tbuckley/cabot-search huggingface dataset:
OS4.3 Feasibility and benefit of Molecular Profiling to Guide Enrollment of Patients with Recurrent Gliomas in Early Phase Trials
Authors: C Baldini, N Younan, E Castanon Alvarez, R Bahleda, A Hollebecque, F Dhermain, S Ammari, A Alentorn, S Dumont, J Frenel, A Di Stefano, F Bielle, K Hoang-Xuan, J Delattre, J Soria, M Sanson, A Idbaih, C Massard, M Touat
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Participation of glioma patients in early phase clinical trials has recently shown to be safe, although clinical benefits reported in this population were marginal. We aimed to evaluate whether an enrichment strategy based on molecular profiling associates with improved outcome in gliomas patients participating in early phase trials. MATERIAL AND METHODS Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2017 were analyzed for clinicopathological characteristics, toxicity, response, median progression-free survival (PFS) and overall survival (OS). The primary objective was to evaluate the feasibility and benefit of using molecular profiling to guide enrollment. RESULTS Ninety-one patients were enrolled, of whom 47/91 (51.6%) were molecularly oriented. Molecular targets included IDH1/2 (n=15) and BRAF (11) mutations, FGFR1-3 fusions (n= 10) and mutations (n = 4), mismatch repair deficiency (8), and MDM2 amplification (1). Grade 3/4 adverse events were reported in 9/91 (9.9%) patients. In patients with IDH1/2-wild-type high-grade glioma (n=45), the overall response rate (24.0% [95% CI 11.5–43.4] vs 0.0% [95% CI 0.0–16.1], P=0.027) was significantly higher in molecularly-oriented vs non-molecularly-oriented patients. Updated outcome results, and clinical and molecular factors associated with response, PFS and OS in multivariate analyses will be presented at the conference. CONCLUSION Using molecular profiling to guide enrollment in early phase trials is feasible and offers potential benefit to gliomas patients. Further studies are warranted to identify the population most likely to benefit from this approach.
Retraction: MIG-7 Controls COX-2/PGE2-Mediated Lung Cancer Metastasis
Authors: Ming-Yi Ho, Shu-Mei Liang, Shao-Wen Hung, Chi-Ming Liang
Journal: Cancer Research (2019)

This article (1) has been retracted at the request of the editors. The editors were made aware of several concerns regarding potential manipulation of data in the article. An internal review by the editors and Academia Sinica (Taipei, Taiwan), the primary affiliation of the authors, determined that multiple Western blot bands were duplicated in Figs. 1A, 1B, 1C, 2B, 4A, and 4B. In addition, bioluminescence signals were duplicated and inappropriately manipulated to represent data from different mice in Fig. 6A.A copy of this Retraction Notice was sent to the last known e-mail addresses of the four authors. One author (Chi-Ming Liang) agreed to the retraction and three authors (Ming-Yi Ho, Shu-Mei Liang, and Shao-Wen Hung) did not respond.
Safety of intravenous (IV) NEPA and oral NEPA for prevention of CINV in patients (pts) with breast cancer (BC) receiving anthracycline/cyclophosphamide (AC) chemotherapy (CT).
Authors: Lee S. Schwartzberg, Daniel Voisin, Giada Rizzi, Kamal Patel, Matti S. Aapro
Journal: Journal of Clinical Oncology (2019)

11594 Background: NEPA, a combination antiemetic agent [NK 1 receptor antagonist (RA) netupitant (oral) or fosnetupitant (IV) + 5-HT 3 RA palonosetron] offers 5-day CINV prevention with a single-dose. Unlike other IV NK 1 RAs, the fosnetupitant solution does not require a surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. In a Phase 3 study in pts receiving cisplatin-based CT, there were no infusion site or anaphylactic reactions related to IV NEPA. In contrast, hypersensitivity reactions and anaphylaxis have been reported with IV aprepitant, fosaprepitant and rolapitant, with the highest rate (35%) for fosaprepitant in the AC setting. This study (NCT03403712) evaluates the safety of IV NEPA in BC pts receiving repeat cycles of AC CT. Methods: This was a Phase 3b, double-blind study in females with BC naïve to highly/moderately emetogenic CT. Pts were randomized 1:1 to receive a single 30-min infusion of IV NEPA or a single oral NEPA capsule on Day 1, prior to AC. Oral dexamethasone was also given to all patients before CT. The primary objective was a safety evaluation of IV NEPA based primarily on treatment-emergent adverse events (TEAEs). No formal between groups statistical comparison was planned. Results: 402 pts were treated with IV NEPA or oral NEPA and included in the safety population. The AE profiles were similar for the two groups; cycle 1 results are reported (Table). Comparable complete response (no emesis, no rescue) rates were seen during the cycle 1 overall phase (0-120h) (73.0% IV NEPA, 77.2% oral NEPA). Conclusions: There were no infusion-site AEs related to IV NEPA and no anaphylaxis reported for either formulation. Consistent with the pivotal study, IV NEPA is safe and effective in pts receiving AC. As a simplified single-dose formulation, IV NEPA may be better tolerated than other NK 1 RAs. Clinical trial information: NCT03403712. [Table: see text]
Treatment of soft tissue sarcoma with a novel cold plasma jet.
