bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined use of albumin and neutrophil-to-lymphocyte ratio as new prognostic and predictive factor in patients with poorly differentiated neuroendocrine carcinomas.
Authors: Colombo Elena , Manca Paolo , Bini Marta , Bottiglieri Achille , Massa Giacomo , Prinzi Natalie , Torchio Martina , Niger Monica , Corti Francesca , Prisciandaro Michele , Zattarin Emma , Proto Claudia , Garassino Marina Chiara , Milione Massimo , Cattaneo Laura , Di Bartolomeo Maria , Platania Marco , De Braud Filippo G. , Lo Russo Giuseppe , Pusceddu Sara 
Published: May 2020

e15543 Background: Outcomes of patients affected by advanced neuroendocrine carcinomas (NEC) with Ki-67 labeling index > 55% are heterogeneous regardless of the primary tumor site. We explored baseline inflammatory indexes and serum albumin levels to identify markers of response to standard first line chemotherapy. Methods: We retrospectively identified patients with advanced NEC treated with cisplatin (CP) or carboplatin (CB) and etoposide between 2015 and 2019 at the National Cancer Institute of Milan. Linear and Cox regressions were used to investigate, respectively, numeric and time-to-event outcomes. Maximization of log-rank statistics was used for optimal cutoffs finding. An artificial intelligence algorithm, random forest, was used to rank the impact of different clinical features on OS and PFS. Results: A total of 81 consecutive patients with different primary tumors (53 small cell lung carcinoma, 12 large cell neuroendocrine carcinoma, 10 gastrointestinal neuroendocrine carcinoma and 6 Merkel cell carcinoma) either treated with CP (n = 39) or CB (n = 42) were analyzed. Overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were, respectively, 50.6%, 5.5 months (m) and 9.1m. Considered together, high serum albumin (SA > 3.5 g/dl) and low neutrophile-to-lymphocyte ratio (NLR < 3.59) identified a group of patients (n = 42) with longer median PFS and OS compared to the rest of the cohort (8.3m vs 1.5m, HR 3.58, CI 2.14-6.02, p < 0.001 for PFS and 12.6m vs 4.4m, HR 3.11, CI 1.88-5.18, p < 0.001 for OS); within this group a higher ORR (74% vs 36%, OR 5.01, CI 1.83-14.64, p = 0.002) was observed. Two multivariate models showed statistically significant associations of SA and NLR with PFS ( p = 0.017 and p = 0.005) and OS ( p = 0.016 and p = 0.036), independent of baseline ECOG performance status, age, sex, body mass index, smoking status, stage, hepatic tumor burden, primary site, histology, lactate dehydrogenase (LDH) serum levels, type of platinating agent and number of cycles. Two random forest models ranked SA, NLR and LDH as the most important factors for PFS and OS prediction. Conclusions: In the setting of advanced NEC with Ki-67 > 55% the combined use of SA and NLR identified two groups of patients with remarkably different outcomes, suggesting that these serum markers at baseline may have prognostic implications and be predictive of response to platinating agents. Prospective studies should validate these preliminary findings.
Whole genome SNP arrays for best practice for detection of diagnostic, prognostic and therapy related copy number changes and copy neutral-loss of heterozygosity across solid tumors and hematologic malignancies.
Authors: Lennon Patrick Alan , Raca Gordana , Fang Min , Wolff Daynna , Li Marilyn M. , Iqbal Anwar M. , Levy Brynn , Schwartz Stuart , Dubuc Adrian M. 
Published: May 2020

