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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e14524-e14524
    Abstract: e14524 Background: Humoral tumor markers are used clinically for real-time assessment of therapeutic efficacy. In pancreatic ductal adenocarcinoma (PDAC) the predominant marker is CA19-9, which is not expressed by 10 to 30% of patients depending on race. We compared plasma cell-free DNA (cfDNA) copy number based assay with changes in serum CA19-9 levels and radiological responses to predict responses to systemic therapy. Methods: In a laboratory blinded, prospective multicenter pilot study, 40 non-resectable PDAC patients, treated with (m)FOLFIRINOX, CAPIRI, or gemcitabine +/- nab-paclitaxel) are currently enrolled. CA19-9 was determined in the local center’s laboratory. Tumor cfDNA was measured with a copy-number instability (CNI) scoring assay, determined by next generation sequencing in a centralized laboratory. The CNI score assesses the amount of cfDNA with somatic macro-alterations originating from malignant neoplasms. The difference of the values before commencing therapy (baseline) and prior to cycle 2 (either rising or falling) was calculated as a predictor of standardized radiological evaluation of chemotherapeutic efficacy. Results: 37 patients (3 drop-outs) had data for baseline and cycle 2, of which CA19-9 was elevated and evaluable in 29 patients. The direction from baseline to cycle 2 of CA19-9 and CNI scores were in agreement in 18/29 patients. 9 of 11 cases with discordant CNI score and CA19-9 had treatment response data, and CNI correlated with 7/9 (78%); in contrast 7/9 had rising CA19-9, when response was stable disease or better (22% concordance). In the 27 patients with available imaging, CNI predicted better (n = 18) than CA19-9 (n = 10) (p = 0.03 Fisher’s exact). Conclusions: This comparative study on cfDNA versus CA19-9 suggest that cfDNA CNI quantitation is a potentially more reliable blood based marker for early real-time assessment of efficacy in systemic PDAC therapy than CA19-9, compared to standard of care imaging. The better prediction after the first cycle might be due to the very short in vivo half-life of cfDNA ( 〈 1hr) compared to about one week for CA19-9. These results justify a larger prospective validation trial.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. e15740-e15740
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 4_suppl ( 2018-02-01), p. 245-245
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 4_suppl ( 2018-02-01), p. 245-245
    Abstract: 245 Background: Skeletal metastasis (SM) in advanced PDAC is an infrequent occurrence and has been previously reported to be 〈 2.5%. However; pathological fractures in these patients can result in intractable pain, immobilization and a significant deterioration in quality of life. Methods: A retrospective analysis was conducted of patients (pts) with advanced PDAC receiving palliative chemotherapy. Data collection included age, gender, ECOG, sites of disease, and overall survival (OS). Statistical analysis included Kaplan Meier survival analysis. Results: The 135 pts included had a median age of 65.8 years (range: 53.7–91.3); 5 (31.2%) were women and 11 (68.7%) had an ECOG performance status of 0 or 1. A majority of patients received combination therapy that was either gemcitabine or 5-flurouracil based. Sixteen pts (11.8%) had skeletal metastasis with the primary tumor located in the pancreatic body/tail (11 pts - 68.7%).The sites of SM included thoracic vertebrae (8), lumbar vertebrae (5), pelvis (5), ribs (4), sacrum (4), scapula (3), acetabulum (2), cervical vertebrae (2), femoral head (2), sternum (1) and humerus head (1). A majority of the lesions were osteolytic (62.5%) with a median time of diagnosis of SM from initial diagnosis being 1.25 months (range 0-33). Bone pain was observed as the initial symptom in 5 pts (32%), 1 pt (6.2%) had a pathological fracture. The mOS for patients with SM was 6.5 months (range 0-38) when compared to 8 months (range 0-147) without SM.The mOS for pts treated with gemcitabine based regimen was 5.75 months (range 2.5-14), and patients who received multiple lines of therapy including gemcitabine and 5-FU based regimens was 15 months (range 5-38). Survival from onset of skeletal metastases ranged from 0-14 months (mOS: 4 months). Conclusions: More effective systemic therapies which improve mOS are likely to result in increased incidence of SM. The most common sites observed were the thoracic and lumbar vertebrae and pathological fractures in these sites can be catastrophic. Therefore careful evaluation of skeletal signs and symptoms, early detection and intervention will be important to prevent morbidity and mortality from pathological fractures.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 13 ( 2015-05-01), p. 1475-1481
    Abstract: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m 2 ), gemcitabine plus TH-302 240 mg/m 2 (G+T240), or gemcitabine plus TH-302 340 mg/m 2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 3_suppl ( 2014-01-20), p. 145-145
