tbuckley/cabot-search huggingface dataset:
The impact of a Veterans Administration NURSE Disease Management Program: The oncology aspect.
Authors: George Anthony Dawson, Deborah Ramirez, Donna Williams, Denise Gentile
Journal: Journal of Clinical Oncology (2016)

6584 Background: In an effort to decrease time to diagnosis and/or treatment intervention in newly diagnosed veteran cancer patients, Hudson Valley administrators chose the disease case management team model as a potential useful solution to enhance and / or expedite health care delivery. In 2008, the DM program was begun. The team consists of three Registered Nurses(RN) who work under the auspices of the Quality Management Division rather than a specific oncology clinic. This report will show the clinical impact of Hudson Valley VA’s Disease Management team. Methods: We assessed the timeline in days for veterans to get scheduled for recommended tests and consults before and after the DM team implementation. We reviewed timeline data for patients diagnosed during fiscal years 2009 to 2014. The percentage change were calculated for Oncology Consults and Intra-facility Consults to DM team and those placed by them. Times from diagnosis to treatment intervention pre and post DM implementation were reviewed for Primary liver, colon and lung cancers. Results: Rate of change: Oncology consults for DM team intervention: 62% increase. Inter-facility consults for tests (PET/CT scans) and treatments (Neurosurgery, Radiation, Urology, and Head and Neck Surgery) placed by DM team: 153% increase. Reduction in time from diagnosis to treatment intervention: colon cancer and Lung Cancer 50% and 46% respectively. Reduction in the time required for getting primary Liver cancer patients into diagnostic tests and tumor board presentations for treatment intervention – days shortened from 92 to ~31 days from 2010/11 to 2015. This reflected a 66% decrease in time to treatment intervention. Conclusions: These data reflect that in a VA care setting, the Disease(cancer) Case Management team model is feasible. These data show that the introduction of the disease management team model shortened the number of days from diagnosis to treatment by facilitating referrals, clinical testing, and/or treatment initiation in Veteran cancer patients resulting in timely care intervention.
Plasma <i>HER2 (ERBB2)</i> copy number to predict response to HER2-targeted therapy in metastatic colorectal cancer.
Authors: Alberto Bardelli, Giulia Siravegna, Andrea Sartore-Bianchi, Rebecca J Nagy, Benedetta Mussolin, Andrea Cassingena, Cosimo Martino, Sara Lonardi, Vittorina Zagonel, Francesco Leone, Alessio Amatu, Livio Trusolino, Justin Odegaard, Richard B. Lanman, Silvia Marsoni, Salvatore Siena
Journal: Journal of Clinical Oncology (2018)

3506 Background: The rate of HER2 (ERBB2) copy number amplification (CNA) in metastatic colorectal cancer (mCRC) ranges from 2-13%. HERACLES, a phase II trial of trastuzumab and lapatinib (T+L) in HER2-positive mCRC showed response rates of 30%, suggesting HER2 as a viable target in this population. Cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) may be an option for ERBB2 CNA determination when biopsy is infeasible or tissue is insufficient. Here we determine the sensitivity of plasma CNA (pCNA) detection using a ctDNA NGS assay and suggest a cutoff predictive of response to HER2-targeted therapy. Methods: Pre-treatment and progression plasma samples (N = 48) from 26 HER2 FISH-positive patients in the HERACLES study were tested using the Guardant360 assay. We correlated ERRB2 pCNA with progression free survival (PFS) and best objective response (BOR) on T+L. To establish a threshold for absolute pCNA predicting response, we analyzed ERBB2 CN relative to panel-wide CNA profile and clonal driver co-occurrence in 819 consecutive mCRC samples tested with Guardant360. Results: 46/47 samples with detectable ctDNA were ERBB2-amplified based on ctDNA (2.55-122 copies; PPA = 96%, 95% CI 85-99%). A threshold of ≥3 copies of ERBB2 in circulation allowed identification of 94% of FISH-positive patients, while excluding 86% of all co-occurring KRAS, NRAS, and BRAF driver mutations in the larger clinical cohort. HERACLES patients below this threshold had reduced PFS (median 4.6 vs. 1.1 months, p = 0.10). Above the threshold, plasma ERBB2 CNA strongly correlated with BOR (r = 0.5) but weakly with PFS (r = 0.37). Conclusions: The ctDNA platform utilized correctly identified 96% of samples as ERBB2-amplified and accurately predicted HER2-targeted therapy response rates. Based on the HERACLES and large clinical cohorts, a cutoff of 3 copies of ERBB2 in plasma is proposed to select patients who will benefit from targeting HER2.
Effect of a delay in definitive surgery in melanoma on overall survival: A NCDB analysis.
Authors: Alina Basnet, Dongliang Wang, Shreya Sinha, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2018)

