tbuckley/cabot-search huggingface dataset:
Assessment of EGFR mutations in plasma from advanced NSCLC patients by modified cell-free DNA extraction method and blocker PCR assays.
Authors: Meiling Zhang, Ziying Gong, Chun Li, Jie Hu, Qunying Hong, Yingyong Hou, Daoyun Zhang, Xin Zhang
Journal: Journal of Clinical Oncology (2017)

e23115 Background: Epidermal growth factor receptor (EGFR) mutation testing in plasma cell-free DNA (cfDNA) for lung cancer patients is an emerging clinical tool.However,the sensitivity of plasma testing,compared with tissue testing, is not high enough. We aimed to investigate the likelihood of improving the plasma testing sensitivity by increase the cell-free DNA(cfDNA )yields using a modified extraction method and blocker PCR. Methods: Blood samples were collected from 106 patients without EGFR-TKI treatment and 127 patients with acquired EGFR-TKI resistance.CfDNA was extracted from plasma by the modified extraction method and mutations were identified by blocker PCR.The yields of circulating tumor DNA (ctDNA) and cfDNA from 106 patients were quantified by standard curve.Next generation sequencing (NGS)was employed to verify the reliability of blocker PCR. Meanwhile,paired tumor tissues were examined by amplification refractory mutation system (ARMS). Results: The novel extraction method can extract small fragment less than 100bp.The yield of total cfDNA of 106 plasma was mostly between4 000and 200,000 copies per milliliter.With regard to exon 19 deletions(E19-DELs) , the ctDNA proportion of 85% samples (17/20)was from 0.1% to 5% . As for L858R mutations, the fraction of ctDNA of 84.6%(11/13)cases was calculated with the range of 0.01% to 0.1%.For 106 patients,the overall concordance rate,sensitivity and specificity between plasma and tumor tissue was 99.06%[k = 0.97; 95% confidence interval (CI), 0.87-0.99; P &lt; 0.0001],94.87%(95% CI, 83.11%-98.58%) and 100 % (95% CI,94.58%-100%).Among the 127patients,40.16%(51/127)T790M was detected in the plasma, 78.44%(40/51) of which coexists with an EGFR activating mutation. Conclusions: The modified extraction method can improve ctDNA yields and thus improve the sensitivity of liquid biopsy.The blocker PCR offers the possibility of detecting mutations in cfDNA with high concordance with tumor tissues.
Association of Prenatal Urinary Concentrations of Phthalates and Bisphenol A and Pubertal Timing in Boys and Girls
Authors: Kimberly Berger, Brenda Eskenazi, Katherine Kogut, Kimberly Parra, Robert H. Lustig, Louise C. Greenspan, Nina Holland, Antonia M. Calafat, Xiaoyun Ye, Kim G. Harley
Journal: Environmental Health Perspectives (2018)

Background: Animal studies suggest that phthalates and bisphenol A (BPA), endocrine-disrupting chemicals found in many consumer products, may impact the timing of puberty. Objectives: We aimed to determine the association of prenatal exposure to high-molecular-weight phthalates and BPA with pubertal timing in boys and girls participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study. Methods: We quantified urinary concentrations of eight phthalate metabolites and BPA at two time points during pregnancy among participating mothers (n=338) and conducted clinical Tanner staging of puberty on their children every 9 months between 9 and 13 y of age. We conducted accelerated failure time models and examined the role of child overweight/obese status in this association. Results: The sum of urinary metabolites of di(2-ethylhexyl) phthalate (∑DEHP), monobenzyl phthalate (MBzP), and BPA were associated with later onset of at least one of the three outcomes assessed in girls (thelarche, pubarche, or menarche) and with earlier onset of at least one of the two outcomes assessed in boys (gondarche and pubarche). We found that monocarboxynonyl phthalate, monocarboxyoctyl phthalate, mono(3-carboxypropyl) phthalate, and BPA were associated with later pubarche and menarche mostly among normal-weight girls but not overweight/obese girls. MBzP was associated with later thelarche in all girls, and ∑DEHP was associated with later thelarche and menarche in all girls. BPA and all phthalate biomarkers were associated with earlier gonadarche and pubarche in all boys as well as in overweight/obese boys when stratified by weight. Among normal-weight boys, associations with BPA were also inverse, whereas associations with phthalate metabolites were close to the null or positive. Conclusions: Several high-molecular-weight phthalates and BPA were associated with later puberty in girls and earlier puberty in boys included in the CHAMACOS cohort study. Childhood overweight/obesity may modify these associations. https://doi.org/10.1289/EHP3424
TCT-756 Acute mechanical unloading of the left ventricle increases ‘functional perfusion’ of the area at risk by enhancing the collateral flow index prior to reperfusion
Authors: Natalia Briceno, Shiva Annamalai, Lara Reyelt, Paige Crowley, Lena Jorde, Robert Pedicini, Divaka Perera, Navin Kapur
Journal: Journal of the American College of Cardiology (2018)
Crystal Structure of V delta 1 T Cell Receptor in Complex with CD1d-Sulfatide Shows MHC-like Recognition of a Self-Lipid by Human gamma delta T Cells.
Authors: A.M Luoma, C.D Castro, T Mayassi, L.A Bembinster, L Bai, D Picard, B Anderson, L Scharf, J.E Kung, L.V Sibener, P.B Savage, B Jabri, A Bendelac, E.J. Adams
Journal: Immunity (2013)
The prognostic significance of infiltrating immune cells subtypes in invasive ductal carcinoma of the breast.
Authors: Qiuhong Zheng
Journal: Journal of Clinical Oncology (2017)

