bluuebunny/crossref_metadata_2025 huggingface dataset:
The ACC melanoma pilot project: “Real-world” evaluation of an NGS platform for molecular characterization of melanoma in Italy.
Authors: Molineris Ivan , Levati Lauretta , Berrino Enrico , D'Atri Stefania , Menin Chiara , Madonna Gabriele , Bulgarelli Jenny , Ghiorzo Paola , Ferraresi Virginia , Venesio Tiziana , Rivoltini Licia , Rodolfo Monica , Lanfrancone Luisa , Mazzarella Luca , Guida Alessandro , Pelicci Pier Giuseppe , De Maria Ruggero , Ascierto Paolo Antonio , Medico Enzo , Russo Giandomenico ,   Alliance Against Cancer-Working Groups: Melanoma, Genomics, Pathology
Published: May 2019

e14600

Background: Alliance Against Cancer (ACC), the network of Italian Cancer Centers, is involved in designing targeted NGS panels to enable sequencing a significant number of therapeutically actionable genes from FFPE tissue samples at the cost of a routine molecular diagnostic test (RMT). In this retrospective study we used the ACC oncochip v.1 on a cohort of stage III-IV metastatic melanoma patients, with the aim of: a) validating the diagnostic use of this oncochip in comparison with RMTs for BRAF mutation detection; b) evaluating how many additional actionable gene mutations can be identified per patient; c) evaluating possible associations between mutational profiles and outcome. Methods: DNA was extracted from 120 FFPE samples from 9 Italian hospitals previously profiled for BRAF status with a RMT, and matching germline samples. 60% of the patients underwent immunotherapy and 40% targeted therapy, with an overall survival ranging from few days to several years. 10-20 ng of DNA were profiled with the amplicon-based ACC Oncochip v.1, that covers ~700 Kb, including the full coding sequence of 182 genes. Samples were sequenced in a Ion Torrent S5 instrument (ThermoFisher), and mutational profiles were generated with the Ion Reporter software. Results: Adequate coverage of the BRAF codon 600 hotspot was reached in 99% of the samples, and BRAF status was 95% concordant with previous RMTs. In 4/6 discordant cases, BRAF V600 mutations were only detected by NGS (with VAF below 10%); in the remaining two cases NGS did not confirm mutations detected by RMT, possibly due to tumor heterogeneity. In accordance with TCGA data, BRAF was mutated in 55% of patients, NRAS in 23% and NF1 in 13%, with almost complete mutual exclusivity; moreover 86% of triple negative patients showed mutations in other actionable genes. We also observed great variability in mutational load, ranging from ~3 to > 500 somatic mutations per Mb; correlation between mutational profiles and clinical outcome is underway. Conclusions: The ACC Oncochip v.1 NGS panel is accurate and affordable, providing a comprehensive mutational profile for the cost of a RMT and allowing a precision medicine approach to melanoma diagnosis and identification of actionable mutations.
Validation and utilization of NGS based HEMEaccuTest panel and analysis software for hematological malignancies.
Authors: Choi Hyun-Jeung , Lee In-seon , Lee Min Kyoung , Im Ji-Eun , Jung Kyongyong , Lee Keunsook Kathy , Moon YoungJoon , Kim Kwang Joong
Published: May 2019

e14606

Background: Hematological malignancies are forms of cancer that originate in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Hematological malignancies can be classified as leukemias, lymphomas, multiple myeloma (MM), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) based on the cell type where they originate. Detection of genetic alteration in hematological malignancies is increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is an advanced technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related for clinical diagnostics. Methods: We developed the targeted NGS panel, HEMEaccuTest and automatic analysis software, NGeneAnalySys for estimating the relative pathogenicity of hematological malignancies. HEMEaccuTest covers about the 310 kilobases with exon regions of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. the diagnostic utility of the panel and software were validated using genotype-known reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600x and a minimum coverage depth of 100x. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity and specificity of the panel were high in a comparison to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by an excellent simulating algorithm of NGeneAnalySys. Conclusions: This analytical validation demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent tool for disease definition and therapeutic strategy in hematological malignancies.
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].
Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform.
Authors: Bindra Ranjit , Sundaram Ranjini K , Aiello Robert J , Marshall Dan , Bourassa Patricia , Csengery Johanna , Zhang Qing , Robinson Brett , lopresti-Morrow Lori , Bechtold Jane , Tylaska Laurie , Paradis Tim , Paralkar Vishwas , Hellsund Per , Glazer Peter
Published: May 2019

