tbuckley/cabot-search huggingface dataset:
Survival, value and relative value of the immune check point inhibitors vs. docetaxel in 2nd-line treatment of non-small-cell lung cancer.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2018)

e21098 Background: The value of the immune check point inhibitors (ICPI) has not been thoroughly assessed vs. Docetaxel (Doc). Objective: Compare median overall survival (OS) and value of nivolumab (Nivo), atezolizumab (Atezo) and pembrolizumab (Pembro) with Doc in 2nd-line non-small-cell lung cancer (NSCLC). Methods: Previously reported OS, doses, protocols and company-posted prices were quoted. Costs of Doc x 12-cycle, ICPI x one year and adverse events treatment costs (AEsTC) were calculated. Cost/life-year gain (C/LYG) was computed as cost/OS day-gain over control x 360. Relative value (RV) were calculated as $100,000/C/LYG. Results: Doc (Shepard FA, JCO 2000) showed OS 87 day-gain, black box warning, grade ¾ incidence > 20%, costs $63,648, AEsTC $5,840 and value $197,528. Nivo, Atezo and Pembro had no black box warnings, approximate AEs ¾ 10%, average costs $152,561 and AEsTC $1,980. Nivo (CheckMate 057) OS was 84 and value $663,891 improving in > 10% PD-L1 subset analysis to 342 and $163,061 respectively. Atezo (OAK) OS was 111 and value $484,570 improving in > 50% to 348 and $154,561. Pembro (KEYNOTE-010) was 57 and value $968,621 improving in > 50% to 201 and $274,684. Enrichment of PD-L1 improved Nivo RV by 4-fold, Atezo 3.2 and Pembro 3.6. Conclusions: In 2nd-line NSCLC in contrast to Doc, the ICPI had no black box warnings, lower ¾ AEs, higher costs and lower AEsTC. Doc demonstrated significant value advantage over ICPI in non-selected PD-L. However, PD-L1-enrichment resulted in unprecedented OS and enhanced value. Due to the limited available comparative data and retrospective subset analyses, one ICPI could not be favored over another.
Immunologic signatures of osteosarcoma: Implications for prognosis and therapy.
Authors: Bushra Weidenbusch, Marc Johannes Weidenbusch, Stefan Burdach
Journal: Journal of Clinical Oncology (2016)

e14564 Background: Osteosarcoma (OS) is the most common primary bone malignancy and the third most common tumor in adolescents. Therapy options are limited with poor survival rates in primary metastatic disease. The role of the immune system in the development of metastases and therapy response is not well defined. Methods: We investigated the expression profile of 61 primary and metastatic human OS patients. Data was compared to an expression profile of a customized atlas of 852 samples and 27 healthy human tissues (NT). Four different gene sets were defined to estimate a multi-variate immunoscoring system. Two previously defined immunoinfiltrate and chemokine signature scores, a costimulatory molecule score, and an antigen presenting machinery (APM) score. Expression normalization and background adjustment was done using Robust Multiarray Average. An exploratory dataset was used to stratify the expression in patients with poor vs. good prognosis. Correlation analysis of survival data was performed on the validation dataset. Results: Most of the genes from the two previously published immunoscores were differentially expressed between OS and NT. The differences were pronounced for CCL3, CXCL9 and CXCL11 (upregulated in OS) and CCL2, CCL4, CCL18 and GZMK (downregulated in OS). In addition, the expression of the majority of APM and T-cell costimulation genes was altered in OS with Upregulation of CD137, PD1 and CTLA4 and almost entire downregulation of LAG3 and CD28 in OS samples. Additional genes like IL15, IL12RA were significantly downregulated. When OS cases were stratified for either of the two previously established immunoscores or newly established gene expression scores for antigen presentation and T cell costimulation, the presence or absence of the respective expression signatures significantly correlated with overall survival in both the discovery and the validation cohort. Conclusions: The present analysis delineates the importance of immunologic mechanisms in OS and presents feasible methods of phenotype stratifications. Efforts to further define the detailed underlying immunologic phenotypes, their immunoinfiltrate and therapeutic implications in OS patients are warranted.
Testicular histopathology after immunotherapy for metastatic melanoma.
Authors: Karl S Benz, Mahir Maruf, Eleonora Duregon, Jody Hooper, Andres Matoso, Amin S Herati
Journal: Journal of Clinical Oncology (2018)