e23177 Background: To explore the correlation between tumour infiltrating immune cell subsets and breast cancer prognosis. Methods: Specimens of 102 patients with invasive breast ductal carcinoma were analyzed for immune -related markers (CD8, CD20, FoxP3 and CD68). The number of positive cells in 3 most highly-stained intratumoural stroma areas of the primary tumour was counted. The mean number of each marker was calculated and used to divide patients into two groups respectively (CD8high/CD8low group, CD20high/CD20low group, FOXP3high/ FOXP3 low group and CD68high/CD68 low group). Results: Kaplan–Meier survival analysis showed : (A) For all patients, high tumour-infiltrating CD8+ and CD20+ B lymphocytes , low tumour-infiltrating FoxP3+ Treg and CD68+ macrophages all increased the OS and DFS (P &lt; 0.05); (B) For both the 35 ER negative and the 45 lymphonode negative patients, high CD8+ CTLs increased the OS and DFS(P &lt; 0.05). Multivariate analysis of OS and DFS showed for all patients, high CD8+ CTLs and low FoxP3+ Treg were related to good OS and DFS(P &lt; 0.05). Conclusions: high number of tumour-infiltrating CD8 and low FoxP3 T lymphocytes both could function as potential independent prognostic markers for invasive ductal breast carcinoma .
BMI as a risk factor for toxicities in patients with advanced soft tissue sarcoma treated with trabectedin.
Authors: Marianna Silletta, Grazia Armento, Giuseppe Badalamenti, Mariella spalato Ceruso, Giovanna Catania, Lorena Incorvaia, Daniele Santini, Giuseppe Tonini, Bruno Vincenzi
Journal: Journal of Clinical Oncology (2017)

e22517 Background: Since the first steps of its clinical development, trabectedin was noticed to be extremely active against myxoid liposarcoma (MLS), whose pathogenesis seems to be associated to the presence of the t(12;16)(q13;p11) translocation, resulting in the expression of FUS-DDIT3 fusion genes. Therefore, the drug seems to induce a maturation of MLS lipoblasts, with transition of the residual spindle non-lipogenic cells into mature vacuolated lipoblasts. This effect could be prevented by the increase of leptin circulating levels in obese patients. For these reasons we designed this retrospective analysis in order to evaluate the BMI status (measure of total adipose content) as a predictors or efficacy of trabectedin in MLS patients. Methods: Patients were treated in cancer centers with trabectedin at the approved dose of 1.5 mg/m 2 , given as a 24-hour infusion every 3 weeks. This retrospective analysis was preformed on the basis of clinical charts or databases. For the purpose of this analysis only patient with a BMI &gt; 18.5 were included and an the population divided into two categories: normal weight if BMI &lt; 25, overweight &gt; 25. An analysis of the correlation between BMI and objective response (OR) rate, tumor control (TC) rate (OR+stable disease lasting ≥3 months), progression-free survival (PFS) and overall survival (OS) was performed. Results: 62 adult patients with recurrent MLS were enrolled (M/F: 33/29; median age: 53 ys). All patients were doxorubicin-pretreated. The median BMI in the whole population was 22.5 (range: 1.85 – 29.8). No statistically significant differences were identified in terms of OR or TC. On the contrary, PFS (6.8 vs. 3.7 months; p&lt; 0.026, log rank test) and OS (14.9 vs. 8.3 months; p&lt; 0.0001, log rank test) were significantly prolonged in normal weighted patients vs over weighted patients. Six and 12-months Kaplan-Meier PFS estimates and survival rates at 12, 24 and 36 months were also better in those patients. Conclusions: these results seem confirm a role o adipose content as a predictor of resistance to trabectedin in MLS patients. Further studies are warranted to confirm this preliminary observation and understand the biological mechanisms of this relationship.
Genomic landscape, clinical characteristics and outcomes of early onset (EO) compared with average onset (AO) colorectal cancer (CRC).
Authors: Gustavo Dos Santos Fernandes, Walid K Chatila, Rona Yaeger, Robin B Mendelsohn, Zsofia Kinga Stadler, Neil Howard Segal, Anna M. Varghese, Diane Reidy Lagunes, Luis A. Diaz, Jinru Shia, Efsevia Vakiani, Jaclyn Frances Hechtman, Nikolaus Schultz, Michael F. Berger, David Michael Hyman, David B. Solit, Leonard B. Saltz, Julio Garcia-Aguilar, Andrea Cercek
Journal: Journal of Clinical Oncology (2018)