e14664

Background: Poly(ADP-ribose)polymerase inhibitors (PARPi’s) are a promising new class of anti-cancer agents, but their clinical application has largely been limited to tumors with homologous recombination deficiency (HRD), such as those with BRCA1/2 mutations. One strategy to target HRD-negative tumors with PARPi’s is to combine them with chemotherapy, although clinical trials indicate that dose-limiting toxicities are a major barrier to achieving synergistic efficacy with these combinations. Methods: We sought to test the hypothesis that HRD-negative cancers can be effectively treated with tumor-targeted PARPi’s in combination with chemotherapy, using our recently developed alphalex platform. This platform allows small molecule anti-cancer agents to penetrate cell membranes only at the low pH associated with the tumor microenvironment and tumor cells, directly delivering drugs to tumors while sparing normal tissue. We tested whether alphalex PARPi-conjugates in combination with chemotherapy could selectively kill cancers independent of HRD status, using a range of in vitro and in vivo tumor models. Results: We conjugated a diverse range of structurally unique PARPi’s using the alphalex platform, and demonstrated that these molecules are delivered directly into tumor cells in a pH-dependent manner. We observed significant reductions in PARylation activity and exquisite synergy with DNA damaging agents in vitro. We then demonstrated that alphalex-PARPi conjugates in combination with both temozolomide (TMZ) and irinotecan induce significant tumor cell killing in HRD-negative tumors in vivo. Importantly, we found that our tumor-targeting approach significantly reduced normal tissue toxicity, with almost complete sparing of the bone marrow relative to TMZ alone. Conclusions: The alphalex platform enables PARPi combinations with clinically relevant chemotherapies, as a means to target HRD-negative cancers without significant bone marrow toxicity. Based on these successful proof-of-concept data, we are now performing IND-enabling studies for an alphalex PARPi conjugate (CBX-11), and we anticipate initiating a Phase I clinical trial in January 2020 in solid tumors independent of HRD status.
A general approach to optimizing tumor treating fields therapy.
Authors: Bomzon Zeev , Urman Noa , Hershkovich Hadas Sara , Kirson Eilon David , Naveh Ariel , Shamir Reuven , Federov Eduard , Wenger Cornelia , Weinberg Uri
Published: May 2019

e14668

Background: Tumor Treating Fields (TTFields) are alternating electric fields used to non-invasively treat cancer. TTFields are delivered via transducer arrays placed on the skin close to the tumor. Post-hoc analysis [1] has shown that delivering higher field power to the tumor and increasing usage (percent of time patient is actively treated) improve patient survival. Thus, optimizing the position of arrays to maximize TTFields power at the tumor could improve survival. At the same time, minimizing the array area to maximize patient comfort and consequently maximizing usage is also likely to improve survival. However, optimizing TTFields delivery is non-trivial since the field distribution is influenced by array positioning and geometry, the anatomy of the patient and the heterogeneous electric properties of different tissues. Here we present a general approach to optimizing Tumor Treating Fields using numerical simulations. Methods: Delivery of TTFields to the brains, lungs and abdomens of realistic computational models was investigated. The effect of the transducer array size and position on the field distribution within the phantoms was analyzed, and an approach for optimizing TTFields delivery developed. Results: Field power is generally highest in the region between the arrays, with larger arrays generally delivering higher field power. Anatomical features such as bones, the spine or a resection cavity significantly influence the field within this region. A general approach to optimizing TTFields delivery is: Maximize field power by using the largest arrays possible. To maximize patient comfort, array size are chose so that significant portions of the skin in the region of disease are not covered by the arrays. Place virtual arrays on a realistic computational model of the patient such that the tumor is located between them and simulate TTFields delivery to the patient. Apply an iterative algorithm to shift the arrays around their initial positions until field power in the tumor bed is maximized. Conclusions: We have developed a general approach to optimizing delivery of TTFields to the tumor. Effective TTFields treatment planning is expected to improve patient outcome. [1] Ballo et. al., submitted to RED Journal 2018.
ABT-806 derived antibody drug conjugates (ADCs) inhibit growth of malignant mesothelioma in-vivo.
Authors: Chia Puey Ling , Cao Diana , Gan Hui Kong , Reilly Edward B. , Phillips Andrew , John Thomas , Scott Andrew Mark
Published: May 2019