e21586 Background: Time delay from diagnosis to definitive surgery has negative impact on the overall and disease-specific survival in breast cancer but the same has not been proven for colon cancer. Using National Cancer Data Base (NCDB), we report the impact of delay in surgery on overall survival of cutaneous melanoma. Methods: We identified patients with stage I to III cutaneous melanoma, age ≥ 18, using the NCDB (2004-2014). Days from diagnosis to definitive surgery was calculated in the increments of the 30 days (d) as 0-30d, 30-60d and > 60d. Overall survival (OS) was calculated using Kaplan Meier analysis with hazard ratio (HR) from cox regression model. Results: The NCDB cohort had 313,329 patients, diagnosed between 2004-2014.Of which patients who had surgical interval from date of diagnosis of < 30d, 31 to 60d and > 60d accounted for 59.05%, 31.89% and 9.05% respectively. Five-year OS and nine-year OS were 80% and 65.6% vs 79.2% and 63.3% vs 72.7% and 56.2% for 0-30d, 31-60d and > 60d time lag respectively. Hazard ratio (HR) with 95% confidence intervals (CI) for the respective groups is shown in table 1. More percent of stage I melanoma were likely to get surgery within first 30 d of diagnosis, whereas more percent of stage III melanoma had surgery after 60 d. Conclusions: OS was statistically significantly lower among patients with melanoma who were to receive surgery after 60d of diagnosis compare to within 60d. Table 1- HR estimates and 95% CI from Cox regression Groups ( in days) Adjusted HR 95% CI 0-30d vs 31-60d 1.025 0.999-1.052 0-30d vs > 60d 0.943 0.908-0.980 31-60d vs > 60d 0.920 0.884-0.957
Toxicity of high-dose chemotherapy in patients with osteosarcoma.
Authors: Nailya Guskova, Oleg Ivanovich Kit, Sergei A. Kuznetsov, Andrey A. Maslov, Maria V. Starzhetskaya, Aleksandra I. Bespalova, Ekaterina Guskova, Svetlana V. Belgova, Anastasia Nozdricheva, Tatiana Yu. Myagkova, Aliya K. Donskaya, Marina A. Gusareva, Kristina Avanesova, Svetlana V. Abakumova, Irina V. Tselishcheva, Nadezhda Golomeeva, Izabella Torpudzhyan, Zinaida P. Lisunova, Viktoria Zakharchenko, Ineya I. Zekhtser
Journal: Journal of Clinical Oncology (2018)

e14508 Background: We monitored the level of methotrexate and some laboratory parameters in patients with osteosarcoma to evaluate the toxicity of high-dosage EURAMOS chemotherapy. Methods: The study included 5 osteosarcoma patients aged 10-17 years receiving chemotherapy with high-dose (12 g/m2) methotrexate (MTX). Plasma levels of MTX were determined (VIVA E, Netherlands) before MTX administration and in 4, 24, 36, 42, 48, 54, 60, 66 and 72 hours. Were investigated C-reactive protein velocity (CRPv), α1-antitrypsin (AAT), urea, creatinine, N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase M-type (CKM), troponin I (TI), albumin, ALT, AST and LDH (Vitros 5600, USA). Results: Before treatment, patients showed a low level of albumin (33.0±2.34 g/l), high СRBv (5.13±0.64 mg/l), moderately elevated AAT (2.6±0.28 g/l) and LDH activity (239.0±8.12 U/L). Urea, creatinine, ALT, AST and NT-proBNP were within the reference range. The highest MTX level (6065.28±56 μmol/L) was determined in patients 4 h after the injection. After 24 hours, the MTX level was 8.4 ± 0.42 mmol / l; 36 h - 1.5 ± 0.14; 42 h – 0.8 ± 0.02, by 72 hours was undetectable. At the peak of the MTX concentration, the urea level decreased by 2.0 times, the NT-proBNP increased by 2.5 times, with the initial values restored to 72 hours, the albumin concentration decreased by 15% from the baseline level, increased AST activity by 3.3 time, ALT - 2.3 and LDH- 1.6. These changes were retained by the end of the assessment course and by the beginning of the next MTX introduction. Levels СRBv, AAT, creatinine, CKM, TI did not change. At subsequent stages of treatment, changes in most of the indicators studied had a similar orientation. The activity of AST, ALT and LDH restored to the initial values due to the massive infusion therapy and accompanying hepatoprotective, detoxification therapy. So, high-dose chemotherapy MTX was accompanied by a transient change in the levels of urea and creatinine and increased activity of ALT, AST, LDH due to the hepatotoxic effect. Conclusions: Monitoring the level of methotrexate and a complex of biochemical parameters with high-dose chemotherapy allows minimizing expected complications in patients with osteogenic sarcoma.
Demographic composition of lung cancer trials: FDA analysis.
Authors: Lola A. Fashoyin-Aje, Laura L. Fernandes, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

