tbuckley/cabot-search huggingface dataset:
In vivo monitoring of the TR4 anti-Notch fusion protein: an imaging approach.
Authors: Agamemnon A. Epenetos, Marianna Prokopi, Costas Pitsillides, Christina Kousparou, Aleksandra Filipovic, Andreas Anayiotos, Konstantinos Kapnisis, Mahendra Deonarain
Journal: Journal of Clinical Oncology (2016)

e23186 Background: The Notch pathway has been associated with cancer and is implicated in tumorigenesis and regulation of cell fate. This pathway is an attractive target for the development of novel anti-Notch cancer therapeutics. We have generated a novel fusion protein TR4 that inhibits Notch at transcriptional level and can reduce tumor growth Methods: TR4 consists of the truncated Mastermind (MAML) peptide that inhibits Notch and the cell penetrating peptide Antennapedia (Antp). We have investigated the pharmacokinetic and pharmacodynamic behavior of fluorescent TR4 using pharmacokinetics and toxicology together with innovative in vivoflow cytometry and whole body fluorescence reflectance imaging Results: The TR4 fusion protein was conjugated to fluorescent markers to enable detection via fluorescence based in vitro and in vivo imaging systems. The cell membrane translocation ability of the TR4 conjugate was confirmed in vitro and in vivo for toxicity at escalating dosages in immune-competent mice . It did not induce any overt toxicity or organ dysfunction . Following IV administration animals were imaged with the in vivo flow cytometer; free/non-internalized protein was rapidly cleared from circulation, fluorescent TR4 appeared to collect in some of the major organs/tissues imaged and was cleared within 24 hrs via the gastrointestinal tract. In vivoimaging demonstrated a reduction in tumor growth over time in the treated mice as compared to controls. Conclusions: The TR4 fusion protein is able to translocate into the cell nucleus and suppress Notch activation reverting the transformed phenotype and inducing apoptosis in highly metastatic epithelial human breast cancer. Furthermore,the studies investigated the dynamics , mode of action and helped optimize the TR4 peptide as a novel therapy for cancer and cancer stem cells..
OS1.2 Stability of EGFR amplification in glioblastoma is differentially impacted based on therapeutic pressure
Authors: M Ahluwalia, Y Narita, Y Muragaki, H Gan, R Merrell, M van den Bent, L Roberts-Rapp, M Guseva, P Ansell, A Lassman
Journal: Neuro-Oncology (2018)

BackgroundDepatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic pressure engenders tumor adaptations, it is important to understand the stability of biomarkers targeted by precision medicine approaches such as depatux-m. Therefore, we assessed EGFR amplification (amp) and expression in longitudinally-sampled GBMs from patients (pts) treated +/- depatux-m to explore biomarker stability.
Impact of body mass index on surgical costs and morbidity for women with endometrial carcinoma/hyperplasia.
Authors: Rudy Sam Suidan, Weiguo He, Charlotte C. Sun, Pamela T. Soliman, Pedro T Ramirez, Hui Zhao, Nicole D. Fleming, Shannon Neville Westin, Karen H. Lu, Sharon Hermes Giordano, Larissa Meyer
Journal: Journal of Clinical Oncology (2016)

