bluuebunny/crossref_metadata_2025_split huggingface dataset:
18F-alfatide PET may predict anti-angiogenic drugs toxicity.
Authors: Liu Jie , Meng Xue , Yu Jinming 
Published: May 2019

e14608 Background: Identifying predictive markers for toxicity could decrease the number of patients experiencing dose-limiting toxicity. The study aims to investigate whether 18F-Alfatide positron emission tomography (PET) can predict the antiangiogenic drugs toxicity. Methods: A549 xenografted mice underwent 18F-Alfatide PET at baseline when tumor volume reached 100-200 mm3 and after treatment with apatinib (100mg/kg once daily), bevacizumab (20mg/kg every four days), endostar (20mg/kg once daily) or vehicle. Tumor growth and body weight were monitored every two days. The changed rate of tumor volume (TV) and organ uptake (OU) after therapy were calculated using the formula: [mean value(negative control) – each value(experimental)]/mean value(negative control)×100%, and [each value(experimental) – mean value(negative control)]/mean value(negative control)×100% for pathological injury degree of organs (PID) after therapy. We compared the antiangiogenic response and organs PID among three groups. Then, linear correlation was analyzed between mean OU and mean TV or mean PID, and between organ uptakes before treatment and PIDs in all model group. Results: TVs treated by endostar was lower than that of bevacizumab, both of which were lower than that of apatinib (mean IR±SD: endostar (13.56±11.78)%, bevacizumab (37.19±12.50)% and apatinib (48.43±8.71)%, respectively, P > 0.05 for the three groups, but P < 0.05 for the comparison of endastar and apatinib groups). The same is true for the PIDs (mean PID±SD for livers: endostar (32.58±11.81) %, bevacizumab (36.12±11.01)% and apatinib (41.12±9.99)%, P > 0.05; mean PID±SD for kidneys: endostar (39.54±4.80)%, bevacizumab (43.24±5.46)% and apatinib (52.90±8.75)%, P > 0.05). There was an excellent linear relationship between mean OU and mean PID (Liver: R2= 0.93, P > 0.05 for OUSUVmean; R2= 0.80, P > 0.05 for OUSUVmax; Kidney: R2= 0.85, P > 0.05 for OUSUVmean; R2= 0.97, P > 0.05 for OUSUVmax) and an excellent linear relationship between mean OU and mean IR (Liver: R2= 0.99, P < 0.05 for OUSUVmean; R2 = 0.97, P > 0.05 for OUSUVmax; Kidney: R2= 0.99, P < 0.05 for OUSUVmean; R2= 0.93, P > 0.05 for OUSUVmax). There was a significantly moderate linear association between the uptakes of organs prior to treatment and the PIDs (Liver: R2= 0.49, P < 0.001 for OUSUVmean; R2= 0.45, P < 0.001 for OUSUVmax; Kidney: R2= 0.57, P < 0.0001 for OUSUVmean; R2= 0.53, P < 0.001 for OUSUVmax). Conclusions: 18F-Alfatide PET may be a useful molecular imaging tool for individual selection with toxicity before antiangiogenic therapy.
Automated breast cancer lesion detection on breast MRI using artificial intelligence.
Authors: Tapia Negrete Nataly , Takhtawala Ruquaiyah , Shaver Madeleine , Kart Turkay , Zhang Yang , Kim Min Jung , Park Vivian Youngjean , Su Min-Ying , Chow Daniel S. , Chang Peter 
Published: May 2019

e14612 Background: Over 40,000 women in the US will die from breast cancer. Early detection of cancer is crucial and is a potential avenue to improve survival. The objective of this research study is to develop a convoluted neural network (CNN), a subset of artificial intelligence, in order to enhance computerized detection of breast lesions on MRIs. Methods: This is an institutional review board approved retrospective study with post contrast MRI data from 238 patients. Breast tumor segmentation was automated with a hybrid 3D/2D CNN designed adapted from U-net, a popular neural network architecture in biomedical image analysis. T1 post-contrast MRI volumes were used to train the network. The data set was separated into training (80%) and validation (20%) sets. Re-sampling and normalization using z-scores were applied to each volume before training. Contracting and expanding arms of the model consist of successive convolutions followed by batch normalization and ReLU operations. Ground truth was established through manual segmentation and previously conducted readings of the images used to train our network. Results: A 5-fold cross validation was performed for analysis. The Dice similarity coefficient was used to assess segmentation accuracy. The hybrid 3D/2D U-Net architecture yielded a Dice score of 0.753 and a Pearson correlation of 0.548 for the breast tumor segmentation. Conclusions: These results demonstrated the feasibility for artificial intelligence applications in accurately identifying the presence of lesions on breast MRI images.
Comparison of diagnostic methodologies to detect chromosomal abnormalities.
Authors: Wong Cynthie , Thangavelu Maya , Hibbard Michele , Blocker Forrest , Weiss Lawrence M. , Funari Vincent Anthony 
Published: May 2019