    Abstract: 145 Background: For the treatment of esophageal and GEJ carcinomas, weekly cisplatin (20-30 mg/m 2 weekly; total dose approximately 100 mg/m 2 ) has demonstrated efficacy and tolerability. Pemetrexed (PEM) in combination with carboplatin and concomitant radiation has also shown activity for treatment of esophageal or lung carcinomas on a tri-weekly schedule, despite tolerability when administered weekly. This is the first phase I trial sought to establish the MTD of bi-weekly PEM in combination with weekly cisplatin and radiation in patients with locally advanced/metastatic esophageal and GEJ carcinomas. Methods: This is a phase I single institution, open-label dose-escalation trial (Fibonacci 3+3). Patients with stage III/IV esophageal cancer received PEM on weeks 1, 3, and 5 at doses of 300, 500, 750 mg/m 2 concurrently with weekly cisplatin (20 mg/m 2 ) and 28 daily fractions of radiation (total 50.4 Gy). If 1 or fewer DLTs were observed, the next cohort of patients received an escalated dose. If two or more patients develop DLTs, then dose escalation halted. Primary endpoint was to determine MTD; secondary endpoints included tolerability and preliminary anti-tumor activity using RECIST (Version 1.0). Results: 8 patients enrolled; median age was 72 (range 56-81); 50% were male; ECOG range was 0-2; 50% of patients had adenocarcinoma (AC), remaining patients had squamous cell carcinoma (SCC); 63% and 37% of patients were stage III and IV, respectively. Dose-escalation proceeded to 750 mg/m 2 dose. The MTD was determined to be 500 mg/m 2 bi-weekly following grade 4 dehydration and esophagitis at 750 mg/m 2 . DLTs observed were grade 4 thrombosis and grade 3 neutropenia at 300 and 500 mg/m 2 , respectively. Complete response was observed in 50% of patients (75% stage III SCC), partial response in 25% of patients (100% Stage IV AC), and disease progression in 1 patient (Stage III AC). 38% of patients proceeded to surgery. Conclusions: The combination of bi-weekly pemetrexed 500 mg/m 2 and weekly cisplatin concomitantly with radiation demonstrates efficacy in patients with advanced or metastatic GEJ carcinomas with manageable safety profile. Clinical trial information: NCT00701857.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2007
    In:  Journal of Clinical Oncology Vol. 25, No. 13 ( 2007-05-01), p. 1779-1784
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 25, No. 13 ( 2007-05-01), p. 1779-1784
    Abstract: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results There were 13 dose levels evaluated, from 20 mg/m 2 /d to 1,000 mg/m 2 /d. The MTD recommended for phase II studies was 875 mg/m 2 /d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m 2 /d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve–dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m 2 /d. Conclusion The phase II recommended dose of imexon is 875 mg/m 2 /d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2007
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS236-TPS236
    Abstract: TPS236 Background: Detection of circulating tumor DNA (ctDNA) in the bloodstream is emerging as a novel marker for identifying of radiographically occult microscopic or minimal residual disease (MRD) in colorectal cancer (CRC) patients (pts) after curative intent treatments. Accumulating data suggest that ct-DNA defined MRD is a highly specific prognostic biomarker for future recurrences with a lead time of several months and prospective clinical trials are being conducted using ct-DNA defined MRD as an integral biomarker for improving risk stratification for adjuvant chemotherapy decision making. However, large scale, prospective data regarding kinetics of ctDNA-defined MRD with accurate pre-analytical methodology for plasma isolation and paired clinical data are limited. Methods: In this multi-center, prospective observational study, 1,000 pts with resectable CRC (stages II – IV) without other active malignancies undergoing therapy with curative intent will be enrolled any time from time of diagnosis up to start of adjuvant therapy (or ≤ 3 months post curative surgery, whichever is earlier). All therapeutic and surveillance visits decisions are at the discretion of the treating physicians. Serial biospecimens including blood (in Cell-Free DNA BCT tubes) to be processed to plasma and buffy coat in ≤ 2 days and formalin fixed tumor tissue will be collected at key time points until the time of radiographic recurrence or up to 5 years of surveillance. Blood draws will be at study entry, after each line of neoadjuvant therapy, post-surgery, during and after adjuvant therapy in addition to each surveillance visit. These blood draws will be coordinated with pts’ standard of care visits in order to minimize additional venipunctures. Relevant clinical data including demographics, cancer history, treatment details and outcomes, serum tumor markers and genomic data will be collected at each time point. Samples will be evaluated retrospectively with a primary objective of evaluating sensitivity and specificity of post-operative MRD for radiographic recurrences utilizing Guardant Health’s Reveal assay. Other key objectives include evaluating ctDNA kinetics with neoadjuvant and adjuvant therapies and to correlate with outcomes. The study is active, and enrollment is ongoing. Clinical trial information: NCT04739072.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 8
    Online Resource
    Online Resource
    Hindawi Limited ; 2015
    In:  BioMed Research International Vol. 2015 ( 2015), p. 1-10
    In: BioMed Research International, Hindawi Limited, Vol. 2015 ( 2015), p. 1-10