e14677

Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have investigated an anti-EGFR antibody (ABT-806), which is tumor specific and robustly inhibits EGFR-expressing tumors. We have previously shown that ABT-806 ADCs demonstrate potent anti-tumor activity in 806 immunohistochemistry (IHC) positive MSTO-211H MM cell line xenograft model. We present data in MM using ABT-806 novel ADCs [ABT-414 (ABT-806- monomethyl auristatin F), ABBV-221 (ABT-806- monomethyl auristatin E) and ABBV-321 (ABT-806- pyrrolobenzodiazepine)] in MM patient derived xenografts (PDX). Methods: We evaluated expression of EGFR and mAb 806 IHC in MM cell lines and PDXs. PDXs were implanted into 5 to 10 NOD-Scid mice per group and treated with control ADC, saline, cisplatin or ABT-806 ADCs and followed longitudinally with caliper measurements. Comparative statistics were performed in Graphpad prism. Results: Three PDX models were selected according to their 806 IHC statuses (2 epithelioid 806 IHC positive, 1 biphasic histology 806 IHC negative). In one epithelioid PDX model, ABBV-321 resulted in significantly reduced tumor growth on day 27 post therapy with median tumor volumes of 180 mm3 (ADC control) compared with 78mm3 (ABBV-321; p = 0.0159 two-sided). Moreover, the median survival was also significantly longer in ABBV-321 treated models (p = 0.018). In the other epithelioid PDX model, ABBV-321 also resulted in significant responses (median 428mm3 (ADC control) vs 167mm3 (ABBV-321, p = 0.0201). In the 806 IHC negative PDX model, the differences in tumor volumes between all groups were found to be non-statistically significant (ADC control vs ABT-414, ADC control vs ABBV-221, ADC-control vs ABBV-321 groups) with p = 0.0597 for one-way ANOVA. MSTO211H cell line xenograft model also demonstrated significant anti-tumor response to both ABT-414 and ABBV-221 (p < 0.01). Conclusions: In a disease with limited therapies, ABT-806 targeting ADCs in MM demonstrated significant responses in 806+ PDX and cell lines. These data support clinical expansion of these compounds in 806+ MM patients.
TrkA neurotrophin receptor and PI3K-Akt signaling involvement in cranial irradiation-induced memory deficit.
Authors: Ji Shengjun , Yang Ming , Yu Jinming
Published: May 2019

e14679

Background: This study aimed to investigate the role of neurotrophin receptor TrkA in cranial radiation-induced memory decline. Methods: Single dose of 10Gy 4MeV electron beam whole brain irradiation (WBI) was given to young male Sprague-Dawley rats (50–60g, day 21). 3 months after WBI, western blot was performed to detect protein level of TrkA and its downstream signaling molecules. The Morris water maze test was performed to evaluate the consequence of WBI on hippocampus-dependent memory formation. Immunohistochemistry was performed to evaluate the consequence of WBI on neurogenesis. For overexpression of TrkA, Adeno-associated virus were injected at the rate of 0.2μl/min (n = 15-20 per group). After that, Morris water maze test was performed again. Results: In Morris water maze test, WBI lead to notable memory deficit, the irradiation rats spent longer latency time than control rats (p < 0.05). In the spatial probe trial, the irradiation rats spent less time in the target quadrant than control rats (p < 0.05). Immunohistochemistry showed that cranial irradiation inhibited proliferation and neurogenesis in hippocampus. The protein level of TrkA expression decreased significantly at 3 months after irradiation compared with control group. Phosphorylation of PI3k, AKT, ERK1/2, CREB were also observed to be significantly inhibited (all p < 0.05). Next, we explored the irradiation-induced apoptotic signal transduction. The increased expression of JNK, caspase-3/9 and reduced expression of BCl2 confirm the irradiation induced apoptosis. After Adeno-associated virus injection, AAV-overexpression TrkA rats showed less escape latency time (p < 0.05) and spent more time (p < 0.05) in the target quadrant than AAV-irradiation rats, but still more escape latency time (p < 0.05) and spent less time (p < 0.05) in the target quadrant than AAV-control rats. Additionally, immunofluorescence staining showed AAV-overexpression-TrkA also rescued radiation-induced neurogenesis impairment Conclusions: TrkA may play a critical role in radiation-induced memory deficit, which indicate the data may have important therapeutic implications.
The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients.
Authors: Zhu Hong , Lin Quan , LI Yuping , Zhang Haoran , Ding Huaxin , Han-Zhang Han , Lin Jing , Xiang Jianxing
Published: May 2019