Authors: Xiaoqian Cheng, Alan Blank, Lawan Ly, Saravana R Murthy, Connor Wakefield, Matthew W. Colman, Marta Batus, Steven Gitelis, Michael Keidar, Jerome Canady
Journal: Journal of Clinical Oncology (2019)

e22562 Background: Soft tissue sarcoma is a malignant tumor that most often develops in adults, but can occur in children as well. Treatment with radiation, en bloc surgical resection and chemotherapy have achieved long-term survival rates up to 65% to 80% in non-metastatic disease. Local microscopic tumor cells can still exist despite complete R-0 surgical excision of the tumor. A novel technology Cold Atmospheric plasma (CAP) is an emerging technology that has shown promising anticancer effects i.e anti-mitotic and less effective on non-cancerous tissue. A new field has developed in medicine Plasma Onco-therapeutics. CAP treatment has the potential to improve the outcome of osteosarcoma patients. Methods: CAP was generated using a US Medical Innovations LLC (USMI) SS-601 MCa high-frequency electrosurgical generator (USMI, Takoma Park, MD, USA) integrated with Canady Cold Plasma Conversion Unit and connected to a Canady Helios Cold Plasma Scalpel. Three types of human sarcoma cells, synovial sarcoma (SW982), connective tissue fibro sarcoma (HT-1080), and rhabdomyosarcoma (RD) were used in this study to test the effect of the CAP generated by the Canady Cold Plasma Conversion System. Cells were treated with various CAP settings including different helium flow rates (1 and 3 LPM) and power settings (20-120p) in order to establish an optimal treatment condition for each cell line. Viability was performed on the cells using MTT assay 48 hours after CAP treatment. Student t test was performed on the data (*p &lt; 0.05). Results: The reduction of the viability of all three sarcomas were dose-dependent and significantly reduced at various time and power combinations tested (Figure 1-3). Helium flow alone did not significantly impact cell viability. The decrease in viability of the sarcoma cells when using 1 LPM required a higher dose. About 20 to 40% of viability reduction was seen on the three cell lines. With 3LPM, viability was reduced to 20% using 80p 2 min for SW982 and HT-1080, and 100p 2min for RD. Conclusions: Our data demonstrates that CAP reduced sarcoma cell viability in a time- and power-dependent manner. With optimal dosage for each cancer type, this study provides a promising treatment for future therapeutic interventions for soft tissue sarcomas.
Prognostic significance of bone metastases (BM) and bisphosphonate (BIS) therapy in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs).
Authors: Rana R. McKay, Xun Lin, Julia Jane Perkins, Ronit Simantov, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

4572 Background: BM are frequently present in patients with mRCC. BM cause significant morbidity and are associated with high rates of skeletal related events (SREs). The purpose of this retrospective analysis was to assess the impact of BM and BIS use on outcomes including progression-free survival (PFS) and overall survival (OS) in patients with mRCC. Methods: We conducted a pooled analysis of patients with mRCC treated from 2003-2011 on phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423). Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 2,749 patients treated with sunitinib (n=1,059), sorafenib (n=335), axitinib (n=359), temsirolimus (TEM) (n=208), TEM + interferon-alfa (IFN) (n=208), or IFN (n=560). Most patients were male (71%), had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and prior nephrectomy (84%). 285 patients (10.4%) received treatment with BIS (zoledronic acid n=233, pamidronate n=57, unspecified n=1). No patients received denosumab. Of the 2,504 patients with data regarding site of metastasis at diagnosis, 31.9% (n=781) had BM. The rate of SREs in patients with BM compared to patients without BM was 6.4% versus 1.4% (p&lt;0.0001). Presence of BM was associated with shorter PFS (5.1 vs. 6.7 months (mo), HR 1.195, 95% CI 1.076-1.328, p&lt;0.0008) and OS (13.2 vs. 20.2 mo, HR 1.292, 95% CI 1.145-1.456, p&lt;0.0001) when compared to those without BM. In patients with BM, the use of BIS was not associated with improved PFS (5.1 vs. 4.9 mo, HR 0.867, 95% CI 0.704-1.067, p=0.1785) or OS (13.3 vs. 13.1 mo, HR 0.904, 95% CI 0.722-1.132, p=0.3801) when compared to patients who did not receive BIS. In patients with BM stratified by type of first-line MTA (TKI, mTOR inhibitor, or IFN-based), use of BIS was not associated with improved PFS or OS. Conclusions: In this analysis, we confirm that the presence of BM is an adverse risk factor for shorter PFS and OS in patients with mRCC treated with MTAs. Treatment with BIS did not have a positive impact on survival in this cohort.