3520 Background: The incidence of CRC in patients (pts) under the age of 50 has been rising over the past decade. Little is known about the biologic differences between early and AO (over the age of 50) CRC, but early reports suggest tumors in these EO patients are more aggressive and present with advanced disease. Methods: To better understand the differences in etiology and biology of these EO tumors, we retrospectively reviewed the charts of all pts with EO CRC (n = 384) treated at Memorial Sloan Kettering Cancer Center between 2014 and 2017 for pathology, radiology, and clinical characteristics and compared these to a cohort of AO CRC cases (n = 543). We also performed tumor sequencing using a targeted NGS panel ( > 300 genes, MSK IMPACT). Pts with CRC related hereditary syndromes such as Lynch Syndrome and inflammatory bowel disease were excluded. Results: In the EO pts median age was 44 (17-50); 52% male and 48% female. Sixty-six % of patients had stage (St) IV disease at diagnosis, 24% had St III, 7% had St II, and 2.6% had St I. Twenty four % of pts wereBMI≥30 and 29% ever smoked. Family history of CRC in first or second degree relatives was present in 29%. The majority of pts had moderately differentiated (74%) and L sided tumors (78%). All EO and AO pts evaluated were MSS with a median mutational burden of 4.9 mut/Mb and 5.0 mut/Mb, respectively. The median age of AO pts was 61 (51-93). EO versus AO CRC identified enrichment of TP53 mutations (87v 78%, p = 0.001, q = .14) and 20q amplifications 5 vs 1% p = .006, q = 0.33). In metastatic pts median OS was higher in EO (73 vs 69, p = 0.022) months. In EO there was a trend towards no difference in outcomes between L vs R sided tumors (HR 1.53 p = 0.13). Conclusions: This is the largest cohort describing a broad range of clinical and genomic characteristics of the EO CRC population with comparison to AO CRC. In our initial analyses EO pts present with predominantly L sided tumors, with similar histology and few molecular differences when compared AO CRC. In contrast to prior reports, EO appears to be associated with better survival. Detailed clinical and molecular characterization and multivariate analysis of EO vs AO will be presented.
Correlates of toxicity in metastatic melanoma patients treated with ipilimumab.
Authors: Sara Valpione, Jacopo Pigozzo, Sandro Pasquali, Luisa Piccin, Simone Mocellin, Luca Giovanni Campana, Vanna Chiarion-Sileni
Journal: Journal of Clinical Oncology (2016)

e21010 Background: The use of ipilimumab for the treatment of metastatic melanoma is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features or blood biomarkers capable of predicting ipilimumab related toxicity. Methods: Weperformed a prospective study aimed to analyze potential clinical or biological markers associated with toxicity. The following prospectively collected data were utilized: patient characteristics, previous therapies and level of serum biomarkers (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases, leukocyte count, lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data from 140 consecutive metastatic melanoma patients treated with ipilimumab (3mg/kg, q3w) at Veneto Institute of Oncology. Results: Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Sex female (OR = 1.5, 95% CI 1.06-2.16 p = .022) and low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34-6.03, p = .007) had a significant and independent association with immune related adverse events. Conclusions: Sex and baseline IL6 serum levels were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in these patients.
Adoptive cellular immunotherapy with APN401, autologous Cbl-b-silenced peripheral blood mononuclear cells, in patients with solid tumors.
Authors: Marc Oliver Salzberg, Pierre Triozzi, Mitra Kooshki, Angela Tatiana Alistar, Rhonda Lynn Bitting, Joyce Fenstermaker, Guenther Lametschwandtner, Hans Loibner
Journal: Journal of Clinical Oncology (2016)

