bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of the first interim analysis of the CARMA study to investigate efficacy and safety profile of catumaxomab in clinical practice.
Authors: Kunzmann Volker , Sehouli Jalid , Schmalfeldt Barbara , Wimberger Pauline , Kurbacher Christian M. , Tempelhoff G.-F. , Vanhoefer Udo J. , Ebeling P. , Breuer F. , Schulz Holger , Welslau Manfred , Finas Dominique , Sagasser Jaqueline , Kiehl M. , Fruehauf S. 
Published: March 2020

e13100^ Background: The trifunctional antibody catumaxomab is approved in the EU for intraperitoneal (i.p.) treatment of malignant ascites in patients (pts) with EpCAM-positive carcinomas. Clinical data for catumaxomab are based on the pivotal trial and several phase I/II trials. So far, the routine use of catumaxomab in clinical practice has not been evaluated systematically. Therefore, a large prospective observational study was started in 2010. The study investigates the administration of catumaxomab in a total of 160 pts with malignant ascites under routine conditions in daily clinical practice. Here we show the results of the first pre-planned interim analysis. Methods: The analysis included 49 pts with malignant ascites due to EpCAM-positive carcinomas treated with i.p. catumaxomab under routine conditions in clinical practice. Participating centres were hospitals and practices of oncologists in Germany. Primary endpoint was puncture-free interval (PFI), secondary endpoints included safety and overall survival (OS). Results: At inclusion into the study pts already had undergone a median number of 9 ascites punctures. Malignant ascites had been diagnosed for the first time 3.3 months before (median). Patients suffered from typical ascites symptoms as follows: swelling (79.6%), pain (44.9%), dyspnea (26.5%), anorexia (26.5%), obstipation (12.2%). 49 pts were treated with catumaxomab, of whom 30 pts received all 4 infusions (61.2%). Median PFI was 108 days (d), the median OS was 102 d. Most frequent adverse events were fever, nausea and diarrhoe. Conclusions: This is the first systematic report on routine use of catumaxomab in clinical practice.. Although The study population mainly comprised patients with advanced tumor diseaset a clinical benefit after catumaxomab therapy could be demonstrated. The treatment showed an acceptable safety profile Theseresults are consistent with the data of the pivotal trial. The data will be evaluated in further analyses including larger patient numbers.
A phase Ib study of CUDC-101, a multitargeted inhibitor of EGFR, HER2, and HDAC, in patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer.
Authors: Fu Siqing , Nemunaitis John J. , Bessudo Alberto , Bauman Julie E. , Hamid Omid , Witta Samir E. , Dy Grace K. , Lai Cheng , Laliberte Robert , Voi Maurizio 
Published: March 2020

e13101 Background: CUDC-101 is a small molecule EGFR/HER2 receptor tyrosine kinase and HDAC inhibitor that has shown promising activity in cancer cell lines and tumor xenograft models. A previous Phase 1 study showed 275 mg/m2 to be the maximum tolerated dose when given daily for 5 days every 2 weeks (QDx5). Dose limiting toxicity included transient creatinine elevation. This expansion Phase 1b study was conducted to further evaluate safety and tolerability of the QDx5 and of a three dose per week (3x/week) schedule for 3 weeks every 4 weeks. Methods: Eligible patients (pts) ≥18 years with advanced breast, gastric, head and neck, NSCLC or liver cancer (n = 10/tumor type); adequate marrow and organ function; and an ECOG PS ≤2 were assigned to receive CUDC-101 (275 mg/m2) on QDx5 or 3x/week schedule. NSCLC patients required documented EGFR exon 19 or 21 mutation/deletion with recent acquired resistance to erlotinib. Study parameters included safety (CTCAE v.3), antitumor response (RECIST v1.1), PK (blood and urine) and PD (tumor biopsy and CTC) assessments. Results: A total of 46 pts were treated (23/dose schedule), including 25 (54%) males, mean age 62 yrs, PS 0/1/2 (33/56/11%), and a median of 3 prior regimens (range, 0-7). The overall incidence and severity of treatment-related AEs were similar between the 2 dose schedules, including fatigue, transiently increased creatinine, nausea, vomiting, decreased appetite, anemia and asthenia, each occurring in <20% of all pts and mostly Grade ≤ 2. Grade 3 AEs were reported in 4 pts. Overall, 15 (33%) pts had SD as their best response: 4 pts had SD for >14 weeks, including 1 with head and neck (QDx5), and 2 with liver (1 lasting 47 weeks) and 1 gastric cancer (all 3 on 3x/week). Paired tumor biopsies were available for one pt showing target inhibition. CTC and PK analyses are ongoing. Conclusions: CUDC-101 was well tolerated using either dosing schedule, with preliminary evidence of antitumor activity. The more convenient 3x/week schedule was selected for an ongoing Phase 1 combination study.
Designing a web application for personalized medicine trials.
Authors: Watt Stuart , Jiao Wei , Brown Andrew M. K. , Petrocelli Teresa , Tran Ben , Zhang Tong , Dancey Janet , Siu Lillian L. , Stein Lincoln D. , Ferretti Vincent 
Published: March 2020