In Vivo Retargeting of Poly(beta aminoester) (OM‐PBAE) Nanoparticles is Influenced by Protein Corona
Authors: Cristina Fornaguera, Marta Guerra‐Rebollo, Miguel Ángel Lázaro, Anna Cascante, Núria Rubio, Jerónimo Blanco, Salvador Borrós
Journal: Advanced Healthcare Materials (2019)

Abstract One of the main bottlenecks in the translation of nanomedicines from research to clinics is the difficulty in designing nanoparticles actively vectorized to the target tissue, a key parameter to ensure efficacy and safety. In this group, a library of poly(beta aminoester) polymers is developed, and it is demonstrated that adding specific combinations of terminal oligopeptides (OM‐PBAE), in vitro transfection is cell selective. The current study aims to actively direct the nanoparticles to the liver by the addition of a targeting molecule. To achieve this objective, retinol, successfully attached to OM‐PBAE, is selected as hepatic targeting moiety. It is demonstrated that organ biodistribution is tailored, achieving the desired liver accumulation. Regarding cell type transfection, antigen presenting cells in the liver are those showing the highest transfection. Thanks to proteomics studies, organ but not cellular biodistribution can be explained by the formation of differential protein coronas. Therefore, organ biodistribution is governed by differential protein corona formed when retinol is present, while cellular biodistribution is controlled by the end oligopeptides type. In summary, this work is a proof of concept that demonstrates the versatility of these OM‐PBAE nanoparticles, in terms of the modification of the biodistribution of OM‐PBAE nanoparticles adding active targeting moieties.
Prognostic understanding in hematologic malignancies: A multicenter longitudinal study.
Authors: Kah Poh Loh, Thomas William LeBlanc, Stephanie Lee, Anthony Back, Paul Duberstein, Supriya Gupta Mohile, Ronald M. Epstein, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2019)

11524 Background: Accurate prognostic understanding facilitates the receipt of goal-concordant medical care. Few studies have evaluated prognostic understanding in patients with hematologic malignancies. In this secondary analysis of a multicenter, longitudinal study of patients with hematologic malignancies referred for a second opinion hematology subspecialty consultation, we assessed changes in prognostic understanding after consultation, and predictors of post-consultation patient-oncologist prognostic discordance. Methods: Patients were recruited from 4 academic centers. Before and 1-7 days after consultation, patients were asked about their perceived chance of cure (options < 10%, 10-19%, and up to 90-100% in 10% increments, and “do not wish to answer”). Oncologists were asked the same question after consultation. Discordance was defined as a difference in response by 2 levels in the patient-oncologist dyads. We used multivariate analysis to assess the demographic and clinical predictors of patient-oncologist discordance. Results: We included 216 patients (median age 55 years, range 22-79) and 46 oncologists (47, 30-70). Overall, ≥On multivariate analysis, discordance before consultation [Odds Ratio (OR) 6.05, 95% Confidence Interval (CI) 2.96-12.36) and < college education (vs. post-graduate education; OR 2.34, 95% CI 1.09-5.14) were associated with discordance after consultation. Other patient demographics, comorbidity, cancer type, psychological distress, social support, decision-making preference, and coping strategies were not associated with discordance. Conclusions: Patient-oncologist concordance in prognostic understanding improved after subspecialty consultation, but over half of patients’ views of their prognosis remained discordant with those of their oncologists. Interventions to improve patient-oncologist communication about prognosis are needed, especially in patients with lower education level.
