Majority (88%) of these patients are with 4 major tumor types, which are lung, gastric, colorectal, and breast cancer. The whole exome of tumor specimen and case-matched normal samples were sequenced in each patient. Clinical decision roadmap recommendations were provided to each patient and their treating physician based on clinical whole exome sequencing (CWES) and globally available treatment options. The treatment implementation and the outcome of each patient have been followed.
Results: Of the 907 prospectively enrolled patients, 80% patients was recommended at least one FDA approved target/immunotherapy drug. 60% patients’ tumors have cancer driver/suppressor gene large segment deletions or amplifications. At the end of December 2016, 98 patients with late stage NSCLC, breast or colorectal cancer had more than 6 months follow up. Ninety five percent of (93) patients received personalized target/immunotherapy recommendations based on CWES, including genomic-matched clinical trials. Thirty percent (29) patients actually received the recommended therapy clinically. Of those 29 patients, 55% (16) patients received the treatments recommended by CWES. And 14 of those 16 patients had stable disease (SD) at the time of this report. 25 patients initially received treatment based on other panel-based recommendations, and 14 of the 25 patients suffered disease progression. Among those 14 patients, 8 patients received recommended treatment based on CWES and achieved SD at a later time.
Conclusions: CWES can provide clinical relevant treatment recommendations for most of the advanced cancer patients. Our preliminary observations suggests that CWES might provide a boarder clinical recommendation roadmap for the cancer patients in China. Longer follow-up is needed to evaluate the clinical significance of CWES on long term prognosis.
Citation Format: Qiang Xu, Guan Wang, Chun Dai, Cheng Chen, Xiaoman Xu, Haining Wang, Angela Wu, Jiping Wang. Application of clinical whole exome sequencing among larger scale advanced cancer patients in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-040. doi:10.1158/1538-7445.AM2017-LB-040
Abstract LB-045: Cogency of AR-V7 unexpected responders determined by using distinct detection technologies
Authors: Bernemann Christof , Humberg Verena , Bögemann Martin , Schrader Andres J. , Steinestel Julie , Lennerz Jochen K. 
Published: July 2017

Abstract
Background: The validity of AR-V7 in CTC’s as a predictive marker for non-response to next generation ADT (abiraterone or enzalutamide) has recently been questioned. Specifically, a subset of AR-V7 positive patients showed responses to abiraterone or enzalutamide and assay performance differences could contribute to these unexpected findings. [[Unsupported Character - Codename &shy;]]To our knowledge a direct performance comparison has not been performed. Here we present comparative head to head analysis of different AR-V7 detection technologies with respect to specificity, accuracy and clinical sensitivity.
Methods: We performed comparison of two different AR-V7 detection technologies using either SYBR Green or TaqMan chemistry. Both assays were tested on identical in vitro samples consisting of genitourinary cancer cell lines as well as dilution series of AR-V7 positive cDNA samples. Finally, clinical samples with previously determined CTC and AR-V7 status using TaqMan chemistry were re-analyzed using SYBR Green chemistry.
Results: Both assays performed identical in detection of AR-V7 in different genitourinary cancer cell lines. Additionally, by performing dilution series analyses we observed the same diagnostic threshold of both assays. When re-analysis of clinical samples was performed, both assays performed undistinguishable in determination of the AR-V7 status of mCRPC patients, including 3 patients exhibiting unexpected response to NHT despite AR-V7 positive CTCs. Finally, loss of AR-V7 positive CTCs in serial CTC analysis of one patient during abiraterone treatment was observed using both detection assays.
Conclusion: By demonstrating nearly identical performance metrics, we excluded assay design differences as an underlying reason for the unexpected responses in a subset of AR-V7 patients. Interestingly, for the first time, we detected an AR-V7 positive mCRPC patient displaying a loss of AR-V7 positive CTCs during NHT therapy. These findings underscore that - irrespective of the method used - AR-V7 positive patients should not systematically be precluded from an otherwise safe treatment attempt.
Citation Format: Christof Bernemann, Verena Humberg, Martin Bögemann, Andres J. Schrader, Julie Steinestel, Jochen K. Lennerz. Cogency of AR-V7 unexpected responders determined by using distinct detection technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-045. doi:10.1158/1538-7445.AM2017-LB-045