bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma concentration of amrubicinol in gamma phase in patients treated for 3 days with amrubicin and hematological toxicities
Authors: Kimura T. , Kudoh S. , Mitsuoka S. , Tanaka H. , Kyoh S. , Suzumura T. , Yoshimura N. , Asai K. , Tochino Y. , Hirata K. 
Published: August 2020

e14606 Background: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-amino-anthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we performed a PK/PD study of AMR in patients with lung cancer treated with AMR alone or the combination of AMR + cisplatin (CDDP). Methods: AMR was given at a dose of 30 or 40 mg/m2 on days 1 to 3. Plasma samples were collected at pretreatment, 24 hours after the 1st injection (day 2), and 24 hours after the 3rd injection (day 4). Plasma concentrations of AMR, AMR-OH, and CDDP were determined by HPLC and AAS. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid Emax model. Results: A total of 35 patients with a median age of 65 years (range 40–78), including 10 with small cell lung cancer (SCLC), 23 with non-small cell lung cancer (NSCLC), 1 with thymic cancer, and 1 with neuroblastoma were enrolled. A total of 107 plasma samples were available for study. Mean concentrations of AMR on day 2, AMR on day 4, AMR-OH on day 2, and AMR-OH on day 4 were 8.52ng/mL+4.63, 16.55ng/mL+11.92, 7.28 ng/mL+3.56 SD, and 13.35ng/mL+5.56 (mean ± SD), with significant increase from day 2 to day 4 for both AMR (p<0.0001) and AMR-OH (p<0.0001). Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (p=.018, p=.012, and p=.025). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (p = .081). No relationships were observed between drug concentrations and responses. The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients with co-administration with CDDP using a sigmoid Emax model. Conclusions: The plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. Assessment of plasma concentration of AMR-OH at one time point might enable prediction of hematological toxicities. No significant financial relationships to disclose.
A strategy for clinical guidance using PD biomarkers revealed from human primary (HuPrime) tumors transplanted in nude mice
Authors: Chen T. , Liu C. , Song X. , Zhang L. , Liu Y. , Wery J. , Chen Y. 
Published: August 2020

e14612 Background: Most anticancer drug candidates, currently in clinical trials, have clear targets in molecular and cellular systems. However, such molecular targets are not always affected (or not correlated with efficacious endpoints) when the candidate is evaluated in a clinical setting. There is an urgent need to develop better biological tools and models to ease the transition between in vitro and in vivo, and between preclinical and clinical settings. Activation of tyrosine kinases in tumor cells has been recognized as key driving force in malignancy; therefore inhibitors of tyrosine kinases (TKI) have often shown efficacy in preclinical in vivo models and beneficial responses in clinical trials. An increasing number of TKI has been approved as anticancer drugs in selected cancer types. Methods: We have developed a unique platform combining our novel HuPrime™ xenograft models with our PD biomarker technologies. This platform is used to better understand the efficacy of novel drug candidates and generate information critical to maximize the chance of a successful clinical development. To illustrate the usefulness of our platform, we have applied it to understand the pharmacodynamic changes (at the molecular level) which are associated with the activity of sunitinib and sorafenib in our sensitive esophageal HuPrime models. Tumor tissues from sensitive esophageal HuPrime models treated with single dose of the respective drugs (and a vehicle control) have been collected at time-points 4, 8, 16, and 24 hour. Results: We have successfully applied immunohistochemistry (IHC) assays on many molecules covering most pathways including proliferation, apoptotic, necrotic, and cell cycle regulation, G2M phase arrest, DNA damage response, etc. Additional markers including angiogenesis can also be included for certain therapeutic compounds. These tissues have been analyzed with our platform and we have uncovered key molecular events which correlate with the efficacy and potency of the drugs. Conclusions: The PD biomarkers validated in this approach have potential for clinical application and patient stratification. [Table: see text]
Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism
Authors: Karimdjee B. S. , Cambien Miss B. , Richard Mrs P. F. , Bereder J. , Scoazec Mr J. , Birnbaum Mr D. , Mounier Mr N. , Schmid Mrs H. A. , Schmid Mrs A. A. 
Published: August 2020