5583 Background: Our objective was to evaluate the impact of body mass index (BMI) on surgical costs and complications for pts with endometrial cancer (EC) and endometrial hyperplasia (EH). Methods: All women who underwent surgery for EC or EH from 2008-2014 and had BMI data were identified from MarketScan, a healthcare claims database. Pts were divided into 3 BMI groups: ≤ 29 (normal/overweight), 30-39 (obese), and ≥ 40 kg/m2 (morbidly obese). Costs included all operative and nonoperative charges incurred, adjusted for inflation. Differences in 30-day surgical complications, acute-care outcomes, and costs were compared between groups using χ2and Wilcoxon rank sum tests. Results: Of 1112 pts, 385 (35%) had a BMI ≤ 29, 406 (36%) had a BMI of 30-39, and 321 (29%) had a BMI ≥ 40. 441 pts (40%) had a laparotomy and 671 (60%) had minimally invasive surgery (MIS). Pts with a BMI ≥ 40 had a higher wound infection rate compared to those with a BMI of 30-39 and ≤ 29 (7% vs 3% vs 3% respectively, p = 0.02). This increase was driven by the subset of pts who had laparotomy (14% vs 5% vs 5%, p < 0.01), and was not seen in those who had MIS (2% vs 2% vs 2%, p = 0.89). Women with a BMI ≥ 40 also had a higher rate of thromboembolic complications (3% vs 0.2% vs 0.3%, p < 0.01). This was similarly driven by pts in the laparotomy group (5% vs 0.6% vs 0.6%, p = 0.01) and was not seen in those in the MIS group (1% vs 0% vs 0%, p = 0.08). There was no difference in other complication types among the 3 BMI groups. Morbidly obese pts had a higher ICU admission rate (7% vs 3% vs 3%, p = 0.02) but there was no difference in length of stay, ED visits, and readmissions. Median 30-day total costs for women with a BMI ≥ 40, 30-39, and ≤ 29 were US $17.3k, $16.8k, and $16.6k respectively (p = 0.53). Median costs were lower for pts who had MIS than those who had laparotomy across all BMI groups ( ≥ 40: $14.9k vs $ 21.6k, p < 0.01; 30-39: $16.1k vs $ 18.9k, p = 0.01, and ≤ 29: $15k vs $19.3k, p < 0.01). Pts who had complications had higher median costs compared to those who did not (laparotomy: $27.7k vs $16.4k, p < 0.01; MIS: $19.9k vs $15k, p < 0.01). Conclusions: MIS in morbidly obese women may decrease costs while minimizing complications associated with obesity. Efforts to increase MIS uptake should be maximized in this population.
Clinical profile, pathological characteristics, mutational profile and disease outcome of non-small cell lung cancer patients treated at the Benavides Cancer Institute-University of Santo Tomas Hospital : A five-year study.
Authors: Maria Diana Aileen Chua Bautista, Priscilla B. Caguioa
Journal: Journal of Clinical Oncology (2017)

e20580 Background: Lung cancer is the most commonly diagnosed cancer worldwide and its incidence continues to grow. Lung cancer mortality and survival rates vary markedly by race and ethnicity resulting into a public health burden that differs by population subgroups. This study determined the association of the clinical profile, pathological characteristics and mutational profile with the disease outcome of Non Small Cell Lung Cancer patients at the Benavides Cancer Institute – University of Santo Tomas Hospital from January 1, 2007 to December 31, 2011. Methods: This is a retrospective descriptive study. Medical records of all of patients diagnosed with non-small cell lung cancer were included. Results: A total of 80 patients with non small cell lung cancer were treated, 78.75% (63) were adenocarcinoma and 13.75% (11) were squamous cell carcinoma. Overall 5-year survival rate was at 5%. The 1 year, 2-year, 3-year survival rates were 38.75%, 21.25% and 12.5% respectively with the mean survival time of 1.6 years. The mean survival time of patients who received adjuvant treatment was 26 months, while for metastatic patients was 18 months. Only the stage at time of diagnosis was correlated with overall survival. Age, gender, family history, smoking history, number of pack years smoking history, histologic subtype, response after first line of treatment and sites of metastases were not associated with overall survival. EGFR mutational analysis was not performed in this study since it was not the standard of care and had limited availability in low to middle income countries at the time of the study period. Conclusions: Similar to global incidence, adenocarcinoma remains the most common type of lung cancer in our center. Stage at diagnosis predicts overall survival among lung cancer patients. There is a need for molecular immunotyping to further characterize patients and response to treatment.
Survival trends of metastatic small intestinal neuroendocrine tumor: SEER analysis.
Authors: Chintan Shah, Athira Unnikrishnan, Rohit Bishnoi, Lazarus Mramba, Sreenivasa R Chandana, Jennifer Michelle Duff
Journal: Journal of Clinical Oncology (2018)