P14.22 Long-term survival of treatment of HGG using PDT
Authors: A Rynda, V Olyushin, D Rostovtsev, Y Zabrodskaya
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND As a supplement to the adjuvant treatment of malignant gliomas of the cerebral hemispheres, the substance of the 2nd generation chlorins e6 was investigated. This study reflects the survival and size of the relapse-free period of patients in the Polenov Russian Research Institute of Neurosurgery, using the base of patients who received adjuvant PDT therapy in addition to surgical resection of the tumor. MATERIAL AND METHODS The analysis of 160 patients with glial brain tumors of supratentorial localization, of various degrees of malignancy, operated on in the Department Neurooncology, Polenov Russian Research Institute of Neurosurgery from 2004 to 2015. 79 patients (study group) removal of a tumor with intraoperative photodynamic therapy with a drug of the chlorin e6 group of the 2nd generation. 81 patients (control group), tumor removal without photodynamic therapy. RESULTS The median survival for patients with Grade III gliomas using PDT was 40.4 ± 7.4 months; in the control group (without PDT) - 23.4 ± 3.9 months (p = 0.0003). The median survival for patients with Grade IV gliomas using PDT was 21.3 ± 5.1 months; in the control group (without PDT) - 13.7 ± 3.7 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade III subgroup was: in the study group, 22.5 ± 3.79 months; in the control group, 16.1 ± 3.22 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade IV subgroup was 11.4 ± 2.49 months in the study group; in the control group - 8.2 ± 2.13 months (p = 0.0001). CONCLUSION Photodynamic therapy is a promising and safe technique that allows intraoperative action on the residual volume of tumor cells located in the perifocal zone. The use of PDT in the complex treatment of glial brain tumors allows to increase the median of survival and the recurrence-free period.
A comparison of automatic cell identification methods for single-cell RNA sequencing data
Authors: Tamim Abdelaal, Lieke Michielsen, Davy Cats, Dylan Hoogduin, Hailiang Mei, Marcel J. T. Reinders, Ahmed Mahfouz
Journal: Genome biology (2019)

Abstract Background Single-cell transcriptomics is rapidly advancing our understanding of the cellular composition of complex tissues and organisms. A major limitation in most analysis pipelines is the reliance on manual annotations to determine cell identities, which are time-consuming and irreproducible. The exponential growth in the number of cells and samples has prompted the adaptation and development of supervised classification methods for automatic cell identification. Results Here, we benchmarked 22 classification methods that automatically assign cell identities including single-cell-specific and general-purpose classifiers. The performance of the methods is evaluated using 27 publicly available single-cell RNA sequencing datasets of different sizes, technologies, species, and levels of complexity. We use 2 experimental setups to evaluate the performance of each method for within dataset predictions (intra-dataset) and across datasets (inter-dataset) based on accuracy, percentage of unclassified cells, and computation time. We further evaluate the methods’ sensitivity to the input features, number of cells per population, and their performance across different annotation levels and datasets. We find that most classifiers perform well on a variety of datasets with decreased accuracy for complex datasets with overlapping classes or deep annotations. The general-purpose support vector machine classifier has overall the best performance across the different experiments. Conclusions We present a comprehensive evaluation of automatic cell identification methods for single-cell RNA sequencing data. All the code used for the evaluation is available on GitHub ( https://github.com/tabdelaal/scRNAseq_Benchmark ). Additionally, we provide a Snakemake workflow to facilitate the benchmarking and to support the extension of new methods and new datasets.
Prognostic implications of tumor associated macrophages (TAMs) in soft tissue sarcoma.