e14619 Background: Liver and lung metastases are the predominant cause of colorectal cancer (CRC) related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate hematopoetic cell movement are implicated in the metastatic process of malignant tumors, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. Methods: To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. Results: In vitro, activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo, systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited metastasis of human and mouse CRC cells to the lung without affecting that to the liver. Also, we measured increased levels of CXCR3 and ligands expression within lung nodules compared to liver tumors. Conclusions: Altogether, our findings indicate that CXCR3 is a key mediator for lung metastasis of colon carcinoma and identify CXCR3-blocking approaches as promising strategies against established lung metastases. No significant financial relationships to disclose.
TKI258, a novel, multitargeted tyrosine kinase inhibitor for the treatment of breast cancer
Authors: Liu H. , Schulz C. O. , Regierer A. C. , Dieing A. , Possinger K. , Eucker J. 
Published: August 2020

e14625 TKI258 (4-amino-5-fluor-3-[5-(4-metylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, formerly known as CHIR258) is an ATP-competitive inhibitor with activities against class III or IV receptor kinases, which include FGFR, VEGFR, PDGFR, FLT3, and KIT. It has been demonstrated to possess strong anti-tumor and anti-angiogenetic activities in different tumor models, and, therefore, this compound is currently being clinically assessed for the treatment of diverse malignancies. In this study, we chose the breast cancer cell line MDA-MB-231, a cell line with high invasive capacities, as an in vitro model to analyze the effect and functional mechanism of TKI258 on the breast cancer invasiveness. Treatment of MDA-MB-231 cells with TKI258 resulted in reduced invasive capacities in a dose-dependent manner. In association with this effect, we observed that TKI258 down-regulated the phosphorylation of ERK1/2 and STAT3 and inhibited the VEGF production in the cell supernatants. Most interestingly, we found TKI258 had influence on the inflammatory chemokines CCL5 and CCL2 level if MDA-MB-231 cells were co-cultured with breast cancer stroma cells. We found that CCL5/CCL2 mRNA level in MDA-MB-231 cells, in stroma cells, or in co-culture of MDA-MB-231/breast cancer stroma was strongly inhibited by TKI258 as detected with real-time PCR. Parallel to this result, the dramatically elevated CCL2/CCL5 level in the media supernatants from co-cultured MDA-MB-231/stroma cells was reduced by TKI258 effectively. Furthermore, we demonstrated that the invasion-promoting effect of the tumor stroma cells was antagonized by TKI258 significantly. CCL5 stimulated invasion of MDA-MB-231 cells could be partially abrogated by TKI58 and/or by CCL5-neutralizing antibody. Therefore, it is most likely that the inhibitory effect of TKI258 on invasion of MDA-MB-231 cells in the presence of stroma cells is achieved, at least in part, by antagonizing the invasion-promoting effect of CCL5. Overall, our data show that TKI258 inhibited invasive capacities of aggressive breast cancer cell line MDA-MB-231, either in the absence or presence of tumor stroma cells in vitro. No significant financial relationships to disclose.
Antisense oligonucleotides targeting the large subunit (R1) of human ribonucleotide reductase synergistically increase the cytotoxicity of doxorubicin and paclitaxel to MCF-7 breast cancer cells
Authors: Jiang X. , Elliott R. L. , Head J. F. 
Published: August 2020