e14617 Background: Traditional technologies such as cytogenetics, FISH, and microarray (CGH) are utilized in most clinical laboratories. Next-Generation Sequencing (NGS) is a relatively new tool to evaluate the cancer genome. Applications of this method include assessing single nucleotide variants (SNVs), indel mutations, and copy number variations (CNVs), including some large chromosomal deletions or gains. Methods: We used a custom Discovery+LOH NGS panel (Agilent, Santa Clara) to determine the utility of NGS in detecting CNV and loss of heterozygosity (LOH) events. Thirty six patients with known DNA structural abnormalities and hematologic disease were tested using cytogenetics, the NGS panel, and CytoScan HD microarray. Results: As shown in the table, NGS detected all abnormalities reported by CGH. NGS failed to detect 14 abnormalities reported by cytogenetics, but detected additional gains and losses from small chromosomal regions as well as LOH events. Notably, NGS found a 16p loss, but cytogenetics detected a full chr16 loss and a 7q loss. NGS detected an 11p loss which was missed by cytogenetics. Table: Comparison of Detection by Methodologies. Conclusions: This study highlights the benefits and limitations of each method using clinical samples with hematologic disease. Cytogenetics provided a gross view of a karyotype, but lacked resolution to detect small aberrations and LOH events. NGS provided high resolution of numerical aberrations and detected LOH events, but was unable to detect some gain and loss events. In examining those missed events, < 30% abnormal cells were found in those specimens, possibly explaining the reduced sensitivity. Importantly, we found two significant discrepant chromosomal aberrations between cytogenetics and NGS. This may result from cytogenetic culture where preferential growth of cells influence the detection of a chromosome gain or loss. These findings suggest advantages in assessing chromosomal abnormalities using NGS in coordination with more traditional methods to improve diagnostic and prognostic determination to assist in treatment selection.[Table: see text]
Impact on U251 glioma cell radiosensitivity and CFL1 level via inhibiting cell motility regulator ROCKII of RhoA-RockII-CFL1 pathway.
Authors: Zhao Mengjie , Chen Ling , Xiao Yong , Xiao Hong , Liu Hongyi 
Published: May 2019

e14630 Background: In response to ionizing radiation, cofilin1 (CFL1) is essential for actin dynamics and tumor metastasis. In our previous study, CFL1 was revealed up-regulated in radioresistant astrocytomas of surgical samples and positively correlated with glioma cell radioresistance. Methods: The present study aims to clarify the potential mechanism of CFL1-mediated radioresistance and to find new molecular targets to improve the radiosensitivity of U251 glioma cell. Radioresistant U251 (RR-U251) was established by serially irradiation with 5Gy until 60 Gy of irradiation was accumulated on human U251 glioma cell. Y-27632, PAK1-shRNA and PAK1-shRNA were respectively utilized to inhibit CFL1 upstream regulators in normal U251 and RR-U251 cells. CFL1 expression level and the alteration of radiosensitivity were evaluated; the cell radiosensitivity was assessed through cell vitality, invasion and migration experiments after irradiation. Results: 20 ¦Ìmol/L Y-27632 was screened and administrated to inhibit ROCKII in glioma cells followed by 5Gy radiation treatment. The CFL1 level was reduced in both normal U251 and RR-U251 cells. Meanwhile, cell viability, migration and invasion abilities significantly decreased in RR-U251 cells. After being transfected with PAK1-shRNA, cell radiosensitivity were significantly improved in both normal U251 and RR-U251 cells; while CFL1 level showed no significant difference after PAK1 silence . After inhibiting MRCK¦Á expression, cell viability, migration and invasion capabilities significantly reduced in both normal and radioresistant cells; while CFL1 levels showed no significant decrease. Conclusions: The results of the present study indicate that inhibiting ROCKII of RhoA-RockII-CFL1 pathway could improve radiosensitivity of radioresistant glioma cells and simultaneously down-regulate CFL1 expression; while the inhibiton of PAK1 or MRCK¦Á ameliorated the radiosensitivity with no significant regulation effect on CFL1. In conclusion, the present study emphasize the involvement of ROCKII in CFL1-mediated radioresistant phenotype and provide potential biomarkers for improvement of further clinical radiotherapy.
Innovative dual system for selective eradication of cancer cells using exosomes carrying natural bacterial toxin-antitoxin (TA).
Authors: Shapira Shiran , Boustanai Ilana , Kazanov Dina , Fokra Ahmad , Bernstein Ezra , Wolf Ido , Arber Nadir 
Published: May 2019