e15575 Background: High resolution single nucleotide polymorphism (SNP) chromosomal microarrays (CMA) detect copy number changes and copy neutral-loss of heterozygosity (CN-LOH) across the entire genome, currently providing the best assessment for these types of genomic variants. Chromosomal microarrays are first tier tests utilized in the postnatal detection of microdeletions, microduplications and uniparental disomy/regions of homozygosity in constitutional disorders involving congenital abnormalities, developmental delay and intellectual disability. Methods: In the oncology setting, aberrations detected may be diagnostic, prognostic, and therapeutic. Because CMA assesses the entire genome and can readily detect aberrations as small as a single exon to as large as a whole chromosome, this is an important clinical tool to bridge the gap between low resolution of metaphase chromosome analysis and PCR-based short read sequencing-based assays. Results: No single genomic technique (metaphase chromosome analysis, FISH, CMA or Next Generation Sequencing, including large targeted gene panels) has the ability to detect all relevant information. Therefore, CMA should be considered an important clinical tool for solid and liquid tumors. Across a wide variety of solid tumors, whole genome assessment (including oncogene amplification, tumor suppressor loss, and copy number burden) leads not only to possible therapy targets but also to opportunities for participation in active clinical trials. Recently, the Cancer Genomics Consortium has published evidenced-based reviews on the clinical utility of CMA for copy number and CN-LOH assessment in a variety of hematologic malignancies, and similar papers in solid tumors are in review. Recognizing the growing evidence for CMA, the American Medical Association (AMA) CPT editorial board recently created a new Tier 1 test for cytogenomic arrays in neoplasia, and Centers for Medicare and Medicaid Services (CMS) approved crosswalking the price of the new code to the well-established constitutional cytogenomic array CPT code. Conclusions: For this presentation, examples of diagnostic, prognostic, and therapeutic utility and inclusion in clinical trials across many hematologic and solid tumor neoplasms will be presented to demonstrate the efficacy, cost effectiveness and sensitivity of whole genome assessment of copy number and copy neutral loss of heterozygosity
Targeted PCR vs NGS for molecular diagnostic in solid tumors and liquid biopsies. How to choose in real-life.
Authors: Merlin Jean-Louis , Gilson Pauline , Husson Marie , Harle Alexandre 
Published: May 2020

e15576 Background: Molecular diagnostic is now part of routine diagnosis in many solid tumors and multiple technical options are available from extensive sequencing (NGS) to fully-automated targeted PCR (FAPCR). Tumor tissue testing is the gold standard, liquid biopsy is becoming a valuable option. Methods: 417 FFPE tumors, and 28 liquid biopsies were analyzed from 233 non small cell lung cancer (NSCLC), 177 colorectal cancer (CRC), 35 melanoma (MEL) in an ISO 15189 certified, French NCI molecular genetics platform. FAPCR analyses were performed individually, every day, using CE-IVD kits for the exclusive analysis of KRAS, NRAS, BRAF and EGFR mutations in NSCLC, CRC and MEL. NGS analyses were performed weekly as 12 or 24 sample runs using custom multiple gene panel capture sequencing. In all cases, prior to analysis, the specimens were macrodissected to warrant tumor cell content > 10% after examination of hematoxylin eosin stained slide by a pathologist. For liquid biopsy, cfDNA was extracted within 3 days from blood samples collected in cfDNA BCT tubes and analyzed using CE-IVD EGFR mutation kits. Time to results was recorded from registration of the specimen to validation of the results. Results: All FFPE tumors were analyzed using either FAPCR (N = 321) or NGS (N = 110) according to the clinician choice. Less than 2% of samples were not analyzable because of tumor cell content < 10% or degradated DNA. Median time to results was 6 days for FA-PCR (range 1-19) and 18 days for NGS (range 7-28). No significant difference was observed between NSCLC, CRC and MEL. Most cases of delay > median were related to pre-analytical defects and the need for a second specimen. For liquid biopsies, time to result was 6 days (range 1-18). The mutation rates were respectively, 13% for EGFR in NSCLC, 57% for KRAS/NRAS/BRAF in CRC and 69% for BRAF/NRAS in MEL. Using NGS led to the identification of additional molecular targetable alterations that were not analyzed by FAPCR in 44% of NSCLC, 22% of CRC and 14% of MEL. Among the 28 liquid biopsies analyzed mostly at progression under anti-EGFR TKI, EGFR mutations including T790M, were detected in 61% of the cases. Conclusions: Independently of cost-effectiveness, using PCR reduces time to results and can accelerate the initiation of targeted therapy but restricts the range of analysis, while extensive NGS delays time to results but identifies additional biomarkers that could be useful for therapeutic stratification. Using liquid biopsy testing could be an alternative and allow dynamic molecular diagnostic at 1st line and during follow-up.
NGSCUP: Phase II trial of site-specific treatment based on gene expression and mutation profiling by next generation sequencing (NGS) for patients (pts) with cancer of unknown primary site (CUP).
Authors: Hayashi Hidetoshi , Takiguchi Yuichi , Minami Hironobu , Akiyoshi Kohei , Segawa Yoshihiko , Ueda Hiroki , Iwamoto Yasuo , Kondoh Chihiro Nakayama , Matsumoto Koji , Takahashi Shin , Yasui Hisateru , Sawa Toshiyuki , Onozawa Yusuke , Chiba Yasutaka , Togashi Yosuke , Sakai Kazuko , Fujita Yoshihiko , Tomida Shuta , Nishio Kazuto , Nakagawa Kazuhiko 
Published: May 2020