e13107 Background: Clinical genomics uses information from a patient's genome in clinical decision-making, an example of personalized medicine. The OICR/UHN Genomics Cohort Study is assessing the feasibility and developing standard operating procedures for clinical genomics in late stage cancer patients to enable larger trials. Tumor DNA from consenting patients is sequenced across 19 genes to identify actionable mutations and inform use of targeted therapeutic agents. Informatics systems are critical as the study involves 40 staff in 5 cancer centres, 2 laboratories, 3 genomics technologies, and spans screening, consent, obtaining/processing biopsy samples, genomic analysis, clinical laboratory verification, and reporting for decision-making. Methods: We used a process-centered method to develop a web system to manage study activities. Initially it tracked patients, samples, genomic results, decisions and reports across the cohort, monitored progress and sent reminders, working alongside an electronic data capture (EDC) system for the trial's clinical and genomic results. We later added a system to read, store, and analyze the genomics data, and a knowledge base of mutations’ tumor frequency (from the COSMIC database) annotated with clinical significance and drug sensitivity to generate reports for clinicians. Results: The web tracker proved highly adaptive. The design method allowed procedural refinements mid-study, including changes in sample preparation, sample sources, and differences in nomenclature across technologies. As the study procedures stabilized, the system provided deeper support for clinical decision making, enabling the generation of draft reports for verification by an expert panel prior to forwarding to the treating physician. The web tracker complemented the EDC system with its fixed modules for collection of clinical data and genomic results. Conclusions: The system effectively complemented clinical trial software. An agile development process enabled procedures to be refined as feasibility issues were found and resolved, and enabled flexible analysis of mutation data. Our design approach helped stabilize effective procedures for a clinical genomics service, and establish means to assess its performance.
Catumaxomab: Pharmacodynamic and pharmacokinetic data from phase IIIb CASIMAS study in patients with malignant ascites.
Authors: Rosenberg Per , Dudnitchenko Alexander Serg , Bondar Vladimir , Salat Christoph , Havsteen Hanne , Bokemeyer Carsten , Berton-Rigaud Dominique , Durando Xavier , Vergote Ignace B. , Wimberger Pauline , Lordick Florian , Lindhofer Horst , Martinius Holger , Sehouli Jalid 
Published: March 2020

e13108^ Background: Catumaxomab (anti-EpCAM x anti-CD3) is approved in the EU for the i.p. locoregional treatment of malignant ascites (MA). The peritoneal cavity invaded by epithelial tumor cells provides an environment for tumor-specific, EpCAM-targeted catumaxomab immunotherapy. In order to monitor the local and systemic pharmacodynamic/ pharmacokinetic (PD/PK) profile of catumaxomab, plasma and ascites samples from patients in the CASIMAS study were investigated. Methods: Plasma and ascites samples were collected in patients prior, during and after catumaxomab i.p. infusions. Samples were analysed for a) Selected cytokines (IL-2, -4, -6, -8, -10, and -12, IFN-gamma, TNF-alpha, and GM-CSF) in 20 patients, b) catumaxomab drug levels in 31 patients (14 patients with MA who received all 4 infusions of 10, 20, 50, and 150 µg were evaluable for systemic PK analysis), c) number of EpCAM+ tumor cells in ascites in 11 patients. Results: Drug levels were highest in ascites fluid ranging from 0 to 219.4 ng/mL at day 10 (n=31/31 patients). Low systemic plasma levels were detected in 7/14 patients (median cmax: 623 pg/mL). In 7/14 subjects no catumaxomab was detected systemically. Furthermore, cytokine concentrations in ascites were higher compared to plasma. Mainly IL-6, -8 & -10 and IFN-gamma were detected; in few cases TNF-alpha and IL-2. Whereas IL-4, -12, and GM-CSF were not detected at all. Anti-tumor activity was proven by i.p. tumor cell elimination. Tumor cell count in ascites dropped markedly below baseline. In the majority (7/11) of patients no EpCAM+ tumor cells were detectable after therapy. Before therapy, in 165/166 evaluable patient samples EpCAM+ tumor cells were detected in the ascites fluid. Conclusions: Catumaxomab represents a locoregional immunological i.p. treatment eliminating tumor cells in the peritoneal cavity and thereby effectively controlling MA. Catumaxomab primarily remains in the peritoneal cavity with low systemic exposure. In line with this, cytokines are mainly released locally, at the site of action. These PD/PK results confirm the results obtained in the pivotal phase II/III study.
Folate-targeted iron oxide nanoparticles loaded with cisplatin for imaging and therapy in head and neck squamous cell carcinoma (HNSCC).
Authors: Kang Hyunseok , Huang Jing , Mao Hui , Chen Zhuo Georgia , Peng Xianghong , Shin Dong Moon 
Published: March 2020

