bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors.
Authors: Turk Anita Ahmed , Leal Ticiana , Chan Nancy , Wesolowski Robert , Spencer Kristen Renee , Malhotra Jyoti , Lang Joshua Michael , McNeel Douglas G. , O'Regan Ruth , Mehnert Janice M. , Eickhoff Jens C. , Liu Glenn , Wisinski Kari Braun 
Published: May 2019

e14640 Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B). Dose escalation is by 3+3 design. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone. Each schedule will have a 6 pt dose expansion at the MTD. The dose level (DL) 1 for schedule B is the previously reported MTD from schedule A (T 250mcg with C AUC 6 + P 80mg/m2). Results: Schedule B results are reported: 15 pts (median age 56 yrs [range 43-76]) have been enrolled. Primary malignancies include colorectal (4), pancreas (4), prostate (2), urothelial (2), and other (3). Dose was initiated at Schedule A MTD. DL2 (T 350mcg with C AUC 6 + P 80mg/m2) exceeded the MTD with 2 of 6 pts experiencing hematologic dose limiting toxicities (DLTs). DL1 is the confirmed schedule B MTD. Dose expansion to 6 pts is ongoing. Of the 11 pts with measurable disease, 3 (27%) had PR and 5 (45%) had SD. Pts were on study a median of 10 weeks (range 5-36+). Most common grade 3/4 AEs include leukopenia (53%), neutropenia (47%), and anemia (47%). One grade 5 AE of intracranial hemorrhage occurred, possibly related to therapy in the setting of grade 3 thrombocytopenia and concern for CNS disease. Conclusions: The schedule B MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m2. Data from the full dose expansion will be presented. This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874.
Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Final results of the phase 1/2 TREAT-ME-1 trial.
Authors: von Einem Jobst C. , Guenther Christine , Volk Hans Dieter , Gruetz Gerald , Hirsch Daniela , Salat Christoph , Stoetzer Oliver J , Nelson Peter J , Michl Marlies , Modest Dominik Paul , Holch Julian , Angele Martin K , Bruns Christiane J. , Niess Hanno , Heinemann Volker 
Published: May 2019

e14648 Background: TREAT-ME-1, a Phase 1/2 open-label, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC),MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Methods: All patients (6 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer’s instructions for 48─72 hours after MSC_apceth_101 injection. Three patients were treated with a total dose of 1.5 x 106cells/kg MSC_apceth_101 (DL1). Ten patients were treated with a total dose of 3.0 x 106cells/kg MSC_apceth_101 (DL2). Immunological and inflammatory markers were assessed.Time to progression, overall survival was evaluated by RECISTwithin 56 days after administration of MSC_apceth_101 administration. Results: A total of 54 AEs occurred in 9/13 patients, thereof 18 AEs in three patients of DL1 and 36 AEs in six patients of DL2. Six AEs were CTC-AE grade 3, all other AEs were lower CTC-AE grades.Five SAEs emerged in two patients of DL1 and six SAEs in four patients of DL2. Eight patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.9 months (95% CI: 1.3, 3.6 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (one year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. Conclusions: MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease. Clinical trial information: NCT02008539.
Identification of new targets and biomarkers in lung cancer.
Authors: Papasotiriou Ioannis , Parsonidis Panagiotis , Ntanovasilis Dimitrios-Athanasios , Iliopoulos Aggelos C , Beis Georgios , Apostolou Panagiotis 
Published: May 2019

e14656 Background: Lung cancer is the second most common type of cancer in both genders; however is the leading cause of cancer deaths. Adenocarcinoma constitutes more than 60% of non-small cell lung cancer (NSCLC), and accounts for approximately 40% of lung cancers. Therefore, early prediction, prognosis of the disease and treatment strategy is of primary importance. Molecular biology assays, including microarrays, enable identification of new targets. The above targets can be used either as biomarkers, useful for early prediction and prognosis of the disease, or as drugable targets, upon proof of their biological action. The present study aimed to identify new biomarkers and/or targets in lung cancer. Methods: Whole genome gene expression microarrays have been performed for 12 lung cancer cell lines (provided be ECACC, ATCC), representing non-small cell lung (adenocarcinoma, squamous, large cell) and small cell lung cancer. Real-time experiments were followed for validation of thirty genes that were overexpressed. The experiments were performed including other cell lines, representing breast, colon, prostate, hepatocellular, melanoma and pancreatic cancer. Sample from healthy donors, as well as normal lung epithelial cell were used. Results: Among the genes that were studied, there was observed downregulation or none expression in normal donors as well as in normal lung epithelia cells. VSIG10 overexpressed in adenocarcinoma and large cells, while no expression observed in breast, prostate, melanoma and pancreatic cancer. DCBLD2 overexpressed in all NSCLC samples, but not in small cells. LIFR was overexpressed mainly in squamous cells, while no expression or downregulation observed in the other types of cancer. The same expression profile was mentioned for PDGFC. Conclusions: Taking everything into consideration, it is obvious that the identification of new biomarkers and/or targets for lung cancer is of primary importance. The present study revealed different genes, with different biological function that might be used primary as biomarkers. Their role need to be clarified also in clinical samples as to be used as drugable targets. However, the above data are encouraging for identification of new therapeutic models in lung cancer.
Integrating CRISPR screening with tumor genomic analyses to identify therapeutic targets in hepatocellular carcinomas (HCC) independent of P53.
Authors: Sheel Ankur , Kwan SuetYan , Xue Wen 
Published: May 2019