e14541 Background: Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, is a major intracellular checkpoint limiting lymphocyte activation. Silencing Cbl-b enhances T cell and natural killer cell antitumor activity in mouse tumor models. APN401, an autologous cellular therapy consisting of Cbl-b silenced peripheral blood mononuclear cells (PBMC), was evaluated in patients with solid tumors. Methods: A siRNA was selected for APN401 from a panel tested in human PBMC for the ability to decrease Cbl-b protein expression and increase cytokine production. Feasibility and safety of three single doses of APN401 were evaluated in patients with refractory metastatic solid tumors. Patients with active autoimmune disease or a requirement for immune suppressive drugs were excluded. PBMC were collected by leukapheresis. The following day PBMC were transfected with Cbl-b siRNA by electroporation to produce APN401 and then infused intravenously over 30 minutes. Results: Three to six patients were treated in each of the three dosing cohorts. PBMC were successfully collected and transfected with Cbl-b siRNA in all patients enrolled. CD3 T cell, CD56 NK cell, CD19 B cell, and CD14 monocytes were transfected with similar efficiencies. APN401 cells produced 4-fold more interferon gamma and 2-fold more interleukin-2 in response to CD3/CD28 stimulation than PBMC that were processed and electroporated without siRNA. From 27.0 to 467 X 106 APN401 cells were infused. Infusions were well tolerated. Mild to moderate chills developed in most patients at the completion of the infusion. Dose-limiting toxicities were not observed. There was no immediate hypersensitivity and no evidence of autoimmune adverse effects. Stable disease was observed in two patients with pancreatic cancer and one with colorectal cancer. Conclusions: APN401 respond to activation with increased cytokine production. A single intravenous infusion of 5.0 x106/kg of APN401 into patients with refractory solid tumors is feasible and safe. The results support testing of multiple infusions and phase II clinical trials. Clinical trial information: NCT02166255.
Michael John Leverton
Authors: Ted Leverton, Jane Smith, Ann Leverton, Clare Leverton
Journal: BMJ (2018)

Brought up on the Nottingham-Derbyshire border, Michael John Leverton (“Mick”) was educated at Worksop College before studying at St Catharine’s College, Cambridge, and St George’s Hospital Medical School, London. He later recalled that sometimes the only way to keep warm was to ride on a tube train for as long as he and his fellow students could manage. His first hospital placement was in Plymouth, then in Banbury and Stratford-upon-Avon, where he met Margaret. They were married in 1962. Posts in Bristol and Crewe followed before Mick moved to Dalton-in-Furness as a locum general practitioner. The couple fell in love with the area, and Mick took a GP post in Millom, in the far south west of the …
Association between genotypes, clinical scores and survival outcome in metastatic colorectal cancer.
Authors: Moreno Reinaldo, Òscar Reig, Francis Esposito, Victoria Sanchez, Patricia Rodriguez, Santiago Albiol, Miriam Cuatrecasas, Eva Hernández, Maria Vila-Cadasesús, Pedro Jares, Leire Pedrosa, Estela Pineda Losada, Jordi Camps, Aleix Prat, Juan Maurel
Journal: Journal of Clinical Oncology (2018)