e13110 Background: Cisplatin (DDP) is a widely used anticancer drug but its application has been limited by side effects and drug resistance. We have previously showed that selective delivery of DDP to tumors using novel nanoparticles could significantly enhance antitumor effects with reduced toxicity. As our group has reported that 45% of 105 HNSCC primary tumors were positive for folate receptor (FR) in Head Neck 31:475-81, 2009, we further developed DDP-loaded folate-targeted iron oxide nanoparticle (FA-IO-DDP) for HNSCC imaging and therapy. Methods: HNSCC cell lines were screened for FR expression by Western blot and surface expression was confirmed by FACS. Intracellular platinum (Pt) and Pt-DNA adducts were quantified by ICP-mass spectrometry. MTT assay was used for cytotoxicity test. T2 weighted MRI was used to detect signal changes induced by FA-IO-DDP. Biodistribution of the nanoparticles was studied using nude mice bearing high FR expressing KB3-1 xenograft. Results: Five cell lines expressing surface FR were identified among sixteen cell lines screened. Three cell lines, PCI15B, SQCCY1 and UMSCC11B with high, intermediate, and negative FR expression respectively, were selected for further investigation. FA-IO-DDP showed significantly enhanced cytotoxicity. Intracellular Pt and Pt-DNA adducts were increased in FR-positive PCI15B cells treated with FA-IO-DDP by 4 fold and 3.2 fold, respectively, compared to cells treated with non-targeted IO-DDP. Similar degree of enhanced uptake was observed in SQCCY1 but not in UMSCC11B. A significant change in T2 signal induced by increased internalization of IO in FA-IO-DDP treated PCI15B cells was detected by MRI. In KB3-1 xenograft model, FA-IO-DDP showed 5.4 fold higher accumulation in tumor compared to free DDP. Conclusions: Our study showed that novel FA-IO-DDP targeting FR remarkably enhanced antitumor effects of DDP in FR-positive HNSCC cells by increasing intracellular Pt concentration and Pt-DNA adducts. MRI may be used to monitor DDP delivery by IO nanoparticles in vivo. Ongoing studies are focused on antitumor effect and toxicities of the FA-IO-DDP using nude mice bearing PCI15B, SQCCY1 and UMSCC11B cells.
Association of clofarabine (Clo)-associated GFR decline (GFRd) with dose and AUC.
Authors: O'Donnell Peter H. , Innocenti Federico , Wickrema Amittha , Stock Wendy , Hardj Marjie , Artz Andrew S. , van Besien Koen 
Published: March 2020