e15577 Background: Although gene profiling is a promising diagnostic technique to determine the tissue of origin for pts with CUP, we reported that site-specific treatment based on gene profiling using microarray did not result in an improvement the survival compared with empirical therapy in the previous randomized phase 2 trial (Hayashi, et. al, JCO 2019). Recently, we have established new integrative diagnostic system combined the gene expression from RNA-sequencing and mutation/copy number variation data from targeted genomic-sequencing using NGS. We have performed a single-arm phase 2 study to assess the efficacy of site-specific therapy determined by this system in previously untreated pts with CUP. Methods: Comprehensive gene profiling was performed by NGS, and an established algorithm was applied to predict tumor origin. Pts with CUP was received site-specific chemotherapy determined by the predicted site. The primary endpoint was one-year survival rate. Results: A total of 111 pts was enrolled and all had sufficient biopsy tissue for gene profiling. Efficacy analysis was performed for 97 pts who received site-specific treatment. Cancer types most commonly predicted were lung (21%), liver (15%), kidney (15%), and colorectal cancer (12%). The one-year survival rate, median overall survival (OS), and progression free survival (PFS) was 53.1% (95%CI, 42.6-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Median OS (15.7 versus 11.0 months, P = .078) and PFS (5.5 versus 2.8 months, P = .019) were better for predicted tumor types categorized as more responsive types than for less responsive ones. Conclusions: Site-specific treatment based on NGS demonstrated promising efficacy. Pts with CUP predicted to have more responsive tumor types had longer survival compared with pts with less responsive tumor types, suggesting that molecular tumor profiling by both DNA and RNA testing contributes to the management of pts with CUP. Clinical trial information: UMIN051180009.
A new model to prognosticate man breast cancer in China.
Authors: Liu Yunjiang , Zhang Shuo , Liu Yueping , Song Chao , Wang Ning , Tang Jiyu , Zhou Meng-Li , Chen Ming-Shuo , Cheng Skye Hung-Chun 
Published: May 2020

e15579 Background: Male breast cancer is rare, and much of our understandings in this disease is still extrapolated from data in women with breast cancer. However, it has been suggested that male breast cancer may exist different etiology and biology from female by comparing the results of 21-gene Breast Recurrence Score (RS). However, the patient cohorts of these studies involved mainly patients being identified as Caucasian. Racial and ethnic disparities exist in genetic and biological factors that could influence the disease. A new model RecurIndex, based on a genomic database from RNA expression of Asian patients predominantly, is mainly developed for predicting the distant metastasis (DM) in female Breast cancer patients. We aim to validate whether this model can prognosticate male breast cancer in China. Methods: A total of 23 male patients with breast cancer were enrolled in a retrospective study in the single medical center. Kaplan-Meier survival curves was used to calculate the survival rate. The primary endpoint was relapse free survival (RFS)。Differences between male and female patients in terms of individual mRNA expression level were also determined. Results: Among the 23 patients enrolled in this study, Recurindex classified 11 patients as low risk 12 patients as high risk in distant metastasis respectively. When the low- and high-risk groups according to the Recurindex results were compared, there were only significant different in lymph node stage among individual clinical factors. 16 Patients with follow-up information which were stratified in DM low risk group have higher survival probability than high risk group. Mean quantitative gene expression of Recurindex signatures comparison between 16 men and 267 women patients reveals gene expression differences in numbers of gene. Conclusions: Based on genetic profiling assay specific designed for Asian population, the current study exhibits some different genetic features of male breast cancer. Our multigene signatures may also be utilized by male patient.
A functional precision medicine 3D microtumor platform to identify and personalize novel indications.
Authors: Apfel Christian , Chen David , Baratta Juliana , Mishra Dhruva K. 
Published: May 2020