e14659 Background: Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments. Moreover, the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Furthermore, the P53 pathway is frequently mutated in HCC therefore identifying targets with therapeutic efficacy irrespective of P53 status is warranted. Methods: To identify kinases essential for HCC proliferation, we performed a kinome wide CRISPR screen in human HCC cell lines with varying P53 mutations and validated our findings using CRISPR-Cas9 mediated genetic manipulations in human HCC cell lines in-vitro and in-vivo. Furthermore, we performed an integrated cancer genomics analyses using patient data from TCGA and the NCI to validate the relevancy of our findings. Results: We identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of P53, P21 and RB-independent senescence in-vitro and in-vivo. Furthermore, we find that TRRAP is upregulated in HCC patient samples independent of TP53 mutations. Integrated cancer genomics analyses using both HCC patient data derived from TCGA and from RNA-sequencing of our in-vitro model identified a chromosomal instability signature that was regulated by TRRAP/KAT5 in-vitro. Furthermore this chromosomal instability signature was also upregulated in HCC patients. Finally, we identify TOP2A as a target in this pathway as genetic depletion of TOP2A inhibited cell growth via induction of senescence. Conclusions: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes in order to potentiate a chromosomal instability signature. Our findings suggest that targeting the TRRAP/KAT5 complex and TOP2A is a therapeutic strategy for HCC, even in tumors that have escaped P53 and RB tumor suppressive programs.
Implication of DYRK1B kinase in dormant glioblastoma cancers and utilization of DYRK1B inhibitors as a novel therapeutic strategy for glioblastoma.
Authors: Vilenchik Maria , Kuznetsova Alexandra , Frid Michael , Duey Menelik , Damiani Arianna , De Leon Lita , Law Jason , Golbin Denis A. , Shishkina Ludmila V. , Potapova Olga 
Published: May 2019

e14670 Background: A major determinant of cancer resistance and recurrence is the presence of quiescent cancer cells. It has long been known that quiescent cancers are resistant to a wide variety of anti-cancer therapeutics relative to actively proliferating cells. However, the presence and relative size of the quiescent compartment is not revealed by standard H&E staining and morphological tumor analysis and, therefore, the data demonstrating its importance and prevalence by tumor type are lacking. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with growth and survival of many types of cancer cells and was shown to play a key role in maintaining the cancer cells in reversible quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Methods: We conducted an immunohistochemical study of 80 human glioblastoma (GBM) tumors (primary / treatment-naive, Grade IV) and 10 cases of normal postmortem brain tissues for expression of DYRK1B, and quiescence and proliferation markers p27 and Ki-67, respectively. For subsection of these tissues, high levels of DYRK1B and p27 expression were observed. Results: In this study, we investigated the functional and therapeutic relevance of DYRK1B expression in glioblastomas, the most common brain cancer in adults. It is an aggressive, highly resistant to treatment tumor type with median survival time of less than 16 months following surgery and treatment. Conclusions: There was a statistically significant correlation between immunostaining of DYRK1B and p27, indicating the presence of dormant cancer cells mixed with the proliferating cancer cells within the patients' tumors. We suggest that DYRK1B inhibitors in combination with chemotherapeutics agents have a potential to improve patient treatment outcome and prolong survival.
Role of ultrasound contrast agent in a tertiary cancer center: Experience in 75 patients with liver biopsy.
Authors: Rahnemai-Azar Amir Ata , Kikano Elias , Smith Daniel Arnold , Ramaiya Nikhil H. , Azar Nami R 
Published: May 2019