e14681

Background: BRAF mutations, occurring in 2-4% NSCLC patients, can be classified into 3 classes based on signaling mechanism and kinase activity: V600-mutant RAS-independent kinase activating monomers (class I), RAS-independent kinase activating dimers (class II) and RAS-dependent kinase inactivating heterodimers (class III). The association between functional classes and clinical features of Chinese NSCLC patients remain elusive. Methods: Sequencing data of either plasma or tissue samples obtained from 8,405 Chinese (Stage I-IV NSCLC) patients were retrospectively analyzed to screen for BRAF mutations. Of the patients with BRAF mutations, 79% (188/238) were diagnosed with adenocarcinoma,7.6% with squamous cell carcinomas (SCC) and the remaining patients were either adenosquamous carcinoma or large cell carcinoma. Results: BRAF mutations were detected in 238 patients, revealing a prevalence of 2.8%. Among them, 32% (75/238), 21% (51/238) and 13% (31/238) had class I, II and III mutations, respectively. The remaining 35% (81/238) had other BRAF mutations. V600 (32%, 75/238) and G469 (13%, 32/238) were the 2 most predominant mutations. BRAF mutations, when considered collectively, including non-class I-III mutations, were more likely to occur in males ( p< 0.01). However, class I mutations have a female predominance (p = 0.003); whereas, class II mutations showed a trend of male predominance (p = 0.09) and class III had no gender preference (p = 0.22). We also revealed no association between histology types and the class of BRAF mutations. Next, we investigated co-occurring classic lung cancer driver mutations in this cohort and revealed that patients with class II and III mutations were more likely to have concurrent KRAS mutations (p = 0.001). We also compared the overall survival (OS) of chemotherapy-treated patients and revealed comparable OS among the 3 groups. Conclusions: Our study revealed a 2.8% BRAF mutation rate in Chinese NSCLC patients. Our data also showed a male predominance when all BRAF mutations were considered collectively, and a female predominance for class I mutations. Furthermore, patients with BRAF V600E is less likely to have concurrent KRAS mutations.
The role of anticoagulants for the primary prophylaxis of venous thromboembolism in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials.
Authors: Barbarawi Mahmoud , Zayed Yazan , Kheiri Babikir , Gakhal Inderdeep , Barbarawi Owais , Bala Areeg , Alabdouh Ahmad , Abdalla Ahmed , Haykal Tarek , Goranta Sowmya , Bachuwa Ghassan , Katato Khalil
Published: May 2019

e14691

Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Despite this, pharmacologic prophylaxis for the primary prevention of VTE is not offered for most medical oncology patients, likely due to the competing risk of bleeding. Recent trials may offer new insight into the role of anticoagulants for the prevention of cancer associated thrombosis (CAT). Accordingly, we conducted a meta-analysis of randomized controlled trials (RCTs) that evaluated anticoagulants for the primary prophylaxis of VTE in cancer patients. Methods: A literature search of Pubmed/MEDLINE, Embase, and Cochrane library was done by two investigators. All RCTs that used anticoagulant in cancer patients for primary prevention of VTE were included. The primary outcomes were VTE events and all-cause mortality; VTE related mortality and major bleeding were secondary outcomes. A random effects model was used to report the risk ratios (RR) with 95% confidence intervals (CIs), and odds ratios (ORs) with Bayesian 95% credible intervals for both direct and network meta-analysis, respectively. Results: Twenty-four RCTs were included with a total of 13,338 patients (7,197 received anticoagulants and 6,141 received placebo). Of these trials, 19 used low-molecular weight heparin (LMWH), 3 used direct oral anticoagulants (DOACs), 2 used warfarin, and 1 used heparin. Mean age ranged between 54.6 to 68.1 years, with 50.5% male. Compared with placebo, LMWH or DOACs were associated with reduced VTE events (RR 0.58; 95% CI 0.48-0.69, p < 0.001) and (RR 0.39; 95% CI 0.24-0.63, p < 0.001), respectively. LMWH compared with placebo was associated with decreased VTE, and all-cause mortality (P < 0.05). While DOACs was associated with decreased PE events only compared with placebo (RR 0.28; 95% CI 0.11-0.71, P = 0.008). Regarding the safety outcome, LMWH and DOACs were associated with an increased risk of major bleeding compared with placebo, but this did not reach statistical significance in this study (RR 1.26; 95% CI 0.92-1.74, p = 0.16 and RR 1.76; 95% CI 0.83-3.73, p = 0.14). Results regarding VTE events and major bleeding were consistent in both lung and pancreatic cancers. Conclusions: Both LMWH and DOACs were associated with a lower number of VTE events compared with placebo. However, this potentially protective effect must be balanced against a possible increased risk of bleeding for some patients.
Direct oral anticoagulants (DOAC) versus warfarin and enoxaparin in ovarian vein thrombosis.
Authors: Covut Fahrettin , Kewan Tariq Zuheir , Perez Oscar , Awada Hassan , Babar Arslan , Thapa Bicky , Haddad Abdo S. , Spiro Timothy Peter , Daw Hamed
Published: May 2019