e14626 Ribonucleotide reductase (RR) is an essential enzyme that catalyzes the reduction of ribonucleotides to deoxyribonucleotides for use in DNA synthesis. Human RR consists of two subunits, a large subunit (R1) and small subunit (R2). RR provides an attractive target for anticancer therapy. In the present study, we synthesized phosphorothioated antisenses oligonucleotides (RR1AS1, RR1AS2, RR1AS3, RR1AS4 and RR1AS5) that target the R1 subunit of RR. We treated the human breast cancer cell line MCF-7 with antisenses, and doxorubicin or paclitaxel for 72 hours. Cell proliferation was measured by 3[H]- thymidine incorporation. The effects of the drug combinations were analyzed with Biosoft Calcusyn software. The levels of RR mRNA were measured by RT-PCR. We found two antisenses, RR1AS2 and RR1AS4, inhibited the proliferation of MCF-7 cells in a dose-dependent pattern (IC50s: 5.32+1.64μm and 2.57+2.72μm, respectively, 72 hours incubation). Also, RR1AS2 and RR1AS4 significantly suppressed the expression of RR1 mRNA. When MCF-7 cells were incubated in media with a mixture of antisense and doxorubicin or paclitaxel, both RR1AS2 and RR1AS4 synergistically increased the cytotoxicity of doxorubicin and paclitaxel. Calcusyn analysis showed that averaged combination index (CI) were 0.59+0.04, 0.66+0.22, 0.83+0.16 and 0.88+0.03, when MCF-7 cells were treated with the mixtures of RR1AS2 + doxorubicin, RR1AS2 + paclitaxel, RR1AS4 + doxorubicin and RR1AS4 + paclitaxel, respectively (CI<1 indicates synergism). These results suggest that the combination of RR antisenses and chemotherapeutic agents, such as doxorubicin or paclitaxel, may decrease both the dosages and side effects of both antisense oligonucleotides and chemotherapeutic agents (doxorubicin and paclitaxel) in cancer therapy. No significant financial relationships to disclose.
Effect of sunitinib on TRAIL-induced apoptosis in preclinical colon cancer models
Authors: Mahalingam D. , Medina E. , Swords R. T. , Kelly K. R. , Carew J. S. , Robbert C. H. , Szegezdi E. , Francis G. J. , de Jong S. , Nawrocki S. T. 
Published: August 2020

e14633 Background: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis, however not all cancers respond to TRAIL, which may be due to activation of survival signals. Sunitinib is a potent inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). These receptors and their signaling cascades promote cell survival and drug resistance. Inhibition of these pathways with sunitinib may augment TRAIL-mediated apoptosis. Aims: 1) Determine sensitivity of colon cancer cell lines to the combination of TRAIL and sunitinib, 2) identify mechanism by which sunitinib enhances TRAIL-mediated apoptosis, and 3) investigate the anticancer activity of this drug combination in xenograft models. Methods & Results: Sunitinib enhanced the anticancer activity of TRAIL in HCT116 and HCT15 colon cancer cell lines, with increased caspase cleavage and DNA fragmentation using western blot analysis and propidium iodide staining, respectively. Overexpression of Bcl-2 in HCT116 cells reduced TRAIL+sunitinib-mediated apoptosis, suggesting that sunitinib enhances TRAIL-induced apoptosis via activation of the mitochondrial apoptotic pathway. Sunitinib enhanced TRAIL-induced JNK activation, which may play a role in TRAIL+sunitinib-mediated apoptosis. Xenograft models of HCT116 and HCT15 were established in nude mice and treated with TRAIL, sunitinib, or the combination. The TRAIL+sunitinib combination significantly reduced tumor burden in both xenograft models compared to either treatment alone. The reduction in tumor volume correlated with increased apoptosis and decreased tumor proliferation and angiogenesis as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry for Proliferating Cell Nuclear Antigen and VEGF. Conclusion: These results are the first to demonstrate that simultaneous treatment with TRAIL and sunitinib reduced cell viability, induced apoptosis, inhibited tumor proliferation and angiogenesis in both in vitro and in vivo models of colon cancer, and warrants further investigation. No significant financial relationships to disclose.
The incidence of non-melanoma skin cancer after a single field treatment with aminolevulinic acid and blue light photodynamic therapy
Authors: Kozyreva O. N. , Konnikov N. 
Published: August 2020