3553 Background: Several prognostic clinical scores for metastatic colorectal cancer (mCRC) GEMCAD (Ann Oncol 25 (Supp 4)), 2014; GERCOR (Oncologist 16, 2011); Köhne (Ann Oncol 13, 2002) are useful for treatment guidance. Next generation sequencing (NGS) allows the evaluation of multiple deregulated pathways (WNT, TGFB, PI3K-RTK-RAS and p53 signaling) (Nature, 2012). We hypothesize that complex vs simple genotypes evaluated by NGS, could be distributed differently according sidedness and clinical scores and would provide independent prognostic value.Methods: NGS by Ion Torrent in 22 CRC significant genes was employed to process samples from 141 consecutive mCRC patients (pts) diagnoses from February 2016 to November 2017 in a single institution. Genotype was defined as Complex:1) BRAF mutant 2) RTK-RAS-PI3K+/-p53+FBXW7 mutant 3) RTK-RAS-PI3K+/-p53+SMAD4 mutant; Simple: 1) RTK-RAS-PI3K mutant alone 2) p53 mutant alone 3) RTK-RAS-PI3K mutant+p53 mutant 4) no mutations. Associations were analyzed with Fisher-t test. Cox proportional hazard models and interaction analyses were used to explored the effect of genotype, primary sidedness and clinical scores with overall survival (OS). Results: Informative cases (128/141); 91%. Complex genotype; 29%; p53 (67%), KRAS (45%), BRAF (14%), SMAD4 (13%), PI3K (12%), FBXW7 (8%), NRAS (3%), other ( < 3%). Complex genotype was not associated with sidedness (p = 0.997) but was associated with high-risk GEMCAD score (p = 0.03). In the Cox model, genotypes by NGS remain significant for OS independently of clinical scores (see Table).Conclusions: NGS genotype provides independent prognostic information beyond clinical scores. The combination of both variables should allow optimal prognostic stratification in mCRC. Prognostic value for overall survival (cox proportional hazard model). GEMCAD GERCOR Köhne HR (95% IC) p HR (95% IC) p HR (95% IC) p Genotype Simple 1 1 1 Complex 1.82 (1.04 – 3.20) 0.037 2.13 (1.22 – 3.73) 0.008 2.31 (1.31 – 4.08) 0.004 Score Low 1 1 1 Intermediate 2.96 (0.67 – 12.94) 0.149 5.32 (0.72 – 39.39) 0.101 2.13 (0.94 – 4.78) 0.067 High 7.83 (1.84 – 33.34) 0.005 14.81 (2.01 –109.40) 0.008 7.78 (3.69 – 16.40) 0.0001
Targeting 6-phosphofructo-2-kinase (PFKFB3) as an immunotherapeutic strategy.
Authors: Jason Alan Chesney, Sucheta Telang, Kavitha Yaddanapudi, Jaspreet Singh Grewal
Journal: Journal of Clinical Oncology (2016)

e14548 Background: Th17 cells are elevated and immunosuppressive in a majority of human cancers and have been found to correlate with decreased patient survival. IL-17 produced by these cells promotes tumor growth by increasing the tumor infiltration and function of myeloid-derived suppressor cells (MDSCs), which in turn stimulate angiogenesis and suppress CD4+ and CD8+ T cell tumor homing. Both Th17 cells and MDSCs require hypoxia inducible factor 1a (HIF-1α) which promotes 6-phosphofructo-2-kinase (PFKFB3) – PFKFB3 synthesizes fructose 2,6-bisphosphate (F2,6BP), an allosteric activator of the rate-limiting glycolytic enzyme 6-phosphofructo-1-kinase (PFK-1). Methods: Human Th17 and MDSCs were differentiated in vitro; B16-F10 melanoma-bearing mice were treated as indicated. Results: In new studies, we have found that human Th17 cells and MDSCs differentiated ex vivo display increased PFKFB3 and F2,6BP relative to CD4+ T cells and monocytes, respectively. We also found that the PFKFB3 inhibitor, PFK-158: (i) suppresses human Th17 cell and MDSC differentiation in vitro; and (ii) decreases tumor-infiltrating Th17 cells, γδT17 cells (which also express HIF-1α), and MDSCs, and increases tumor-infiltrating CD4+ and CD8+ T cells in the tumors of B16-F10 melanoma-bearing mice. Furthermore, we observed that genomic deletion of Pfkfb3 in C57Bl/6 mice (but not in implanted B16 melanoma cells) reduces B16 tumor growth, decreases tumor-infiltrating Th17 cells, γδT17 cells and MDSCs, and increases tumor-infiltrating CD4+ and CD8+ T cells. Based on these immunostimulatory effects, we predicted that PFK-158 would improve the anti-tumor activity of the immune checkpoint inhibitor, anti-CTLA4, in the B16-F10 model – we observed a marked increase in tumor growth inhibition by anti-CTLA4 when combined with PFK-158 in vivo. Conclusions: In conclusion, this novel immunomodulatory mechanism of action of PFK-158 provides key rationale for phase 1/2 trials that combine PFK-158 with immune checkpoint inhibitors and other immunotherapeutic agents such as the oncolytic virus talimogene laherparepvec.