e13561 Background: Incidence rates of small intestinal neuroendocrine tumors (SNETs) are increasing and has become the most common type of small intestinal cancer. SNETs often present with distant metastasis. Significant uncertainty prevails regards to the management for metastatic SNETs. The aim of our study is to evaluate survival trends metastatic SNET patients based on therapy rendered. Methods: We analyzed the data from the SEER database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2016 Sub (1973-2014 varying). Relative survival rates (RSR) and hazard ratios (HR) were measured for patients diagnosed between 2000 and 2014. Therapy received was divided into two broad categories; surgery resection and no surgery. It was further subcategorized into local resection (LR) and radical resection (RR). Results: A total of 1138 SNET cases were identified. The median age of patients was 61 years. The median relative survival of entire patient population was 41 months with 5 years RSR of 72%. Age > 50 years (HR 2.10, P < 0.001), neuroendocrine histology compared to carcinoid (HR 0.68, P = 0.001), and poorly differentiated histology (HR 3.50, P < 0.001) showed poor outcome. Similarly, tumor size > 2 cm showed the trend towards poor outcome (HR 1.27, P = 0.07). The group which did not receive any tumor directed surgery showed the worst survival (5 years RSR 45.30% vs 76%, respectively for no surgery vs surgery group, P < 0.001). Upon further stratification, surgery significantly improved survival on patients who were > 50 years old (HR 0.37), primary tumor location at duodenum (HR 0.13), tumor size ≤ 2 cm (HR 0.26), poorly or undifferentiated histology (HR 0.29). We found no significant difference in survival between LR and RR (HR 1.01, P = 0.92). Conclusions: Surgery (LR or RR) for primary tumor significantly improves survival in SNET patients even in presence of distant organ metastasis. Poor prognostic factors include, age more than 50 years, duodenum as the location for primary tumor, tumor size > 2 cm, neuroendocrine histology compared to carcinoid, and poor differentiation of the tumor.
Assessment of clinical outcomes and prognostic factors in patients (pts) with non-small cell lung carcinoma (NSCLC) and brain metastases (BM): Results from a single institution.
Authors: Mariachiara Dipasquale, Orazio Caffo, Viviana Murgia, Antonello Veccia, Andrea Bolner, Sonia Brugnara, Alessia Caldara, Giovanni Fellin, Antonella Ferro, Michela Frisinghelli, Elena Magri, Francesca Maines, Salvatore Mussari, Michele Nagliati, Giuseppe Pani, Tiziana Proto, Chiara Trentin, Valentina Vanoni, Luigi Tomio, Enzo Galligioni
Journal: Journal of Clinical Oncology (2016)

e20594 Background: BM development, which is frequently observed in pts with NSCLC, is usually associated with a poor outcome. Systemic treatments and whole brain radiotherapy (WBRT) are widely used but increasingly, more aggressive local treatments such as surgery (S) or stereotactic radiotherapy (SRT) are being employed in selected cases. The present study is aimed to assess the factors affecting outcomes in NSCLC patients with BM. Methods: We retrospectively reviewed the clinical records of pts with NSCLC and BM consecutively treated in our Institution from October 2000 to December 2010. For each pt we recorded the clinical history and outcomes and collected the pt’s disease and treatment-related prognostic factors. Variables were examined in univariate and multivariate analysis. Results: We collected data of 113 pts (87% male, 13% female) with a median age of 65 yrs (range 26-85). The histotype was squamous in 23%, non squamous in 57%, and NOS in 20% of the case, respectively. BM were diagnosed at the time of the diagnosis or thereafter in 56 % and in 44% of the cases, respectively. BM were managed by local treatments in 87 % of the cases (S 12 pts, WBRT 53 pts, SRT 7), with 14 pts receiving multiple local treatments. Chemotherapy after BM diagnosis was administered in 53 pts (47%), while a TKi was administered in 6 pts (5%). Median overall survival (OS) after BM diagnosis was 7 mos, with 1-y OS of 27.4%. The OS by variables which resulted statistically significant at Cox proportional hazards analysis are showed in the table. Conclusions: From our preliminary results it appears that better performance status and the possibility to perform radical local treatments as well as chemotherapy after BM diagnosis are favourable prognostic factors in NSCLC patients with BM. Variable Value Median OS Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value ECOG 0-1 9 0.312 0.186- 0.522 0.0001 0.449 0.262- 0.769 0.004 ≥2 3 Neurological symptoms No 9 0.650 0.440- 0.961 0.030 Yes 4 S or SRT No 5 2.882 1.535- 5.439 0.001 2.567 1.275- 5.169 0.008 Yes 12 Chemo post BM diagnosis No 4 2.218 1.498- 3.283 0.0001 1.855 1.162- 2.962 0.01 Yes 10
Effective prevention of cancer in p53 null mice by depleting Rlip.
Authors: Sanjay Awasthi
Journal: Journal of Clinical Oncology (2018)