e14635 Background: Inactivation of P53 and activation of ras are frequent genetic alterations in cancer. We have shown in vitro and in vivo, that the TA system can selectively and effectively eradicate RAS-mutated cancer cells. Aim: Selective killing of cancer cells while sparing the normal cells based on tumor genetic signature. Methods: A “first generation” ΔE1/ΔE3 human type-5 adenoviral-vectors for gene delivery were designed and constructed to specifically target cancer cells. They are designated as "PY4-mazF-mCherry" (PY4, ras responsive element), "ΔPY4-mazF-mCherry" (control viruses) and "RGC-mazE-IRES-GFP" (RGC, P53 responsive element). Their potency was tested in vitro, by the enzymatic MTT assay, microscopic observation, colony formation assay and FACS analysis, and in a xenograft model of CRC. Next, we generated, small natural vesicles, exosomes, that directly targeted cancer through specific small antibody fragments against CD24 that is expressed in most cancer cells and rarely on normal cells. Results: The TA system ("PY4-mazF-mCherry"+"RGC-mazE-IRES-GFP") induced a massive cell death, in a dose-dependent manner in vitro, 69% as compared to 19% in control co-infected ("ΔPY4-mazF-mCherry"+"RGC-mazE-IRES-GFP") HCT116 CRC cells (mutated RAS and p53). In vivo, growth of HCT116-/- ( KRASmutand P53mut) and HCT116+/+ ( KRASmut and P53wt) tumors were significantly inhibited (70% and 65%, respectively). Conclusions: 1. Abusing the P53 genetic status and the activated Ras pathway holds promising effective and safe strategy to target tumor cells while sparing normal tissues. 2. It is a proof of concept for personalized cancer therapy based on the tumor genetic profile.
Bioinformatic inspired nanoparticles engineered for enhanced delivery to the bone.
Authors: Gdowski Andrew , Ranjan Amalendu , Lampe Jana , Lin Victor , Wang Yu-Chieh , Mukerjee Anindita , Vishwanatha Jamboor 
Published: May 2019

e14637 Background: We have engineered a programmable-bioinspired nanoparticle (P-BiNP) delivery system to simultaneously target the bone and increase uptake in homotypic tumor cells by coating polymeric nanoparticles with programmed cancer cell membranes. This approach is unique in that we have incorporated relevant clinical bioinformatics data to guide the design of these nanoparticles. Methods: A gene ontology search identified potential homotypic cell-cell adhesion genes. These were cross referenced with RNAseq expression levels from patients with metastatic prostate cancer to various organ locations using the Cbioportal database. C4-2B prostate cancer cells were grown and stimulated to express membrane ɑVβ3 by treatment with recombinant human CXCL12. The cell membrane from these cancer cells were used to coat polymeric nanoparticles by an extrusion process. Physico-chemical optimization and characterization of the P-BiNPs was performed. In vitro testing was done with flow cytometry and MTT assays. A murine model was used with high resolution near infrared imaging to identify nanoparticle localization. Results: Analysis of RNAseq from mCRPC samples (n = 118) identified ITGB3 as increased in bone metastatic lesions compared to metastases from other sites (P < 0.0001). ITGB3 is a subunit of integrin ɑVβ3 and was selected as a target for enhancement to improve P-BiNP homotypic targeting and bone localization. After optimization, P-BiNPs showed optimal physico-chemical characteristics for drug delivery. Both in vitro testing and in vivo testing showed the P-BiNPs to be superior in homotypic uptake and localization to the bone. Conclusions: This platform of identifying clinically relevant targets for dual homotypic and bone targeting has potential as a strategy for treatment and imaging modalities in cancers that affects the bone as well as implications for delivering nanoparticles to other organs of interest.
Real-world application of next generation sequencing to guide therapeutic options in lymphoma.
Authors: Tokaz Molly , Scott Anthony , Shango Maryann , Devata Sumana , Carty Shannon , Chinnaiyan Arul , Kaminski Mark , Phillips Tycel Jovelle , Wilcox Ryan A. 
Published: May 2019