e14646 Background: Non-melanoma skin cancer (NMSC) is the most common form of human cancer. Aminolevulinic acid photodynamic therapy (ALA PDT) is a safe and effective treatment for NMSC precursors. It is unknown if ALA PDT treatment will affect incidence of NMSC in high risk patients (pts). Methods: A retrospective study was undertaken using a Veteran Affairs Boston Health Care System Medical Record Database. Study population included immunocompetent pts with history of NMSC, multiple actinic keratosis (AKs), and moderate to severe dermatoheliosis (DH). Study pts received a single application of 20 % ALA to the face or scalp following by exposure to blue light at 10 J/cm2. Differences in incidence of NMSC two years prior and two years after ALA PDT were tested using the Wilcoxon rank sum test. Data were analyzed by the median and interquartile range (IQR). Results: 43 Caucasian males (range 59- 87 yrs), 37 (87%) had history of NMSC on the face or scalp, 32 (78%) had basal cell carcinoma (BCC), 11 (22%) squamous cell carcinoma (SCC), 100% of patients had multiple (>4) AKs prior to treatment and 23 (75% ) had moderate to severe DH determined by Griffiths scale. Prior to ALA-PDT 74 NMSC's were documented: 40 (54%) BCC and 34 (46%) SCC. 46 NMSC's were documented following ALA-PDT: 22 (48%) BCC and 24 (52%) SCC. Prior to ALA-PDT, the frequency of BCC averaged 2 [IQR 1 to 3, max=4], and the frequency of SCC averaged 1 [IQR 1 to 1, max=3]. Following ALA-PDT, the occurrence of BCC averaged 1 [IQR 0 to 1, max=5], and that of SCC averaged 1 [IQR 0 to 2, max= 4]. The difference between BCC frequency before and after ALA-PDT treatment shown a significant reduction in BCC incidence (P = 0.0018). No such differences were observed between the frequency of SCC before and after ALA-PDT (P=0.6230) Conclusions: A single ALA-PDT treatment to the face or scalp in high risk patients significantly reduces the incidence of BCC, the incidence of SCC was not reduced. The potential role of ALA PDT as a NMSC chemopreventive modality warrants further investigation in larger samples with an alternative treatment protocols. No significant financial relationships to disclose.
The number of lymph node metastases as a prognostic indicator of disease-specific survival in the era of sentinel lymph node mapping in colon cancer
Authors: Saha S. , Sirop S. , Korant A. , Chakravarty B. , Krishnaiah N. , Wiese D. , Soni M. , Arora M. , Nagpal S. , Singh T. 
Published: August 2020

e15000 Introduction: Sentinel Lymph Node Mapping (SLNM) in colon cancer (CCa) is shown to be successful, sensitive and accurate. We aimed to evaluate the survival of patients (pts) undergoing SLNM in addition to the standard colon resection, compare it to pts without SLNM and correlate it to the number of LN metastasis. Methods: Staging and survival analysis from our prospective database (gpA, 195 pts) were compared to the Surveillance, Epidemiology, and End Results (SEER) database (gpB, 126,484 pts) between 1996–2003. All pts had invasive CCa. GpA pts underwent SLNM plus complete resection. The minimum follow up (F/U) was 5 years. The primary outcome was cancer-specific survival. Exclusion criteria were stage IV disease, 2nd malignancy, or lost to F/U. Cancer specific survival of gpA was then analyzed according to the number of positive LNs. Results: In gpA (195 pts), SLNM was successful in 99.7%, of pts with a sensitivity, negative (-ve) predictive value, and false -ve rates of 86.3%, 91.7% and 14.6% respectively. In 15.1% of node +ve pts, the disease was upstaged because of micrometastasis (0.2–2mm). In gpA, 128 pts were included, of which 17(13.3%) lost to F/U as compared to 89,483 pts included in gpB, of which 47,168 (52.7%) lost to F/U. The average number of LNs examined per pt was 15 in gpA as compared to 12.4 in gpB (p=<0.0001). The 5 year-cancer specific survival of pts in gpA vs gpB was 100% vs 94.9% in stage I, 91.2% vs 83.5% in stage II and 81.8% vs 63% in stage III disease. For gpA pts, the 5 year cancer-specific survival decreased from 95.0% in node -ve disease to 92.8% when 1 LN was +ve, 83.3% when 2 LNs were +ve and 71.4% when 3 or more LNs were +ve (Table). Conclusions: A significant number of pts with CCa are being upstaged and the true node -ve disease is being identified when SLNM is performed at the time of surgery leading to improved survival as compared to conventional surgery. Our study showed that the number of LN metastasis is a predictor of cancer specific survival even after SLNM in CCa. [Table: see text] No significant financial relationships to disclose.
Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Price T. J. , Peeters M. , Douillard J. , Mitchell E. , Cohn A. , Strickland A. H. , Rivera F. , Xu F. , Gansert J. , Siena S. 
Published: August 2020