e14698

Background: Ovarian vein thrombosis (OVT) is a rare condition that is commonly associated with malignancy. Efficacy and safety profile of DOAC in OVT has not been compared with warfarin and low-molecular-weight-heparin in the literature. Methods: We reviewed patients who were diagnosed with OVT between 11/2012 and 1/2018 and had follow-up imaging with computed tomography to assess resolution of thrombus. The outcomes of interests were thrombus resolution, recurrent thromboembolic events, and 1-year cumulative incidence of clinically significant bleeding events. Cumulative incidence was calculated with death and discontinuation of therapeutic anticoagulation as competing risks. Results: We identified 36 patients, 17 (47%) had right, 14 (39%) had left, and 5 (14%) had bilateral OVT. Median age and body mass index at diagnosis were 47 (range: 25 - 86) and 28 (range: 19 – 43), respectively. At least one predisposing factor was identified for 32 (92%) patients, 16 (44%) had underlying active malignancy. Overall, 27 (75%) patients achieved complete or partial recanalization at follow up CT after median of 4 months (range: 1 – 13) from initiation of anticoagulation. Ten (28%) and 11 (31%) patients were treated with DOAC and warfarin after median of 3 and 2 days of anticoagulation with unfractionated heparin or enoxaparin, and follow up CT after median of 6 and 4 months showed complete/partial recanalization rates of 70% and 55%, respectively (p = 0.47). Whereas, 15 patients received enoxaparin and follow up CT after median of 3 months showed that 93% of patients achieved complete/partial recanalization (p = 0.12 between DOAC vs enoxaparin cohorts). Recurrent thromboembolic event has not occurred in any patient during median follow-up of 14 months (range: 3 – 71). One-year cumulative incidence of clinically significant any bleeding for DOAC cohort versus warfarin and enoxaparin cohorts was 10% (95% CI: 9 – 28) versus 18% (95% CI: 12 – 41), p = 0.64, and 25% (95% CI: 4 – 46), p = 0.42, respectively. Conclusions: Apixaban and rivaroxaban showed similar risk-benefit ratio as warfarin and enoxaparin, hence, they can be considered as alternatives for OVT patients.
Changes of estrogen receptor, progesterone receptor and HER2 expression in breast cancer with/without neoadjuvant chemotherapy or endocrine therapy.
Authors: Maeda Shigeto
Published: May 2019

e14699

Background: Concordance in hormone receptor and Human Epidermal Growth Factor Type 2 (HER2) status in breast cancer was observed between initial biopsy and surgical specimens. This study aimed to analyze the correlation in Estrogen receptor (ER), Progesterone receptor (PR) and HER2 status of the initial biopsy and surgical specimen in non-neoadjuvant therapy (CON), neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NAE). Secondary aim is to know the changed expression of ER, PR and HER2 as predictive marker for overall survival. Methods: We retrospectively analyzed 1265 surgical specimens from April 2007 to January 2018 in National Nagasaki Medical Center. Out of 1265 patients, 752 CON, 144 NAC and 28 NAE pairs of samples from initial core biopsy and surgical specimen were compared to the expression of the ER, PR and HER2 by immunohistochemically. Spearman’s rank correlation coefficient is calculated. Results: See table. Conclusions: ER and PR expression percentage is highly correlated between core needle biopsy and surgical specimen. After neoadjuvant chemotherapy, PR lost 8.2% after NAC and 40.8% after NAE. PR loss may become predictive marker after systemic therapy.[Table: see text][Table: see text]