e15588 Background: We have previously validated our 3D microtumor platform that captures the tumor heterogeneity of a patient's primary tumor biopsy using a patient-derived xenograft model (Nikolov et al. ASCO 2019, e17076). Here we describe its utility to identify FDA approved therapies that may be effective for tumors previously not considered. Methods: A fresh tumor sample of a liver metastasis of a 45-year-old colorectal cancer patient was shipped overnight and processed to create hundreds of live 3D microtumors. These microtumors were treated with a panel of 12 commonly used drugs including chemotherapies and targeted therapies. Treatment effects were quantified and validated on fresh and cryopreserved/thawed samples using our metabolic and proprietary multiplexed fluorescent staining technologies to quantify the ratio of live and dead cells in those microtumors. Results: None of the conventional treatments in the 12-panel drug test suggested any efficacy as determined by the log of efficacy concentrations (in µmol/l): Oxaliplatin 2.59, 5-FU 3.00 (upper cut-off value), paclitaxel 1.72, topotecan 3.00, irinotecan (SN-38) 2.33, gemcitabine 2.44, and bevacizumab 3.00. The microtumors also appeared resistant to several targeted therapies that are not commonly given, ranging from 1.85 to 2.44. However, abemaciclib had an efficacy of 0.49, which was confirmed on thawed samples with all drug efficacy concentrations again suggesting resistance, except for abemaciclib at 0.67. Conclusions: Our 3D microtumor platform may be a useful tool a) to identify rescue treatment options for metastatic patients that have multi-resistant tumors and b) to identify novel indications to personalize FDA-approved cytotoxic or targeted therapies as a companion diagnostic.
NRG1 fusion-driven cancers: A systematic literature review and meta-analysis.
Authors: Stalbovskaya Viktoriya , Wasserman Ernesto , Fryzek Jon , Bylsma Lauren C , Sirulnik L. Andres 
Published: May 2020

e15605 Background: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Methods: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Results: Out of 212 articles identified in the literature as of 31-Jul-2019, 37 met the inclusion criteria and were abstracted. 13 different tumor types were identified as harboring NRG1 fusions including 5 tumor (sub)types which met the criteria for frequency meta-analysis (Table 1). NRG1 fusions were most frequent in pancreatic adenocarcinoma (3.3%, 95% confidence intervals (CI): 0.3-28.7%; apparent enrichment in KRAS WT) and NSCLC (0.8% 95% CI: 0.3-2.7%) with an enrichment in invasive mucinous adenocarcinoma (9.8%, 95% CI: 4.7-19.6%). Statistically significant heterogeneity was observed indicating substantial variation across studies in each analysis. For tumor types that did not meet the criteria for meta-analysis (uterine, renal cell, ovarian, colorectal, head and neck, bladder, prostate and sarcoma) the reported frequency of NRG1 fusions was typically less than 1%. Conclusions: NRG1 fusions are present across a wide range of different solid tumor types, most frequently in NSCLC and PDAC. NRG1 fusion-driven cancers represent a potential tumor-agnostic therapeutic target. The advent of new treatment options and increased genomic testing will allow a more precise estimation of the frequency of NRG1 fusions in cancer. [Table: see text]
The AVI-PDX: An innovative in vivo platform of miniaturized patient-derived xenografts for preclinical developments and personalized medicine.
Authors: Berget Frédéric , Costechareyre Clélia , Jarrosson Loraine , Delloye-Bourgeois Céline , Castellani Valerie 
Published: May 2020

