bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of metallic nanoparticles on tumor growth: In vivo study.
Authors: Zlatnik Elena Yu. , Triandafilidi Elena I. , Bykadorova Oksana V. , Kit Oleg I. , Zhukova Galina V. , Goroshinskaya Irina A. 
Published: May 2020

e15650 Background: The aim of the study was to assess the effect of metallic nanoparticles on growth of transplanted ascitic tumor sarcoma 37 in mice. Methods: Nanoparticles (NP) of transition metals were experimentally developed and kindly provided us by Prof. V.B. Borodulin. Ultradispersed metallic powders (NP Cu, NP Zn, NP Fe) 30-100 nm sized were dispersed by ultrasound in 0.85% NaCl before use and daily administrated intraperitoneally to tumor-bearing mice with ascitic sarcoma 37. Injections of NP 500 µl (10 µg/ml) were performed for 4 days, and 4 days after the completion of the course mice were sacrificed. The control group received 0.85% NaCl. Ascitic fluid volume was measured and living cells were counted. Results: In all the tumor-bearing mice the progression of ascites was noted: it was maximal in controls, less in animals having received NP Fe and NP Cu, minimal – in mice after injection of NP Zn. The volume of the latter was 0.78±0.31 ml in comparison with control data: 1.79±0.66 ml (p < 0.05); it was also less than in mice after administration of NP Cu (2.16±0.68 ml) and NP Fe (3.3±1.3 ml). Similar difference was seen in the amount of tumor cells in ascitic fluid: (1.67±0.5)х106/ml after the injection of NP Zn and (27.7±2.86)х106/мл in the control group. Effect of NP Cu and NP Fe was less pronounced than of NP Zn though obvious in spite of the noted tendency of the increase of the ascitic fluid volume. The most significant changes were observed when absolute amount of living tumor cells was counted per one mouse – it was minimal after NP Zn administration (0.636±0.2)х106/ml and maximal in the control group (23.98±10.5)х106/ml), i.e. only 2.6% of tumor cells had survived after NP Zn injection. Conclusions: Our results demonstrate that metallic NP were able to produce antitumor in vivo without any supplements like laser or hyperthermia: the effect was likely to depend upon the metal and was the highest in NP Zn compared to NP Cu and Fe.
Role of mutant KRAS as a biomarker in FL118-induced apoptosis, reactive oxygen species (ROS) production and inhibition of survivin, Mcl-1 and XIAP in human bladder cancer.
Authors: Santha Sreevidya , Aljahdali Ieman , Rasam Sailee Suryakant , Wang Xue , Ling Xiang , Liao Jianqun , Wang Jue , Fountzilas Christos , Li Qingyong , Qu Jun , Li Fengzhi 
Published: May 2020

e15651 Background: Effective treatment of bladder cancer patients has not been realized over the past two decades due to heterogeneity with key oncogenic and tumor suppressor gene mutations, which is a major hurdle for effective treatment of the disease. Methods: Cancer cell growth/viability was determined using MTT assays; protein gene expression profiles were determined by both Western blots and proteomics technologies; PARP cleavage were determined by Western blots; genetic modulation of protein gene expression was realized by shRNA silencing or forced expression of the gene; reactive oxygen species (ROS) production was measured using a ROS assay kit; and human bladder xenograft tumor growth was determined using animal models. Results: Our study indicated that FL118, an innovative small molecule, exhibits differential anticancer efficacy in high-grade bladder cancer cell lines (HT1376, T24, UMUC-3). FL118 is highly effective at inhibiting the viability of T24 and UMUC-3 bladder cancer cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 with wild-type Ras exhibits insensitivity to FL118-mediated inhibition of cell viability. Consistently, FL118 strongly induced PARP cleavage (hallmark of apoptosis) and inhibited the expression of survivin, XIAP and/or Mcl-1 in both T24 and UMUC-3 cells but not in the HT1376 cells. Our studies further indicated that the constitutive AKT and ERK1/2 signaling does not play a major role in these FL118-mediated effects. Instead, mutant Kras appeared to be involved in FL118 efficacy and played a positive role in mediating FL118 effects. Silencing of mutant Kras via shRNA reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC-3 cells, suggesting mutant Kras is required for FL118 to exhibit high efficacy. FL118 increases ROS production in T24 and UMUC-3 cells but not in HT1376 cells. Silencing of mutant Kras with shRNA in UMUC-3 cells significantly reduced FL118-mediated ROS generation. Additionally, proteomics analyses of UMUC3 and HT1376 cell protein profiles after FL118 treatment support the obtained results described above. Consistent with these in vitro results, in vivo studies indicated that UMUC3 is highly sensitive and HT1376 is highly resistant to FL118 treatment. Conclusions: Our studies suggest that mutant Kras is a favorable biomarker for FL118 targeted treatment in human bladder cancer.
FGFR2 inhibition could suppress spermatogenesis.
Authors: Tsimafeyeu Ilya , Lapina Nataliya , Byakhov Mikhail , Dragun Nadezhda , Gavrilova Evgenia , Skorobogatova Anastasia , Stosman Kira , Melikhova Marina , Vakunenkova Olga , Kashuro Vadim , Rozhko Mikhail , Tjulandin Sergei 
Published: May 2020