e14645 Background: Despite the increasing availability of targeted and novel therapies, successful treatment of many relapsed/refractory lymphomas remains a challenge. Tumor sequencing is becoming an increasingly available technique to identify potential therapeutic targets; however, there remains considerable uncertainty about the successful application of this data in a “real world” clinical setting. Methods: Herein, we describe 91 lymphoma patients who underwent DNA & RNA sequencing of tumor biopsies via the MIONCOSEQ protocol to identify actionable therapeutic targets. Their charts were reviewed for the clinical use of MIONCOSEQ recommendations. Results: Among the 91 patients were 13 Lymphoma subtypes. Most patients had Stage III/IV disease (68%) at diagnosis, underwent an average of 4 treatments before sequencing (range 0-16) and had approximately 47 distinct molecular alterations (range 2-447). Of the cohort, 60 patients (65%) had actionable targets identified of which 11 ultimately received treatment based on MIONCOSEQ recommendations. The remaining patients did not receive treatment due to multiple reasons: prior CR or on surveillance not requiring treatment (10); death (12); trial ineligibility (4); trial unavailability at the institution (8); patient preference for local treatment (6); and already on alternative treatments (9). Taken as a whole, sequencing late in the disease course and a lack of available clinical trials were identified as barriers for the incorporation of MIONCOSEQ data into clinical practice. Therefore, earlier sequencing and strategies to bolster the availability of targeted therapies may significantly increase the application of genomic data and precision medicine in clinical practice. Conclusions: While next generation sequencing (NGS) is a powerful tool for advancing precision medicine, meaningful clinical application of these results remains a challenge. Our study indicates that early sequencing and improved trial availability could be beneficial in increasing real-world therapeutic options for relapsed/refractory lymphoma. Further research is needed to determine the extent to which a personalized approach, informed by NGS data, improves outcomes.
Preclinical studies evaluate pivotal TNFα nanomedicine clinical trial design.
Authors: Nilubol Naris , Oarr David , Tamarkin Lawrence 
Published: May 2019

e14646 Background: The clinically-tested CYT-6091 nanomedicine is comprised of TNF alpha (TNF) bound to 27 nm pegylated gold nanoparticles. Preclinical research has shown that CYT-6091 disrupts solid tumor blood vessels, reduces interstitial fluid pressure and increases accumulation of follow-on chemotherapy in the tumor microenvironment. While systemic toxicity has limited treatment of cancer patients with TNF, isolated limb perfusion of patients with in-transit melanoma using 1-4 mg of TNF followed by chemotherapy has demonstrated up to 90% complete response rates with one treatment. In a single-agent, phase I clinical study in advanced-stage cancer patients, we found that multiple CYT-6091 treatments can systemically and safely deliver up to 1.2 mg of TNF per dose. Methods: Our current research was conducted to validate administering CYT-6091 prior to standard-of-care chemotherapy in a phase II clinical trial. As part of the NCI’s Experimental Therapeutics (NExT) evaluation, CYT-6091 was studied in combination with paclitaxel (PTX) in C57BL/6 murine xenografts, using three cancer cell lines: MC-38 colon carcinoma (cancer cells sensitive to TNF, but insensitive to PTX), B16/F10 melanoma (cancer cells insensitive to TNF, but sensitive to PTX), Lewis lung carcinoma (cancer cells insensitive to both TNF and PTX), where sensitivity was based on inhibiting cancer cell growth at the studied dosing amounts and frequency. CYT-6091 was administered 3-hours before PTX, and three PTX doses were administered in each model. Results: In every model, CYT-6091 + any dose of PTX was more effective in reducing or controlling tumor growth than the highest dose of PTX alone (p < 0.01). Interestingly, we also found that CYT-6091 alone demonstrated significant anti-cancer activity (p < 0.01), suggesting that additional studies may be warranted to determine optimal frequency and dose of CYT-6091 as a single agent. Conclusions: These preclinical studies demonstrate for the first time that CYT-6091 + PTX was superior to PTX (p < 0.01) or CYT-6091 alone (P < 0.05) in TNF insensitive cell lines, which represent the majority of cancers. Findings support systemically administering CYT-6091 plus standard-of-care chemotherapy in a pivotal clinical trial.
Molecular characterization of trophoblast cell surface antigen 2 (Trop-2) positive triple negative breast cancer (TNBC).
Authors: Khoury Katia , Feldman Rebecca , Pohlmann Paula Raffin , Heeke Arielle Lutterman , Gatalica Zoran , Veloso Yvonne , Vidal Gregory A. , Schwartzberg Lee S. , Swain Sandra M. , Isaacs Claudine , Lynce Filipa 
Published: May 2019