e13120^ Background: Clo, a nucleoside analog, is approved for pediatric ALL, but also has activity in AML. We conducted a ph I-II trial of clo-melphalan-alemtuzumab for allo transplant and found grade 3-5 renal toxicity in 16 of 74 patients, despite prolonging infusion time to reduce Cmax (BBMT 2011, Epub). Methods: Clo pharmacokinetics were analyzed in 65 pts (Clo doses 10-40 mg/m2, infusion time 1 or 3 hrs) of 74 pts; baseline GFR estimated by modified MDRD equation. Clo levels were drawn at 1, 1.5, 2, 3, 5, 7, 9 and 24 hrs following the 1st and 3rd (or 4th) dose. GFRd (in ml/min/m2) between start of Clo (d-7) and day of transplant constituted the outcome of interest. Results: Median age 53 (21-73), median baseline GFR 94 ml/min/m2 (46-120). Mean (range) Cmax, clearance (CL) and AUC were 531 ng/ml (119-1010), 42002 ml/min (13979-88020) and 2052 ng*hr/ml (471-5835), respectively. Mean AUC per dose was 32.0 ng*hr/ml/mg (14-32). Systemic exposure was similar between d1 and d3. Further analyses used the highest AUC and Cmax. Decreases in GFR ranging from 10-100 ml/min/m2 (average 44 ml/min/m2) occurred in 30 of 65 patients. There was no correlation between Clo dose and GFRd (r=-0.02,p=0.87). There was a significant correlation between Clo AUC and GFRd (r=0.53, p <0.0001), Clo AUC per dose and GFRd (r=0.62, p<0.001) and between Clo CL and GRFd (r=-0.38, p=0.0001). There was a weaker correlation between Clo Cmax and GFRd (r=0.22, p=0.07). Clo CL was highly correlated with baseline GFR (r=0.4, p=0.0009). Of interest baseline GFR was inversely correlated with pt age (r=-0.46, p=0.0001) and age was significantly correlated with AUC (r=0.4, p=0.001), AUC per dose (r=0.36, p=0.003) and with GFRd (r=0.34, p=0.005). Conclusions: Decline in GFR is associated with inter-patient variability in exposure to Clo. Baseline GFR affects Clo CL and thus AUC, and potentially increases risk for renal toxicity. Older age is associated with decreased baseline GFR and risk for toxicity. Clo may require dose adjustment based upon renal function and/or age. These data require confirmation in further studies.
Targeting the upregulation of the AKT pathway and homologous recombination repair as a therapeutic strategy for epithelial ovarian cancer.
Authors: Ratner Elena , Lin Z-Ping , Rutherford Thomas J. , Azodi Masoud , Santin Alessandro , Schwartz Peter E. , Sartorelli Alan 
Published: March 2020

e13125 Background: Epithelial ovarian cancer (EOC) is the second most common gynecologic cancer in the United States, and carries the highest mortality in this category in the West. The progression free survival and overall survival depend greatly on tumor sensitivity to a platinum chemotherapy. Once platinum resistance is encountered, response rates of only 6–30% are achieved. A relatively new modality in EOC that would allow targeted treatments is a PARP inhibitor, a drug that inhibits the enzyme poly (ADP-ribose) polymerase (PARP), which is showing promise for the treatment of EOC with mutations in the BRCA1 or BRCA2 tumor suppressors. Triapine, a novel small-molecule drug developed in our laboratory, potently inhibits the activity of ribonucleotide reductase involved in the key step of DNA synthesis and replication. Methods: 1. Cell sensitivity to varying ratios of treating drug combinations (Triapine with cisplatin; PARP inhibitor, olaparib) was carried out by clonogenic survival assays using multiple EOC cell lines (A2780, Caov-3, EFO, IGROV-1, BG-1, PEO1, SKOV3). 2. AKT level was measured in the cell lines before and after treatment. 3. BRCA1 wild-type and BRCA1-knockdown EOC cells were treated with cisplatin or PARP alone and in combination with Triapine. Drug-induced DNA damage was assessed by the levels of g-H2AX, the marker of double stranded breaks (DSBs), and of Rad51 foci, a marker of HR repair of DSBs. Results: Treatment with Triapine leads to synergistic sensitization of BRCA1 wild-type EOC cells to platinum drugs and to olaparib. Both platinum drugs and olaparib induce DNA damage that is repaired by HR. This suggests that Triapine inhibits HR and sensitizes EOC cells to these drugs. Triapine attenuates olaparib-induced Rad51 foci in BRCA1-wild type cells, which resembles the impairment of such foci formation in BRCA1-knockdown cells. Triapine causes down-regulation of AKT activity in EOC cells. Conclusions: Triapine produces synthetic lethality by inhibiting both DNA repair and pro-survival pathways. Combination of Triapine and platinum drugs/PARP inhibitors represents a rational and innovative therapy that targets EOC with a high level of AKT activity.
ApoStream, a novel device for antibody-independent capture of circulating cancercells (CCCs) from blood of patients with various types of cancer.
Authors: Gupta Vishal , Jafferji Insiya , Garza Miguel , Sukumaran Sujita , Woo Jacky , Hasegawa Dave , Melnikova Vladislava O. , Davis Darren W. 
Published: March 2020