e15659 Background: The incidence of cancer among the people of reproductive age is constantly increasing. Although FGF2/FGFR2 expression in the male reproductive tract has been reported, there is no evidence of the impact of FGFRs inhibitors on sperm function. Therefore, the objective of this large study was to determine the effects of alofanib, selective FGFR2 allosteric extracellular inhibitor on the regulation of sperm physiology using the rat and rabbit models. Methods: Two-hundred forty Sprague-Dawley rats and 30 Chinchilla white rabbits received alofanib (0–40.5 and 0–21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for six months. Eighty rats and 8 rabbits were in the control group. The subchronic study evaluated high doses (300 mg/kg/day) of alofanib for 2 months in 15 male rats. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. Results: Animals were active. After injections of a dose equivalent to a human therapeutic dose during 6 months, most of the seminiferous tubules were empty, the elements of spermatogenesis were not classified, and altered primary spermatogonia and spermatocytes were distinguished in male rats. After injections of a five-fold dose, all seminiferous tubules were empty and expelled by a cylindrical epithelium. Very similar changes in sperm physiology were founded in rabbits. Most of the seminiferous tubules were blank, and some tubules contained eosinophilic amorphous masses. High doses of alofanib resulted in pronounced atrophy of the spermatogenic tubule epithelium. Multinucleated giant cells were observed in the lumen of a part of the tubules. There were no changes in untreated animals. Conclusions: FGFR2 inhibition led to the suppression of spermatogenesis. Male cancer patients should be informed of this potential adverse event before treatment with FGFR2 inhibitors.
Novel CTC test followed by iodine therapy for the terminal stage of cancer patients.
Authors: Shirakawa Taro 
Published: May 2020

e15661 Background: 5 years of survival rate of stage IV cancer patients have kept poor for these 30 years. This is mainly due to inevitability of anti-cancer drugs for them because of multi-organ metastasis. We developed a novel CTC technique to identify CTCs responsible for metastasis, and provided a method to kill those dangerous cells by Iodine therapy. Methods: We did 314 CTC tests, and 53 patients received it more than twice (average prognosis of 4.5 months). Our CTC tests by flouring 4cc blood of the patients into a special device with > 50,000 pores of 8μ diameters, this device can only catch CTCs. We also stained with cytokeratin and vimentin anti-bodies (see table). Iodine water was made of 10,000 ppm of NaI with certain numbers of additional chemicals. This preclinical trial was accepted by our ethical committee. Results: We developed a novel CTC technique to catch 95% of CTCs and identified 3 types of CTCs (see table). Without any therapy, type 1 cells disappeared, while all patients with type 2 cells died within a couple of months, this may be due to EMT (epithelial mesenchymal transformation) on them. We tested certain numbers of ant-cancer drugs and found that no drugs can kill type 2 cells, only stable Iodine water provided by our clinic can kill type 2 cells perfectly within two months, and 51 out of 53, the terminal stage of patients can survive more than a year. Conclusions: Novel CTC test can identify 3 types of CTCs and type 2 cells can be responsible for the poor survival of terminal stage cancer patients because they are responsible for metastasis, and anti-cancer drugs cannot kill them. It has been well-known that Iodine induces PPARγ which can promote apoptosis of type 2 cells and inhibit EMT. Iodine may improve their poor prognosis.[Table: see text]
Preclinical evaluation of LX-086, a small molecule as a selective inhibitor of PI3K.
Authors: Dong Jiaqiang , Wang Tie-Lin , Huang Jingjie , Zhou Ji , Tan Ye , Yu Tao , Wu Chengde , Chen Shuhui 
Published: May 2020