Authors: Shailaja KS Raj, Mitra Kooshki, Melissa Winters, Greg B. Russell, Lance D Miller, Javier A Laurini, Triozzi Pierre, Paul David Savage
Journal: Journal of Clinical Oncology (2019)

e22548 Background: Clinical responses in patients with soft tissue sarcoma administered immune checkpoint inhibitors have been infrequent. Little is known regarding the immune microenvironment in soft tissue sarcoma that leads to a lack of effective responses with immune therapies. Whilst several studies have shown T cell infiltration in sarcomas, these tumors do not respond to immunotherapies. Macrophages are important regulators of immune responses in the tumor microenvironment. Studies in mouse models indicate that macrophages regulate immune checkpoint inhibitor response. With the overall goal of developing more effective combination immunotherapies for sarcoma, we examined tumor associated macrophages in patients with soft tissue sarcoma administered neoadjuvant chemotherapy. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were also assessed using publicly available RNAseq and exome mutation data. Methods: Immunohistochemistry was performed on formalin fixed soft tissue sarcoma tissue. Tissues from 20 patients with soft tissue sarcoma pre and post neo-adjuvant chemotherapy were included. TAMs were detected by CD68; M2 subtype were detected by CD163. CD4, CD8, and CD25 T cells were also examined. The density of CD68+ TAMs, CD163+ TAMs and the ratio of CD163+ TAMs / CD68+ TAMs were calculated and their correlation with survival was also made. Publicly available RNAseq and exome mutation data were assembled from The Cancer Genome Atlas (TCGA) sarcoma cohort (n = 259). For each tumor, a relative measure of abundance of tumor-infiltrating macrophages was estimated using gene expression. Tumor mutational burden (TMB), expressed as the rate of non- synonymous mutations per megabase of sequenced DNA, was used as a measure of tumor immunogenicity. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were assessed by Cox regression and Kaplan-Meier analysis. Categorical relationships involving clinical, immunologic, and genomic features of the tumor immune subclasses were compared. Results: Specific alteration in the density of CD68+ TAMs, CD163+ TAMs, and the CD163 / CD68 ratio were observed in patients with soft tissue sarcoma responding to neoadjuvant chemotherapy. Categorical relationships involving macrophage infiltration, TMB, and survival were also observed. Conclusions: These study support the targeting of tumor associated macrophages in patients with soft tissue sarcoma and suggest that changes in TAMs may be achievable using neoadjuvant chemotherapy.
P03.13 Evaluation of PIK3CA mutational status in glioma molecular subgroups
Authors: C Brito, A Azevedo, S Esteves, C Martins, M Mafra, L Roque, M Pojo
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Gliomas are the most common and lethal malignant tumors of central nervous system. In 2016, World Health Organization (WHO) classification included IDH mutations and 1p/19q codeletion as diagnostic criteria to define glioma entities. However, new biomarkers for diagnosis, prognosis and response to therapy are needed. In this context, PIK3CA mutations have been described as constitutive mutations, which highlights their relevance in gliomas. Here we clarified the clinical relevance of PIK3CA mutations according to the 2016 WHO classification, the potential impact on diagnosis, prognosis, response to therapy, as well as their correlation with EGFR amplification and PTEN deletion. MATERIAL AND METHODS A cohort of 444 adult diffuse glioma samples from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) was classified according to the 2016 WHO Classification. The mutational status of exon 9 and 20 of PIK3CA was evaluated in molecular subgroups of gliomas by Sanger sequencing. PTEN deletion and EGFR amplification were identified by Fluorescent in situ hybridization (FISH). RESULTS PIK3CA mutations showed a higher frequency in the subgroup of gliomas with IDH mutations and 1p/19q codeletion - oligodendrogliomas (10%). In Glioblastoma (GBM) IDH-mutant and IDH-wildtype these oncogenic mutations were observed in 9% and 3% of cases, respectively. Similar results were obtained using The Cancer Genome Atlas (TCGA) data, which was 8% and 2%, respectively. H1047R and E542K were the most frequent mutations identified in the glioma molecular subgroups. Importantly, we found 3 unreported pathogenic variants in exon 20 of PIK3CA (c.3112T&gt;C, c.2988T&gt;C, c.3040C&gt;T) and one polymorphic variant (c.3210A&gt;G). In addition, PIK3CA mutations, PTEN deletion and EGFR amplification were not mutually exclusive alterations in glioma molecular subgroups. For the first time in gliomas, it was identified the rs45455192 polymorphism at a frequency of 16% in astrocytomas IDH-mutant, 24% in oligodendrogliomas and 18% in both molecular subgroups of GBM, although this polymorphism did not have prognostic value. The analysis of PIK3CA mutations in glioma recurrences showed that these mutations are maintained during glioma progression. CONCLUSION In two independent cohorts (IPOLFG and TCGA), it was obtained similar frequencies of PIK3CA mutations in GBM molecular subgroups. In addition, these mutations are more relevant in less aggressive gliomas (IDH-mutated and 1p/19q codeleted). These alterations seem to be important in tumor maintenance and progression, which makes this gene a potential therapeutic target. In the future, we will investigate the effect of the in vitro pharmacological inhibition of PIK3CA in GBM mutant cell lines.