e15005 Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies. [Table: see text] [Table: see text]
FOLFIRI + bevacizumab as first-line treatment in advanced colorectal cancer (ACC): Final results (prot. GOIM 2601)
Authors: Giuliani F. , De Vita F. , Lorusso V. , Cinieri S. , Nugnes I. , Orditura M. , Maiello E. , Del Prete S. , Leo S. , Colucci G. 
Published: August 2020

e15007 Background: The addition of Bev to IFL obtained better OS and RR than chemotherapy alone. However IFL is not considered an optimal regimen and is certainly more toxic than FOLFIRI. To investigate the activity and efficacy of the addition of Bev to FOLFIRI, the GOIM started the following phase II study. Methods: seventy-two untreated pts with histologically/citologically confirmed diagnosis of colorectal cancer, with at least one measurable disease, age > 18 yrs, PS < 2 (ECOG), adequate bone marrow reserve and hepatic and renal function, with no history of cardiovascular disease, thromboembolic events or coagulative disorders and who signed informed written consent, were enrolled and received the following treatment: CPT-11 at 180 mg/m/mq on day 1, FA at 100 mg/mq as 2h infusion on days 1–2, FU at 400 mg/mq bolus on days 1–2 and FU at 600 mg/mq as 22h infusion on days 1–2 (FOLFIRI) plus Bev at 5 mg/Kg on day 1, every two weeks. A maximum of 12 cycles of chemotherapy was planned and a maintenance with Bev for 6 months was permitted. The evaluation of activity (Recist criteria) was performed every 4 cycles Results: all the enrolled pts were evaluable for activity and safety. Their main characteristics were M/F: 38/34; median PS: 0; median age 60 (range 33–73); primary site colon/rectum: 50/22 (69.4%/30.6%); main sites of disease liver: 50 (69.4%), lung: 18 (25%), lymph nodes: 19 (26.4%); synchronous/metacronous disease: 55/17 (77.7%/22.3%); multiple/single lesions: 40/32 (55.5%/44.5%).Seven (9.6%) CR, 25 (34.8%) PR, 33 (45.8%) SD and 7 PRO were observed for an ORR of 44.4% and a disease control of 90.3%. The response rate according to the main sites of disease were: liver 25/50 (50%), lung 6/18 (33.3%). The median number of administered cycle were 9 and the median TTP was 10.0 months. The main haematologic side-effects (% G3–4 NCI criteria) were: neutropenia 11%, thrombocytopenia 2.7% and anemia 4.7%, while diarrhea affected only 2.7% of pts; hypertension, thromboembolic and bleeding events were observed in 2.7%, 1.3% and 1.3% respectively. Conclusions: the addition of Bev to FOLFIRI is an active and effective first-line treatment in ACC with a good safety profile. Survival data will be presented during the meeting. No significant financial relationships to disclose.