e15662 Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. PI3Kα is ubiquitously expressed, and associates with angiogenesis and glucose homeostasis. Gain of function mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common somatic alterations in solid tumors. The purpose of this study is to investigate the in vitro/ in vivo antitumor activity, and safety of LX-086, a small molecule of PI3Kα selective inhibitor, in preclinical models of solid cancer with PIK3CA mutation or amplification. Methods: Kinase inhibitory activity and selectivity of LX-086 were determined with PI3K kinase assays. Cellular pAktS473 inhibitory activity and selectivity were evaluated in BT-474, MDA-MB-468, RAW264.7 and Jeko-1 cell lines (cell lines PI3Kα/β/γ/δ are specifically highly expressed respectively). The antitumor activity of LX-086 was evaluated in vivo in PIK3CA amplified or mutant breast cancer BT-474, T47D and ovarian cancer SK-OV-3 cell-derived mouse xenograft (CDX) models. Results: LX-086 displayed potent kinase inhibitory activity for WT PI3Kα, PI3KαE545K, PI3KαH1047R with IC50 1.80 nM/1.13 nM/0.69 nM, respectively. LX-086 inhibited cell pAktS473 in BT-474 cells with IC50 35.4 nM. The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. LX-086 showed antitumor efficacy in HER2+/HR+, PIK3CA amplified breast cancer BT-474 CDX model (TGI = 106% @40 mpk, QD), as well as in the HER2-/HR+, PIK3CA H1047R breast cancer T47D CDX model ( TGI = 84.7%@ 40 mpk, QD) and PIK3CA H1047R ovarian cancer SK-OV-3 CDX model ( TGI = 69.2%@ 40 mpk, QD). The 28-days toxicity study in dog also indicated that LX-086 had similar therapeutic index with alpelisib, with low risk of hyperglycemia. Conclusions: We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.
Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist.
Authors: Motwani Monica , Modi Dimple , Penugonda Sudhir , Zhang Chun , Palma Joann , Cunningham Alexis , Calvo Emiliano , de Jonge Maja J.A. , LoRusso Patricia 
Published: May 2020

e15668 Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209). In a dose-expansion cohort, patients (pts) with KRAS-mutant colorectal cancer (n = 24) and pancreatic cancer (n = 24) were evaluated at 3 dose levels with 12 mandatory paired biopsies per tumor type (pretreatment [Tx] and on-Tx collection). Following eftoza dosing, RNA and protein expression including posttranslational modifications were assessed in tumor biopsies to understand the target engagement and downstream pathway activation. Plasma was evaluated for changes in somatic mutant allele frequency and M30, M65 (circulating apoptotic markers). Methods: Biopsies were collected anytime during the screening period (pre-Tx) and 24±4 h following 2nd or 3rd infusion (on-Tx). Of the requested 4–6 fresh biopsy cores, 1–2 cores were collected as formalin fixed paraffin embedded (FFPE) and the rest were frozen tissue. FFPE tissue was analyzed by multiplex immunohistochemistry (IHC) and RNAseq; reverse phase protein array was used for frozen cores. Plasma was collected at cycle 1 predose and 2, 8, 24, 48, and 168 h postdose and analyzed for M30, M65 (by ELISA) and circulating tumor DNA (64-gene PlasmaSELECT assay). Results: Twenty-five pts consented to biopsies; paired biopsies were obtained from 16 pts at a 64% success rate: FFPE (n = 15) and frozen cores (n = 12). Tumor cells were detected in 11/15 (73%) FFPE and 4/12 (33%) frozen cores. Increase in M30, activated caspases, and cleaved PARP levels was observed in on-Tx biopsy samples compared with pre-Tx, thus serving as evidence for apoptosis induction in tumors following eftoza dosing. Changes in the tumor microenvironment were observed post-Tx by RNAseq and multiplex IHC (eg, CD68 level). Downregulation of prosurvival signaling pathways (eg, AKT/MEK) was also observed following eftoza dosing. Thirteen out of 16 pts showed transient increase in mutant allele fractions post eftoza Tx that correlated with increased plasma circulating tumor markers M30 and M65 at similar time points, suggesting activation of apoptosis pathway. Increase in M30, M65 levels also preceded increase in liver enzymes (ALT/AST) at 2, 48 hr post-Tx. Conclusions: Pharmacodynamic effect of eftoza was successfully demonstrated in blood and tumor tissue, including induction of apoptosis and modulation of PI3K and MEK signaling pathways. Clinical trial information: NCT03082209.
Actionable alterations (AA) in gastrointestinal (GI) cancers: Rate of detection and receipt of matched therapies (MT).
Authors: Greally Megan , Tuvy Yaelle , Millang Brittanie M , O'Reilly Eileen Mary , Yaeger Rona , Saltz Leonard B. , Ku Geoffrey Yuyat 
Published: May 2020