e13540 Background: TP53 (gene encoding the p53 protein) is a stress-responsive tumor suppressor whose functions are lost or altered in most malignancies. The importance of p53 as a tumor suppressor is evident from the >70% likelihood of cancer in persons with Li-Fraumeni syndrome, caused by p53 deficiency; it is also evident from the 100% incidence of lethal malignancy at age < 30 weeks in p53 homozygous knockout (p53-/-) mice. These mice are good models for discovery of drugs to prevent cancer in persons with p53 deficiency. Though a few previous genetic manipulations had shown slight prolongation in time to cancer development or switch in histological type of cancer, but none have resulted in cancer-free survival of 100% of p53-/- mice beyond 8 months of age. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral-effector involved in clathrin-dependent endocytosis. In stark contrast to p53-/- mice, Rlip-/- mice are highly resistant to carcinogenesis. Methods: We evaluated the survival and spontaneous carcinogenesis in p53-/-Rlip+/+, p53-/-Rlip+/-, p53-/-Rlip-/-, and p53+/-Rlip+/- micegenerated by cross breeding of P53+/- with Rlip-/-mice. For cancer prevention studies we administered R508 (508GGCTCCTGAATTGGCTTTTTC529), to deplete Rlip, or CAS by i.p. injection starting at 8 week age until euthanasia. RNAseq, Whole-genome bisulfite sequencing and reduced representation bisulfite sequencing (RRBS) assays were performed in liver samples of treated and control animals. Results: We report here that partial Rlip depletion switched off the cancer susceptibility of p53-/- mice and reverted promoter demethylation to wild-type. No previous intervention has accomplished this. Conclusions: Our findings provide promise of therapeutics for prevention of cancers in Li-Fraumeni syndrome.
Mutation analysis in 35 cases of newly diagnosed therapy-related acute myeloid leukemia (AML) by next-generation sequencing (NGS): A clinico-pathologic correlation.
Authors: Parsa Hodjat, Kankana Ghosh, Priyanka Priyanka, Beenu Thakral, Keyur Patel, Mark Routbort, Rashmi Kanagal-Shamana, Cameron C. Yin, Zhuang Zuo, Rajyalakshmi Luthra, Tariq Muzzafar
Journal: Journal of Clinical Oncology (2016)

e18525 Background: AML has numerous mutations that predict response to treatment and overall survival. We aimed to assess various mutations in newly diagnosed therapy related AML cases by NGS and their association with clinicopathologic parameters. Methods: We performed molecular studies on DNA extracted from bone marrow aspirate specimens in 35 newly diagnosed treatment naïve therapy related AML (WHO 2008 criteria) patients (8/2013 to 8/2015). Entire coding sequences of 28 genes (ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53, WT1) were sequenced using TruSeq chemistry on Illumina MiSeq platform. FLT3 and CEBPA mutation analysis were detected by PCR. Results: Median age was 71 years with 49% males and 51% females. Twelve (34.3%) and 3 (8.6%) patients had prior MDS and MDS/MPN respectively. CBC: [median (range)]: Hb 9 g/dL (4.9-12.9), platelets 48 K/μL (3-378), WBC 4.6 K/μL (0.4-156.6), ANC 1.3 K/μL (0-27.21), AMC 0.2 K/μL (0-14.2). BM blast % [median (range)]: 35% (5-92). Karyotype (n = 35): 7 (20%) diploid, 9 (25.7%) 1, 3 (8.6%) had 2, 1 (2.9%) had 3, 15 (42.9%) > three abnormalities, 17 (48.6%) monosomies, 10 (28.6%) trisomies. Three cases (8.6%) had t(8;21) , 3 (8.6%) t(9;11)(p22;q23), 1 (3%) t(15;17), 1 (3%) t(1;22). MRC risk categories were: favorable 4 (11.4%), intermediate 14 (40%), adverse 17 (48.6%). Mutations are detailed in Table 1. 13 (37.1%) had mutations in 1, 9 (25.7%) in 2, 4 (11.4%) in 3 and 2 (5.7%) in > 3 genes. Positive associations identified were: WBC and ASXL1, platelet count and JAK2, ASXL1, PTPN11, and peripheral blood (PB) blast % and FLT3. Conclusions: Therapy related AML is heterogeneous at the genetic level and multiple mutations likely indicate clonal evolution. With longer follow-up, we could use this data to refine prognostic models for AML. Genes No. of cases % of cases TP53 12 34.29% DNMT3A 6 17.14% TET2 6 17.14% FLT3 5 14.29% NRAS 5 14.29% IDH1 3 8.57% RUNX1 3 8.57% ASXL1 2 5.71% KRAS 2 5.71% NPM1 2 5.71% PTPN11 2 5.71% GATA1 1 2.86% JAK2 1 2.86% IDH2 1 2.86% KIT 1 2.86% WT1 1 2.86%
Real-world EQ5D health utility values for metastatic lung cancer patients by molecular alteration and response to therapy.
Authors: Catherine Labbe, Erin L. Stewart, Catherine Brown, Andrea Perez Cosio, Ashlee Vennettilli, Devalben Patel, Nicholas Y. Cheng, Mindy Liang, Gursharan Gill, Alexandra Rett, Yvonne Leung, Hiten Naik, Lawson Eng, Nicole Mittmann, Natasha B. Leighl, Ronald Feld, Penelope Ann Bradbury, Frances A. Shepherd, Doris Howell, Geoffrey Liu
Journal: Journal of Clinical Oncology (2016)