e15607 Background: The conception of preclinical paradigms to predict the patient response is a major goal for the development of novel therapies and the design of personalized treatments in oncology. Patient-Derived Xenograft (PDX) mouse models require tumoral material in significant amount, not always compatible with practiced biopsies, are limited by a very low tumor intake rate, and a long delay to obtain exploitable tumors. Moreover, xenografts in mice are usually performed subcutaneously, thus in a tissue irrelevant regarding microenvironmental specificities. Finally, these models are not scaled for global molecular analysis to uncover biomarkers of patient heterogeneity and response to treatments. Apart from shortening tumor formation, alternatives of grafting tumoral cells on the chicken chorio-allantoid membrane (CAM model) bare all inconvenient of mice models Methods: We have developed an innovative in vivo technological platform, consisting in (i) grafting tiny human tumoral samples within tissues of chicken embryos, selected for their homology to primary or metastatic sites, (ii) administrating therapeutic treatments, (iii) analyzing tumor responses using 3D imaging and identifying treatment-specific molecular signatures. Results: Originally conceived for a pediatric cancer (Delloye-Bourgeois et al, 2017), the platform was next adapted to a range of adult cancers. Grafted cells from patient samples exhibited exceptionally fast and efficient rate of tumor ingrowth, and replicas retained molecular features of the initial sample. The platform is already exploited for the identification of novel therapeutic targets, the evaluation of candidate therapies efficacy, the design of combination of therapies and the characterization of molecular signatures in several cancer indications, including germ line tumors, neuroblastoma, pancreatic cancers, triple negative breast cancer and melanoma. Conclusions: Overall, this breakthrough technology should considerably improve and shorten the process of molecule discovery and accelerate access of novel therapies to patients.
Molecular mechanism(s) of resistance to vandetanib in medullary thyroid carcinoma.
Authors: Glassberg Brittany , Khan Sophia , Pemov Alex , Hawley Robert , Widemann Brigitte C. , Khan Javed , Glod John 
Published: May 2020

e15628 Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid. Pediatric cases of this cancer are associated with the diagnosis of multiple endocrine neoplasia, which is caused by a mutation in the rearranged during transfection ( RET) gene. Vandetanib, an oral receptor tyrosine kinase inhibitor, is approved for the treatment of patients with progressive MTC. While there is a response rate of 50%, the majority of patients eventually develop resistant disease. The goal of this work is to understand genetic and epigenetic underpinnings of sensitivity and resistance to vandetanib, and develop novel synergistic combination therapies in medullary thyroid carcinoma. Methods: The TT cell line (RET mutation p.C634W) was cultured in increasing concentrations of vandetanib in order to generate a vandetanib resistant cell line. Both vandetanib-sensitive and vandetanib-resistant lines were evaluated. Each line underwent exome sequencing, RNA sequencing, and methylation array analysis. In parallel we performed Genome-wide CRISPR knock-out and CRISPR activation of both cell lines using the TKO Version 3 Library, consisting of 71,090 gRNAs targeting 18,000 genes, and the Calabrese P65-HSF activation Library, using 56,762 guides for 18,000 genes. Results: Both whole exome and RNA sequencing demonstrate increased expression of RET C634W in both cell lines, to a significantly greater extent in the drug-resistant line than in the sensitive line. RNA sequencing demonstrates differential expression of transcripts between the vandetanib-sensitive and vandetanib-resistant cell lines, including multidrug-resistance 1 (which confers drug resistance in other cancers) and autotaxin (promotes cell survival). Genome-wide CRISPR knock-out showed enrichment of genes necessary for growth suppression by vandetanib, including MACROD2, GORASP2, and MAP3K genes. Gene set enrichment analysis of the CRISPR knock-out data showed enrichment of the proteasome pathway as a potential candidate of growth suppression by vandetanib, which was validated via exposure of the cell lines to bortezomib (IC50 = 3.62nM), a molecularly targeted proteasome-inhibitor. Conclusions: DNA mutations and epigenetic modification confer resistance of medullary thyroid carcinoma to tyrosine kinase inhibition. Adding further therapeutic agents to target these genetic alterations is a potential strategy for overcoming resistance.