9088 Background: Lung cancer is the leading cause of cancer death; in the US non-small cell lung cancer (NSCLC) accounts for 80% of the lung cancer diagnoses. Enrollment of a diverse population in clinical trials (CTs) of new cancer drugs may provide information regarding the safety and efficacy of treatments in demographic subgroups that are disproportionately represented among new cases of, and deaths from, cancer. This analysis characterizes the demographics of patients enrolled in CTs submitted to FDA in support of marketing applications for FDA-approved NSCLC drugs. Methods: Reviewed datasets in the applications of original approval for new NSCLC drugs (2011- 17), and pooled demographic data from CTs that provided primary safety and efficacy data for drug approval. Results: This table illustrates enrollment by demographics at all sites and in the US. Conclusions: Enrollment of females is slightly higher (54%) than predicted based on corresponding incidence rates (48%) for this subgroup in the Surveillance, Epidemiology, and End Results database. Enrollment of younger patients is also higher than predicted based on incidence rate; patients < 65 years comprise 68% of all enrolled patients compared to 28% of new cases. These differences may be attributable, in part, to the number of CTs for new drugs for biomarker-defined NSCLC subtypes that occur more frequently in females and younger patients than in NSCLC in general. In contrast, there is lower representation of racial/ethnic minority patients ( < 1%) and patients ≥ 65 years of age (32%) in these CTs than predicted by incidence rates (65.9, 83.7, 312 and 15 cases per 100,000 in patients who are White male, Black male, > 65 years, and < 65 years, respectively). Targeted enrollment of racial/ethnic minorities and older patients is needed to improve their access to CTs; such efforts may facilitate an assessment of safety and efficacy in these subgroups. All n = 9711% US n = 1149% Age < 65 years 68 72 65-80 years 31 25 > 80 years 2 2 Sex* Female 54 55 Race# American Indian/ Alaskan Nativea < 1 < 1 Asian 43 10 Black/African American < 1 2 Native Hawaiian / Other Pacific Islandera < 1 < 1 Other 2 4 White 50 82 Ethnicity Hispanic 2 3 Not Hispanic 19 21 Other 3 12 Missing/Not Collected 76 65 *Missing ‘Sex’ (n = 2); #Missing ‘race’(n = 484). a (n = 3).
In vitro and in vivo anti-melanoma activity of ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties.
Authors: Fengdong Cheng, Andressa Sodre Laino, Hongwei Wang, Jie Chen, Alejandro Villagra, David Michael Woods, Jeffrey S. Weber, Steven Quayle, Simon S. Jones, Eduardo M. Sotomayor
Journal: Journal of Clinical Oncology (2016)