e14651 Background: Trop-2 is a glycoprotein found in various carcinomas, known to play a role in tumor development and progression. A humanized antibody drug conjugate (ADC) targeting Trop-2 for delivery of the topoisomerase-I (TOPO1) inhibitor SN-38 (payload) is currently in clinical development for TNBC. Clinical response in a previously reported phase I/II study was associated with Trop-2 immunohistochemistry (IHC) staining intensity (Bardia A et al. J Clin Oncol 2017). Herein we investigated the prevalence of Trop-2 expression in an unselected cohort of TNBC tumors, and the association with other markers of interest that could suggest novel drug combinations. Methods: A cohort of 68 TNBC specimens with available archival tumor submitted to Caris Life Sciences were tested via protein expression (IHC) for Trop-2 with dichotomous categorization for results. Positivity required at least 10% of tumor cells to be stained, with an intensity of 1+ (weak), 2+ (moderate) and 3+ (strong), with same cutoff used in ongoing clinical trials of Trop-2 ADC. Comprehensive molecular profiles were performed using 592-gene next generation sequencing (average read depth 500X). Chi-square tests were used for statistics. Results: The median age in this cohort was 54 (range: 28-90). 38 (56%) tumors were positive for Trop-2. There was no difference in age distribution between Trop-2 positive and negative tumors. Trop-2 expression was present in 48.6% (17/35) and 63.6% (21/33) of primary and metastatic sites, respectively. TOPO1 by IHC was negative in 11 (29%) of Trop-2 positive tumors. Trop-2 expression was inversely associated with PIK3CA and RB1 mutations (p = 0.012 and 0.011, respectively). There was no difference in PDL1 expression by IHC, tumor mutational burden (TMB), BRCA1/2 or other homologous recombination deficiency gene mutations between Trop-2 positive and negative tumors. Conclusions: In a cohort that used the same cutoffs in ongoing trials with Trop-2 ADC, we found a lower prevalence of Trop-2 positivity in TNBC than what has been previously reported. One third of Trop-2 positive tumors were TOPO1 negative which may have treatment implications given the pharmacology of ADC currently in development.
Meta-analysis of toxicity data in thoracic and abdominal malignancies from: Clinical trials in tumor treating fields.
Authors: Vergote Ignace , Rivera Fernando , Pless Miklos , Ceresoli Giovanni L. 
Published: May 2019

e14658 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antimitotic treatment modality, which has been approved for the treatment of glioblastoma (GBM) by the FDA. Mild-moderate localized dermatitis was reported in 52% of newly diagnosed GBM patients treated in the EF-14 [NCT0091640] phase 3 trial (with only 2% having Grade 3 skin toxicity). The toxicity of TTFields has been investigated in a number of pilot studies for malignancies located outside of the brain, and here we present a meta-analysis of toxicities reported in them. Methods: A total of 192 patients from four pilot clinical studies in the following malignancies were included: Advanced lung cancer, advanced pancreatic cancer, pleural mesothelioma and recurrent ovarian cancer. All patients received chemotherapy in addition to TTFields. Adverse events (AEs) and their association with the treatment were evaluated using CTCAE Criteria. Toxicities were reported as incidence by body system and MedDRA term out of the number of patients who received any amount of TTFields treatment. Results: The median age of patients was 63 (range: 44-78), 73 (49-81), 67 (27-78) and 60 (45-77) for EF-15 [NCT00749346], PANOVA [NCT01971281], STELLAR [NCT02397928] and INNOVATE [NCT02244502], respectively. The incidence of several low grade gastrointestinal (GI) toxicities was ≥5%: constipation (16%), diarrhea (14%), nausea (27%), vomiting (13%). None of the GI toxicities was associated with TTFields. Low grade general disorders such as asthenia (12%) and fatigue (18%) were common but not associated with TTFields. The incidence of arrhythmias was ≤2%. 58% of the patients had dermatological AEs, but only 6% had grade 3 dermatitis. 9% of patients had low grade pruritus. Conclusions: No new safety signals associated with TTFields were identified in this meta-analysis. The incidence of TTFields-related skin toxicity was similar to that reported in glioblastoma patients. The application of TTFields to the torso is safe. Clinical trial information: [NCT00749346], [NCT01971281], [NCT02397928], [NCT02244502].