    Abstract: Pancreatic adenocarcinoma is one of the deadliest human malignancies. Early detection is difficult and effective treatment is limited. Verifying the presence of micrometastatic dissemination and vessel invasion remains elusive, limiting radiological staging once this diagnosis is made. Diagnostic imaging provides independent tools to evaluate and characterize the biologic behavior of pancreatic cancer. Conventional anatomic imaging alone with either CT or MRI yields useful information on organ involvement but is limited in providing molecular and physiological information. Molecular imaging techniques such as PET or MRS provide information on metabolic and signaling pathways. Advanced MR sequences that target physiological parameters expand imaging options to characterize these tumors. By considering the parametric data from these three imaging approaches (anatomic, molecular, and physiological) we can better define specific tumor signatures. Such parametric characterization can provide insight into tumor metabolism, cellular density, protein expression, focal perfusion, and vascular permeability of these tumors. Radiogenomics research has already demonstrated ability to obtain information about cancer’s genotype and phenotype; this is without invasive procedures or surgery. Further advances in these areas of experimental imaging hold promise to enable future clinical advances in detection and therapy of pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 2314-6133 , 2314-6141
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2015
    detail.hit.zdb_id: 2698540-8
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. A021-A021
    Abstract: Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant pleural mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines in vitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL). As such, there is an unmet need for effective and tolerable treatments. Trial design: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields therapy with GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields therapy + GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed every 4 wks; CT scans of the chest and abdomen will be taken every 8 wks. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields therapy + GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Furthermore, usage information from the NovoTTF-200T System is provided to both pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 120 sites, globally. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Citation Format: Vincent J. Picozzi, Teresa Macarulla, Philip Agop Philip, Carlos Roberto Becerra, Tomislav Dragovich. Tumor Treating Fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: the phase 3 PANOVA-3 study [abstract] . In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A021.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5544-5544
    Abstract: Pancreatic adenocarcinoma is expected to be the second leading cause of cancer-related death by 2020 and has a dismal 5-year survival rate of 8%. The high mortality rate is in part due to the lack of available methods to detect the disease at an early stage or stratify patient populations into more effective treatment regiments in meaningful time frames. To accomplish this, robust quality-controlled OMIC molecular profiling platforms and analytic solutions need to be developed and incorporated into discovery precision medicine protocols to align with translation goals and ensure utility of each sample type. Project Survival, a multisite prospective longitudinal study, is in year 3 of enrolling subjects within 6 categories: healthy volunteers with a relative with pancreatic cancer (N=50), pancreatitis (N=50), pancreatic cystic neoplasm (N=50), suspicious pancreatic masses with pathology other than pancreatic cancer (N=50), early stage (N=200), and metastatic pancreatic cancer (N=200). This study utilizes a systems medicine approach for translational biomarker discovery by performing analysis of matched subject sera, plasma, buffy coat, saliva, urine, and tumor/adjacent normal tissues and integrating them with the respective full clinical annotation using the BERG Interrogative Biology® platform. Multiple longitudinal time points are taken over the course of the six-year timeline, enabling dynamic modeling. Proteomic, signaling lipidomic, structural lipidomic, and metabolomic analysis are performed on all samples and stringent quality control metrics are engaged to ensure quantitative accuracy of the platforms over time. Additionally, several analytic normalization tools are employed to align longitudinal OMIC datasets for quantitative comparisons. We utilized bAIcis™ (BERG Artificial Intelligence Clinical Information System) to align multi-omic profiles with longitudinal clinical information to infer probabilistic cause-and-effect relationships among molecular and clinical variables in a network-based model. We will be presenting updated enrollment and preliminary quality metrics across the study and sites, along with initial molecular stratification markers for clinical endpoints. Citation Format: Eric Michael Grund, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan, John Crowley, Amy Stoll-D'Astice, Tori Singer, Corrine Decicco, Wendy Hori, Valerie Bussberg, Karl Diedrich, Leonardo Rodrigues, Emily Chen, Vivek Vishnudas, Robert Najarian, Tomislav Dragovich, Manuel Hidalgo, Niven Narain, A. James Moser. Project Survival: Year 3 update on a 7-year prospective clinical study driven by quality metrics, multi-omic analysis and artificial intelligence to develop translational biomarkers for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5544.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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