e14671 Background: The sensitivity of B-mode ultrasound (US) in detecting hepatic lesions has been reported to be between 55-85%. A recently FDA approved US contrast agent has been shown to increase the detectability of liver lesions; yet, there is paucity of knowledge regarding its application in US guided biopsies. The aim of this study was to determine accuracy and applicability of contrast enhanced US (CEUS) guided biopsies of liver lesions in cancer patients. Methods: A prospective registry of 75 patients (M = 54%, F = 46%, Age: 63y±14), that underwent CEUS guided liver biopsy in 2017-2018, were retrospectively reviewed. The decision to apply US contrast was made based on pre-procedural and intra-procedural clinical findings. Lesions with negative biopsy results were reviewed in follow up imaging to determine any evidence of potential positive malignancy. Results: History of renal failure that precluded application of iodinated IV contrast was the main pre-procedural indication (17%). Intra-procedural indications included: poor visualization of lesions in B-mode US (78%), targeting enhancing part of lesions (necrotic, post ablation or cystic) (16%), and lesion selection (6%). Diameter of the lesions were ≤ 20mm in 46% of patients. Biopsy results were positive in 50 patients, and included 32% primary liver tumors (hepatocellular carcinoma and cholangiocarcinoma) and 68% metastasis (pancreas: 24%, breast: 12%, GI tract: 10%, lung: 8% and other: 14%). Of the 25 patients with negative biopsy results, 6 did not have follow up imaging and 3 were later found to have positive malignancy (Negative predictive value: 84%, accuracy: 96%). Genomic sequencing was established in 34% of the patients. Based on the biopsy/genomics results, patients underwent systemic treatment (56%), locoregional treatment (16%), combination (6%) or surgery (2%). 10% of patients selected hospice care and 10% lost follow up. Conclusions: CEUS increases the accuracy of US guided biopsies of focal liver lesions, by improving visualization, targeting viable parts and also in patients with renal failure, or small lesions. Findings from these biopsies could improve management of cancer patients by categorizing them into different treatment groups.
A retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia: Red blood cell transfusion versus erythrocyte stimulating agent (ESA) administration.
Authors: Bryer Emily Jane , Henry David H. 
Published: May 2019

e14685 Background: Anemia is a common and unfortunate consequence of chemotherapy; patients receiving a variety of chemotherapy regimens often develop chemotherapy–induced anemia (CIA), which contributes to poor outcomes including increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Optimal therapy of CIA is controversial and involves the solitary and combined use of intravenous iron, red blood cell (RBC) transfusions, and erythropoietin stimulating agents (ESAs). Despite the baseline coagulopathies present in patients with malignancy, administration of both RBC transfusions and ESAs is associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive RBC transfusions or ESAs. Methods: A retrospective single-institution study analyzed 7360 patients with varying malignancies who developed CIA and received ESAs and RBC transfusion from 1998-2017. These patients were evaluated for subsequent development of VTE and categorized by prior receipt of RBC transfusion or ESA. Results: Among the 7360 patients with CIA, 5503 received either RBC transfusion or ESA and 1857 received both. Among all patients, 3466/7360 (47.1%) developed a VTE. The absolute risk of developing a VTE with receipt of a RBC transfusion was 0.38 compared to 0.19 with ESA. Patients with CIA who received RBC had twice the risk of developing a VTE compared with those who received ESA (p < 0.0001). Conclusions: While both RBC transfusion and ESA administration are independently associated with VTE, our data suggests a greater risk of VTE development with RBC transfusion as compared with ESA administration.[Table: see text]
Biofabricated tumor microenvironments for studying colorectal cancer in vitro and in vivo.
Authors: Devarasetty Mahesh , Herberg Samuel , Dominijanni Anthony , Willey-Shelkey Ethan , Skardal Aleksander , Soker Shay 
Published: May 2019

e14689 Background: Microenvironmental mechanics have a tremendous effect on the progression, phenotype, and therapeutic response of cancer cells positioning it as a high-potential target for novel therapeutic development. Laboratory modeling of the microenvironment and its multitude of effects is imperative for developing new avenues of anti-cancer therapy that can target non-traditional vectors such as the extracellular matrix (ECM) and stromal cells. Researchers have developed in vitro models of the tumor microenvironment (TME) to meet this need. While in vitro modeling is an important step in therapeutic development, there are few studies that validate in vitro generated results to gold-standard in vivo models, and further, to patient-derived data. Previously, we have developed a model of the colorectal tumor microenvironment and found a connection between collagen ultrastructure and cancer cell phenotype. Using this characterized organoid model, we implant bioengineered TMEs into mice to track long-term growth and progression of cancer and compare our results to clinical biopsies. Methods: Tumor organoids are produced by combining stromal cells and type I collagen. Cancer cell spheroids are embedded into the organoid for long term observation. Organoids are either observed in vitro or implanted subcutaneously into mice for in vivo tracking. Results: Organoids retain structure and viability during long term culture in vitro and in vivo, and embedded cancer cells respond significantly differently depending on the architecture of the surrounding TME. Cancer cells assume a mesenchymal, invasive, and proliferative phenotype in unorganized TMEs, and revert to an epithelial phenotype in an ordered TME. In addition, analysis of biopsied tissue, across tumor grade, demonstrates a correlation between cancer cell phenotype and microenvironmental architecture. Conclusions: In all this is the first study to establish a connection between TME micro-structure and cancer cell phenotype consistently across three distinct research modalities. These results have the potential to pave the way for utilizing bioengineered microenvironmental models as therapeutic development platforms and for targeting TME micro-structure to control colorectal cancer cell progression.
Anticoagulants for the treatment of venous thromboembolism in patients with cancer: An updated pairwise and network meta-analysis of randomized trials.
Authors: Sidahmed Shima , Abdalla Ahmed , Kheiri Babikir , Bala Areeg , Salih Mohammed , Kafri Zyad , Bachuwa Ghassan 
Published: May 2019