e21075 Background: Previously, we have shown that pan-HDAC inhibitors induce apoptosis and changes in the immunogenicity of melanoma cells. Further studies identified HDAC6 playing a central role in regulating melanoma immunogenicity. Genetic knockdown (KD) of HDAC6 in murine and human melanoma cells increased the expression of MHCI and costimulatory molecules as well as melanoma associated antigens. In vivo studies demonstrated that the growth of melanoma cells lacking HDAC6 was significantly delayed as compared to wild-type cells. Methods: C57BL/6 mice were given melanoma cells sc. When mice developed a palpable mass they were treated with vehicle control, ricolinostat alone, or in combination with anti PD-1 or anti CTLA-4 antibodies. To assess the effects of ricolinostat upon T cells, murine T-cells were activated with anti-CD3/CD28 dynabeads in the presence -or not- of 1 uM ricolinostat for 24 hour. Then, cells were adoptively transferred into B16 bearing mice. T-cell subpopulations from the lymph nodes were analyzed ex vivo. Results: First, in vivo treatment of melanoma bearing mice with ricolinostat resulted in a dose-dependent inhibition of tumor growth (p < 0.05). No toxicities were observed at the doses studied. Second, the antitumor effect exerted by ricolinostat was not observed when melanoma bearing SCID mice were treated with this compound, indicating that an intact adaptive immune system is required for the observed antitumor activity. In lieu of these previously unknown immunomodulatory properties of ricolinostat, we next assessed the effects of this compound upon T-cells in vivo. We show here that treatment of murine T-cells with ricolinostat resulted in a significant increase in central memory T-cells endowed with a strong anti-melanoma activity in vivo as compared to control-treated T-cells (p < 0.05). Finally, the addition of ricolinostat treatment to either anti-CTLA-4 or anti-PD-1 treatment was associated with an enhanced inhibition of melanoma tumor growth. Conclusions: Our results have identified HDAC6 as a novel target for melanoma immunotherapy and point to ricolinostat as an attractive agent to add to the immuno-oncology armamentarium.
Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries
Authors: Marcus C. Parrish, Yuan Jin Tan, Kevin V. Grimes, Daria Mochly-Rosen
Journal: The Annual Review of Pharmacology and Toxicology (2018)

With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need.
Synthesis and preclinical characterization of novel ruthenium (II) arene complexes for the treatment of solid tumors.
Authors: Veronica Corrales-Sanchez, Ana Isabel Ojeda-Amador, Cristina Nieto-Jimenez, Álex Shafir, Lewis Broomfield, Carlos Alonso Moreno, Alberto Ocana
Journal: Journal of Clinical Oncology (2018)

e14512 Background: The development of metallopharmaceutics has placed organometallic ruthenium (II) complexes in the spotlight of interest. Although platinum agents are still the main therapeutic option for the treatment of many solid tumors, resistance to these agents is an unresolved problem. Methods: The modular synthesis of the aminophosphine core has been exploited as tool for rapid development of antitumoral metallodrug candidates. Starting with a series of structurally diverse aminophosphines, all obtained in a single step from commercial amines, a family of novel ruthenium(II) arene complexes were generatedby adding dichloromethane to a mixture of the aminophospineligands and [RuCl2(p-cym)]2. Thereafter their activity was evaluated by using MTTs assays in a series of 14 cell lines from five different tumor types, including non-small cell lung cancer, prostate, breast, ovarian and colon (HS578T, SKBR3, BT474, MCF7, MDA-MB231, BT549, PC3, DU145, A549, HT29, IGROV-1, OVCAR-8, SKOV-3, A2780). In addition, two cell lines models resistant to cisplatin (MDA-MB231R, A2780R) were evaluated. We compared their activity with approved platinum agents; cisplatin, carboplatin, and oxaliplatin. Results: The novel ruthenium(II) arene complexes (1-15) were synthetized and fully characterized by NMR, elemental analysis, and RX-diffraction studies. Two of them (Ru-14 and Ru-15) were selected as lead compounds. Ru-14 showed relevant activity in several cell lines with an IC50 below 500 nM in BT474, IGROV-1, MCF7, OVCAR8 and A2780. In all cell lines tested Ru-14 showed the most active profile compared with Ru-15 and RAPTA. Significantly, Ru-14 was more active than platinum compounds (cisplatin, carboplatin and oxaliplatin) in HS578t, SKOV3, BT549, DU145, A549, SKBR3, HT29, OVCAR8, A2780, PC3, BT474, IGROV1 and MCF7. Finally, Ru-14 showed antiproliferative activity in the cisplatin resistant ovarian model A2780. Conclusions: We have synthetized a series of novel metallodrugs based on ruthenium. One of this family of complexes, Ru14, showed antitumor activity in a wide number of cell lines, being more active than platinum compounds, and with activity in platinum resistant cells.
Serum autoantibodies against tumor-associated antigen cyclin D1 represent a potential biomarker of malignancy in well-differentiated thyroid tumors
Authors: P.V. Belousov, A.V. Bogolyubova, P.R. Efimova, D.E. Demin, A.Y. Abrosimov, K. Lanshchakov, V.E. Vanushko, A.M. Schwartz
Journal: Annals of Oncology (2018)