e15677 Background: Next generation sequencing (NGS) is widely used in pts with advanced cancer to personalize care. Current NCCN guidelines endorse Her2, PD-L1 and MSI testing in esophagogastric cancer (EGC), RAS, BRAF, Her2 and MSI testing in colorectal cancer (CRC) and germline, somatic and MSI testing in pancreas cancer (PC). The proportion of GI cancer pts who receive MT based on NGS is unclear. Methods: We identified pts with advanced EGC (2016-18), PC (2017) and CRC (2016) who underwent NGS with MSK-IMPACT. We assessed the proportion of pts with ≥1 AA as defined by OncoKB (at the time of analysis, levels 1/2a were accepted practice and levels 2b/3/4 were investigational; Chakravaty, JCO PO 2017), those who received MT on trial or off label and 3 and 6 months (mos) progression-free survival (PFS). Results: We identified 260 EGC, 357 PC and 438 CRC pts. After excluding pts who had ongoing benefit from standard therapy (tx), were treated elsewhere or had no active stage IV disease, potential level 2/3/4 AAs occurred in 37% (n = 97) of EGC pts, 32.5% (n = 116) of PC pts and 26.7% (n = 117) of CRC pts (Table). 10, 1 and 17 pts with EGC, PC and CRC respectively were MSI. 1 pt in each subtype had an NTRK fusion (OncoKB level 1). In EGC, 6 pts (6.2% of those with AAs) received MT: 2 pts with MET amplification (a) and 1 each with BRCA2 mutation (m), TSC2m, ERBB2m and EGFRa. The pts with METa treated with crizotinib achieved 3 but not 6 mos PFS. In PC, 11 pts (9.5%) got MT: 10 pts for BRCAm and 1 for NTRK3 fusion. 9 pts with BRCAm treated with PARP inhibitors (i) achieved ≥3 mos PFS and 5 pts reached ≥6 mos PFS. The pt treated with NTRKi progressed rapidly. In CRC, 5 pts with ERBB2a and 9 pts with BRAFm received MT (12%). 3 pts and 2 pts treated with anti-Her2 tx achieved ≥3 and ≥6 mos PFS respectively. Of 6 pts treated with BRAF/MEKi plus irinotecan or anti-EGFR tx, all achieved ≥3 mos PFS; 3 reached ≥6 mos PFS. 3 pts received novel BRAF and ERK1/2i; none reached 3 mos PFS. Conclusions: NGS frequently identified OncoKB level 2 AAs. Few pts received MT, and of those, some achieved ≥6 mos PFS. Pts with CRC and PC received MT which subsequently became standard NCCN recommendations; therefore, a more current analysis may show increased MT use. Still, MT for level 3 and 4 alterations were rare, suggesting expectations of NGS must be managed appropriately. [Table: see text]
Hepatic arterial infusion (HAI) chemotherapy via the medtronic pump-assessing dose delivery, response rates and toxicity.
Authors: Connell Louise Catherine , Fiedler Laura , Dickinson Shannan , Ly Michele , Harrington Kate , Jarnagin William R. , Kingham T. Peter , Drebin Jeffery A. , Balachandran Vinod P. , Wei Alice C. , D'Angelica Michael Ian , Kemeny Nancy E. 
Published: May 2020