e13500 Background: The detection of circulating tumor cells (CTCs) using immunomagnetic EpCAM-based capture methods has been conceptually accepted as a “liquid tumor biopsy”. However, these methods have limited the recovery of CTCs for molecular profiling applications. We developed a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, ApoStream for antibody-independent capture of circulating cancer cells (CCCs), with improved recovery across multiple cancer types and preserved viability of CCCs for downstream characterization. Methods: The performance of ApoStream was demonstrated using a low EpCAM expressing cell line, SKOV3. ApoStream was further used to enrich CCCs from various cancer patient blood. Prostate, breast and NSCLC CCCs were stained for cytokeratin (CK), CD45, and DAPI; melanoma CCCs were stained with S100, CD45 and DAPI. CCC enumeration was performed using laser scanning cytometry. Results: In system precision performance studies, average inter-day recovery on the ApoStream was 80.3 ± 3.5%, CV = 4.3% when cancer cells were spiked into buffer, and 78.5 ± 3.0%, CV = 3.3% when cancer cells spiked into ~10 million healthy peripheral blood mononuclear cells (PBMCs). Linearity performance was demonstrated with spiking 5-2600 SKOV3 cells into 10 million PBMCs (R2=1). Cell viability was not affected by processing through ApoStream device. High CCC recovery from metastatic cancer patient blood samples was obtained with counts ranging from 0 - 2630 (NSCLC, n=66), 0 - 3490 (prostate, n=29), 10 - 968 (breast, n=11), and 3 - 3120 (melanoma, n=13) CCCs per 7.5 mL blood. Positive CCC counts were obtained in 90% of NSCLC samples, 93% of prostate cancer samples, 100% breast cancer and melanoma specimens. There were no CK+ cells detected in healthy donor blood controls. Conclusions: Improved CCC recovery from various cancer types was demonstrated with the ApoStream device. ApoStream provides an antibody-independent method for capture of viable CCCs that enables further downstream molecular characterization of rare cells for use in clinical applications. Acknowledgements: Funded by NCI Contract No. HHSN261200800001E.
Effect of microRNA-124 on homologous recombination protein RAD51 and glioblastoma cells undergoing radiation.
Authors: Schäfer Henning S , Agami Reuven , van Haaften Gijs 
Published: March 2020

e13515 Background: The DNA damage repair (DDR) pathways are an essential cell survival mechanism to preserve genomic integrity. In tumor cells, DDR pathways have a huge impact in cell survival, response to therapy and thus prognosis. Our objective is to investigate whether microRNAs (miRs) can influence specific DNA repair pathways. For our studies we focussed on double-strand break (DSB) repair by homologous - (HR) or non-homologous recombination (NHEJ). DSBs are the main lethal lesions induced by ionizing radiation. Methods: A retroviral miR expression library of ~500 miRs was transduced into a HR reporter cell line. For less abundant miRs found in this analysis in silico analysis was performed to detect potential targets. Regulation of HR protein RAD51 by miR-124 could be shown by luciferase assays and immunoblotting. Overexpression of miR-124 in glioblastoma cell line U87 was done by lentiviral constructs. Effect of miR-124 overexpression was revealed by colony – and competetive growth assays. Results: In an unbiased screen we found that miR-124 is less abundantly expressed in a reporter cell population sufficient for HR, suggesting a negative role for these miRs in DSB repair via HR. Reporter assays revealed a negative regulation of RAD51, a key protein of HR pathway, by miR-124. This regulation was specific to a conserved binding motif at the 3` UTR of RAD51. This regulation could also be detected in vivo whereas overexpression of miR-124 leads to downregulation of RAD51 protein levels. Functional experiments in glioblastoma cell line (U87), that express hardly no miR-124, revealed increased sensitivity to ionizing radiation if miR-124 is (re)-expressed. Conclusions: In this work we uncover miRs influencing the cellular DNA-repair machinery. We show that miR-124 influences the repair of DSBs by HR. This effect is specific and mediated by the regulation of RAD51 protein level, an essential component of the HR pathway. Re-expression of miR-124 sensitizes glioblastoma cell line (U87) to radiation in functional experiments. We propose that (re)-expressing miR-124 in glioblastomas could be a new treatment strategy to sensitize this tumors to radiation therapy.