e14692 Background: Cancer-associated venous thromboembolism (VTE) is common. Although low molecular weight heparin (LMWH) is the standard therapy in this setting, little is known with regard to non-vitamin K antagonist oral anticoagulants (NOACs). Therefore, we thought about evaluating the safety and efficacy of various anticoagulants in this vulnerable population. Methods: Electronic database search was conducted to identify randomized clinical trials (RCTs) that compared LMWH, NOACs, and/or vitamin-K-antagonists (VKA) in cancer patients. We performed frequentist direct and Bayesian network meta-analysis using random-effects model to calculate odds ratios (ORs), 95% confidence intervals (CIs), and 95% credible intervals (CrIs). The primary outcome was VTE (pulmonary embolism and deep-vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. Results: We identified 13 RCTs with 6,595 total patients (mean age 62.4 ± 12.2; 50.4% female; 17.7% hematological malignancies; and 6 months median follow-up). The most common cancer type was colorectal and 48% of the population had metastatic cancer at baseline. NOACs were associated with significantly reduced VTE recurrence compared with VKA (OR = 0.58; 95% CI = 0.40-0.83; P < 0.01; number needed to treat [NNT] = 40) and LMWH (OR = 0.46; 95% CI = 0.25-0.85; P = 0.01; NNT = 20). LMHW was associated with significantly reduced VTE recurrence compared with VKA (OR = 0.52; 95% CI = 0.39-0.71; P < 0.01; NNT = 18). NOACs were associated with significantly reduced major bleeding compared with VKA (OR = 0.56; 95% CI = 0.35-0.91; P = 0.02; NNT = 64). There was no significant difference identified between the anticoagulant groups in regard to all-cause mortality. Conclusions: Among cancer patients with VTE, NOACs were associated with significantly reduced VTE recurrence compared to LMWH and VKA, and significantly reduced major bleeding compared with VKA. LMWH was associated with significantly reduced VTE recurrence compared with VKA.
A phase I study investigating the absorption, metabolism, and excretion of [14C] anlotinib in patients with advanced refractory solid tumors.
Authors: Liu Yiqian , Xu Tongpeng , Liu Lianke , Shu Yongqian 
Published: May 2019

e14701 Background: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret, and has shown antitumor activity in patients with advanced refractory solid tumors. The human plasma pharmacokinetics of anlotinib have been described previously, but detailed analyses of the absorption, metabolism and excretion pathways of anlotinib have not yet been published. Methods: Six male patients were divided into two groups, one group included two patients was performed by 13.51mg Anlotinib hydrochloride and 0.64 mg/80 μCi [14C] anlotinib hydrochloride and the rest four patients in another group received 13.19mg anlotinib hydrochloride and 0.96mg/120 μCi [14C] anlotinib hydrochloride, followed by collection of blood, urine, and fecal samples. The primary outcomes of study were absorption, metabolism, and excretion of [14C] anlotinib and the second outcomes were efficacy and safety. Results: In plasma, the average time of total plasma radioactivity peak (Tmax) was 4.42h and the average peak concentration (Cmax) was 18.80 ng Eq./g. The average value of AUC last was 4071 h∙ng Eq./g, AUC0-∞ was 13555 h∙ng Eq./g, and MRT0-t was 145h. The average recovery rate of total radioactivity in urine and feces was 62.03%. Prototype drugs and metabolites were mainly excreted through feces, accounting for 48.52% of the administered dose, otherwise rine excretion accounted for 13.51%. The liver and kidney were the main drug excretion organs. Five patients developed adverse reactions, and one person developed SAE. Three of study population were assessed as stable disease (SD), two with partial response (PR), and one had progressive disease (PD). Conclusions: Anlotinib showed a favourable pharmacokinetic profile with high absolute bioavailability and an extensive hepatic metabolism. The adverse events and efficacy were as expected. Clinical trial information: CTR20160329.