6567 Background: Economic analyses benefit from real world health utility values. In a new era of targeted therapy, current sets of utility values are important. Methods: A cross-sectional, longitudinal single-institution study evaluated 1516 EQ5D-3L-derived health utility values in 467 outpatients with metastatic lung cancer across various disease states. Patients with EGFR (n = 182) and ALK (n = 31) driver alterations were enriched through targeted enrolment; patients with wildtype (WT; n = 254) tumors were sampled randomly. Results: Population characteristics were as expected, with greater proportions of never smokers, Asians and adenocarcinoma in patients with mutations (each p < 0.001). The mean (SD) number of assessments was 3.2 (2.7) per patient (range 1-16). Patients completed questionnaires across the entire disease spectrum from 0-204 months (median, 12) after initial diagnosis. Intra-individual utility variability (measured as coefficients of variation) averaged 8-12% in various health states. For patients stable on treatment, mean (SD) utility values were 0.80 (0.16) and 0.82 (0.12) while receiving EGFR and ALK tyrosine kinase inhibitors (TKIs), respectively, (with no striking differences across agents) and significantly higher than the WT group stable on chemotherapy: 0.77 (0.13), p = 0.009. In mutation-specific comparisons, disease stability on appropriate therapy resulted in significantly higher mean utility values (p = 0.002-0.009) than when disease was progressing (EGFR, 0.70 [0.15]; ALK, 0.62 [0.25]; WT, 0.64 [0.20]). Stability on immunotherapy in WT patients had mean utilities of 0.80 (0.11). In stable/asymptomatic slow progression states off-treatment, mutation status did not affect mean utility values. Conclusions: Health utility values used in pharmaco-economic analyses of metastatic lung cancer patients should be specific for different molecular alterations under treatment-dependent disease states.
Treatments for locally advanced oropharyngeal cancer: A systematic review of clinical effectiveness and cost-effectiveness.
Authors: Chuong Ho, Kelsey Seal, Charlene Argaez, Cheryl Ho
Journal: Journal of Clinical Oncology (2018)

e18071 Background: The superiority of primary surgery versus primary concurrent chemoradiotherapy (CRT) in the treatment of locally advanced oropharyngeal cancer (LAOPC) is not apparent. This systematic review compares the clinical and cost-effectiveness of primary surgery versus primary CRT for adults with LAOPC. Methods: A systematic search using PubMed, Ovid, the Cochrane Library, University of York Centre for Reviews and Dissemination databases was conducted to search for studies reporting results comparing primary surgery and primary CRT for adults with LAOPC up to September 2016. Oncologic, functional, toxicity, complications and cost-effectiveness outcomes were reported. Results: We identified 14 observational studies and 1 economic evaluation. After 5 years follow-up, overall survival and disease-specific survival were statistically significant in favour of surgery in 3 out of 7 and 2 out 4 studies, respectively. No statistically significant difference was found between the two approaches on disease-free survival, local regional recurrence and control, local regional recurrence-free survival, progression-free and distant metastasis-free survivals, and on the most common complications. Subgroup analyses showed that the type of surgery (open or transoral) did not change the comparative oncologic outcomes. Quality-of-life scores favoured the CRT group while transoral surgery led to better swallowing outcomes. Recurrence rate was the determining factor for the cost-effectiveness, with concurrent CRT being the dominant strategy based on a base case of a non-smoking, HPV-positive 65-year-old man with LAOPC in an US context. Primary CRT dominated transoral robotic surgery (TORS) in almost every situation, except when the recurrence risk after CRT was high, or the risk after TORS was very low. Conclusions: Our review revealed that comparison between primary surgery and primary CRT for adults with LAOPC is inconclusive due to inconsistent results across studies and lack of consistent statistical significance. Primary CRT is cost-effective in some contexts. Large randomized controlled trials with long-term follow-up are needed.