e16007 Background: Due to the termination of the Codman pump, in order to administer hepatic arterial infusion (HAI) chemotherapy, the Medtronic pump has been used with the Codman catheter at MSKCC since 2018. Methods: Retrospective review of patients(pts) receiving HAI therapy via Medtronic pumps. Expected versus actual dose delivery of HAI FUDR, response rates and safety were reviewed. Results: Pts included; unresectable colorectal liver metastases (CRLM) (94 pts), resected CLRM (66 pts) and unresectable intrahepatic cholangiocarcinoma (ICC) (11 pts). Baseline characteristics of the 171 evaluable pts are shown in Table. In 120 pts with mCRC, 51.8% (n = 58) had 10 or more hepatic tumors and 23.2%( n = 26) had 50% or more liver involvement by metastases. 52 out of 171 pts (30.4%) had 100% of the expected FUDR doses by completion of the 3rdcycle. Another 49.7% (85/171) had greater than or equal to 50% of the expected FUDR dose. 96 pts had measurable disease (unresectable CLRM and ICC subgroups) evaluated by RECIST 1.1 with an MSK radiologist. The partial response for unresectable CRLM pts was 47% (41/87), and 28% (24/87) were stable. The partial response for ICC pts was 22% (2/9), and 33% (3/9) were stable. Conclusions: We evaluated 171 pts who were heavily pretreated and had extensive disease prior to pump placement. Partial response by RECIST 1.1 of 47% was evident in those pts with CRLM and 22% for pts with ICC. Dose delivery of HAI FUDR was compatible with that seen with the Codman pump and no increase in toxicity was noted. An updated analysis with additional evaluable pts will be presented at the meeting. [Table: see text]
Clinical implications of assumptions in cost-effectiveness analyses of systemic therapies for metastatic colorectal cancer.
Authors: Degeling Koen , Vu Martin , Koffijberg Hendrik , Wong Hui-Li , Koopman Miriam , Gibbs Peter , IJzerman Maarten J. 
Published: May 2020

e16021 Background: Considerable variation is observed in model-based cost-effectiveness analyses of systemic therapies for metastatic colorectal cancer (mCRC). This review provides a comprehensive and detailed discussion of structural and methodological assumptions in such analyses, and how those might impact health and economic outcomes. Methods: Five databases (EMBASE, MEDLINE, Cochrane Library, Health Technology Assessment, and National Health Service Health Economic Evaluation Database) were searched for model-based health economic evaluations of systemic mCRC treatment. Study selection, appraisal using the Consolidated Health Economic Evaluation Reporting Standards checklist, and data extraction was performed by two reviewers independently. Data extraction included general study characteristics, economic methods and assumptions, model structures and modelling technique, evidence used, extrapolation methods, validation efforts, and analyses performed. Economic outcomes were indexed to 2019 US$. Results: The search yielded 1,418 publications of which 54 were included, representing 51 unique studies. Most studies focused on first-line treatment (n = 29, 57%), followed by third-line treatment (n = 13, 25%). Although most studies mentioned consideration of further treatments (n = 29, 57%), this was typically only done by means of a lumpsum treatment cost (n = 21). Studies used varied modelling techniques and model structures, and different control strategies were adopted by studies aiming to estimate the cost-effectiveness of the same treatment. Only 15 studies (29%) reported some sort of model validation. Health economic outcomes for specific strategies differed substantially between studies. For example, survival following first-line treatment with fluorouracil, leucovorin, and oxaliplatin ranged from 1.21 to 7.33 years, with treatment costs ranging from US$8,125 to US$126,606. Conclusions: Model-based cost-effectiveness analyses of systemic mCRC treatments have adopted varied modelling methods and structures, which has resulted in substantial different health economic outcome estimates between studies, for example in terms of overall survival and average treatment cost per patient. Models generally focus on first-line treatment without considering the use of downstream treatments, suggesting these studies likely present biased results. This may impact the uptake of new systemic therapies.