Background: Preoperative differential diagnosis of benign and malignant thyroid tumors remains a challenge in many cases, thus complicating the optimal planning of patients' treatment. We have recently demonstrated the possibility of discrimination between benign and malignant thyroid lesions using serum autoantibody biomarkers. Here we further assessed whether a protein commonly overexpressed in malignant thyroid tumors may elicit an autoantibody response that may be used for serum-based preoperative differential diagnosis of thyroid nodular lesions. Methods: A protein cyclin D1 (CCND1) commonly used as a tissue biomarker of malignancy in thyroid lesions was produced as purified recombinant protein, and its serological reactivity was assessed using Western-blot analysis in a cohort of 70 patients with various thyroid tumors (classical papillary carcinomas (n = 25), follicular-patterned carcinomas (n = 15), borderline «uncertain malignant potential» tumors (n = 10), benign follicular adenomas (n = 20)) and 30 healthy volunteers. Results: Autoantibodies against cyclin D1 (CCND1) were found in 4/25 (16%) and 1/15 (7%) of patients with classical papillary and follicular-patterned carcinomas, respectively. None of patients with non-malignant tumors and healthy volunteers demonstrated any autoantibody response against CCND1 (p = 0.037 compared to classical variant papillary carcinomas). Conclusions: Malignant but not benign thyroid neoplasms may trigger specific autoantibody response against cyclin D1. This finding is in line with the known expression pattern of CCND1 and its role as a key downstream effector of hyperactivated MAP-kinase cascade. The 100% specificity of anti-CCND1 autoantibodies in detection of cancer may allow the use of this candidate serum biomarker for preoperative diagnosis of thyroid lesions, particularly in conjunction with other potential biomarkers to compensate for a low diagnostic sensitivity. This work is supported by grant 16-15-10423 from Russian Science Foundation. Legal entity responsible for the study: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences Engelhardt Institute of Molecular Biology, Russian Academy of Sciences Engelhardt Institute of Molecular Biology, Russian Academy of Sciences. Funding: Russian Scientific Foundation. Disclosure: All authors have declared no conflicts of interest.
Multicenter study for the correlation among PD-L1 antibodies, tumor mutation burden (TMB) and lung immune prognostic index (lipi) in Chinese patients with advanced lung adenocarcinoma.
Authors: Jianming Ying, Pei Yuan, Yuan Li, Lili Jiang, Yueping Liu, Li Junling
Journal: Journal of Clinical Oncology (2018)

e21218 Background: Anti-PD-1/PD-L1 immunotherapy was approved as first-line treatment on the part of NSCLC patients, but not all patients can benefit from immunotherapy, so the research emphasis is how to predict the immunotherapy efficacy or to screen the potential benefit population. A number of studies have shown that PD-L1 expression, Tumor Mutation Burden (TMB) and Lung Immune Prognostic Index (LIPI) can be respectively used as an effect predictor of NSCLC immunotherapy. We aim to explore the correlation of the PD-L1 expression, TMB and LIPI in Chinese patients with advanced lung adenocarcinoma. Methods: In this multicenter study, we enrolled a total of 65 biopsy specimens of the advanced lung adenocarcinoma patients from four China centers from September to December 2017, then collected the results of complete blood cell counts and lactate dehydrogenase (LDH) before biopsy, detected the PD-L1 level by five IHC assays (22C3, 28-8, SP263, SP142 and RM311) and detected driver genes and TMB by targeted NGS. Results: There were 11 specimens (17.2%,11/64) with positive PD-L1 results (≥50%) based on the 22C3 assays. 22C3, 28-8 and SP263 assays were highly concordant for tumor cells staining when using a 4-categories scale or not (ρ = 0.754-0.831). Lower concordance was observed for immune cells staining in the same situation (ρ = 0.267-0.620). The two pathologists showed high consistency in the interpretation of the positive tumor cells (ρ = 0.728-0.890), especially on 22C3 and SP263 assays, whereas the immune cells had a generally low level of interpretation (ρ = 0.587-0.732). Here we just showed the analysis of four IHC assays (22C3, 28-8, SP263 and RM311), the remaining results have yet to be tested and analyzed. Conclusions: 28-8, 22C3 and SP263 assays were aligned on tumor cell staining, which may potentially be used interchangeably to identify the potential benefit patients of anti-PD-1/PD-L1 immunotherapy. The present challenge is the standard staining and interpretation of immune cells in the tumor. This multicenter study may provide the research basis of effectively screening the potential benefit population of the immunotherapy.