e15114 Background: Ipilimumab, Pembrolizumab, and Nivolumab are immune checkpoint inhibitors (ICI) used in the setting of metastatic melanoma and their effect on male fertility is largely unknown. Based on the anecdotal findings of an index patient who developed azoospermia following ICI treatment, we sought to characterize the histologic effect of ICI-based monoclonal antibodies on spermatogenesis in men treated for metastatic melanoma. Methods: Testicular specimens from 2015-2017 were obtained from adult males with advanced melanoma who had undergone immunotherapy for > 1 month at a single tertiary care center. Patients that received systemic radiation or chemotherapy were excluded. Hematoxylin and eosin stained slides were used for morphological analysis under light microscopy. A retrospective review was performed to collect patient demographics, melanoma treatment history, type of immunotherapy, and duration of therapy. Results: The cohort included six adult males with a median age of 58.5 years [range 30-67]. The specimens examined consisted of one testicular biopsy performed for fertility work-up (index case), and 5 testes from 5 autopsies. Four patients (66.7%) received Ipilmumab and Nivolumab and two patients (33.3%) received Ipilimumab and Pembrolizumab. On microscopic analysis, three morphological patterns were observed: three patients (50%) showed a aspermatogenesis with Sertoli cell only pattern, two patients (33.3%) exhibited hypospermatogenesis, and one patient (16.7%) had normal spermatogenesis. The median ages at biopsy were 33 years [range 30-66] old for specimens showing a aspermatogenesis and Sertoli cell only pattern, 63 years [range 59-67] old for specimens showing hypospermatogenesis, and 58 years old for the patient with normal findings. All specimens were characterized by normal number of Leydig cells in the interstitium. None of the cases showed a testicular neoplasia including intratubular germ cell neoplasia in-situ. Conclusions: Adverse events related to ICIs require further investigation. Spermatogenesis may be impacted by these immunotherapies, though the mechanism remains uncertain. These cases highlight potentially significant adverse events that have been previously unreported.
P02.09 Proteomic analysis of meningioma discovers new pathways and their activation including NEK9 and AKT
Authors: C O Hanemann, J Dunn, S Ferluga, V Sharma, M Futschik, D Hilton, C Adams, E Lasonder
Journal: Neuro-Oncology (2018)

Meningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is still hampered by the poor knowledge of the molecular signature of these tumours In order to elucidate the proteomic profiling of meningiomas and identify proteins involved in their pathogenesis, we completed a comparative mass spectrometry analysis of meningioma tissue of all WHO grades, analysing global proteins, phosphoproteins and phosphopeptides. We performed differential expression analyses and functional annotation studies to identify commonly upregulated proteins and phosphoprotein in all grades of meningioma compared to meningeal tissue as well as grade-specific candidates relevant for tumour progression. Top candidates werevalidated by Western blotting and immunohistochemistry in an additional sample set We confirmed significant overexpression of proteins including EGFR, STAT2 and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation in all grades of the total and activated phosphorylated form of the NIMArelated kinase, NEK9, involved in mitotic progression. Novel proteins identified in meningioma and validated as commonly overexpressed in all grades were the nuclear proto-oncogene SET and the splicing factor SF2/ASF, while another newly identified protein that was specific for higher grades was hexokinase-2, involved in cellular metabolism Overall, we generated a proteomic thesaurus of meningiomas in order to decipher aberrantly expressed proteins and activated pathways; this body of knowledge will eventually lead to the identification of relevant biomarkers and therapeutic targets.
The demography of human papillomavirus (HPV) infections in oropharyngeal cancer patients from 2011-2016: A single Veteran Administration institution.
Authors: George Anthony Dawson, Yue Hua Zhang, Angela Laurio, Patricia Smith, Michael Dellatto, Fiona T. Innis-Gordon, Anthony Reino
Journal: Journal of Clinical Oncology (2017)

e17532 Background: Human papilloma virus (HPV) is a known biologic (viral) carcinogen and has a predilection for tissue in head and neck sites- HPV types 16/18. Current NCCN guidelines recommend HPV testing on newly diagnosed cancers - Head and Neck region - specifically the oropharynx. Methods: After IRB approval, data from our center ranging from 01/01/2011 to 12/31/2016 were collected by using international classification codes (ICD-9) 142, 143, and 146. We enrolled 81 patients for review from of these anatomic sites: Base of tongue, Tonsils, Posterior hypo-pharyngeal wall, soft palate and unknown primary + neck nodes. Data collected: HPV status / age / stage at diagnosis. Risk factors collected were marital status, ethnicity, age, alcohol and tobacco use, and other co-factors. Results: A total of 73 of 81 cases met our criteria for inclusion into review: excluded - 5 with Non-Hodgkin’s lymphoma; 1 with plasma cell neoplasm; 2 excluded - p16 testing only. All enrollees were male. Age range 45 - 91. Mean age: HPV + 64.11 / HPV – 66.76yrs. Anatomic site:BOT-35(48%) /Tonsil-25 (34%) /unknown primacy- 6(8%) /Soft palate– 4(0.05%) /Hypo-pharnyx-3(0.04%). Ethnicity: Non-Hispanic White– 32(44%) /Black-19(26%) /Hispanic – 20 (27%) /American Indian – 1(0.01%) /Unknown – 0. Seventy-three tested for HPV: 36 pos (49%) /37 neg (51% ). Whites were of 49% HPV+. HPV16/18+ in 34 of 36 (94%) tumors. Tobacco exposure ever:32/37(75%) HPV + and 26/36 (75%) HPV - groups. Alcohol use ever: HPV+ 75%; HPV – 67%. Location:BOT/Tonsils were 32/36 (80%) HPV+ cases and 27/37(73%) of HPV – cases. HPV + Marital status: Married 9 (26%) / Never mar 9/Divced 15/Sep 2/Wid 1 - 74% not married. HPV – 37: Married 12 (32%) /Never mar 9 /Divced 9/Sep 5/Wid 2 – 68% not married. Conclusions: HPV +16/18 (34 of 36) infections in our patients (73) were 49% of the overall group. BOT and Tonsil cancers most were the common sites in both groups (+/-). Compared to non-VA patients, our HPV + group used more alcohol and smoked more, and were older - though both groups (+/-) had high usage rates. We noted more divorcees, and lower marriage rate in the HPV+ group. Whites were 44% overall but 49% of HPV + group.
<i>Vital Signs</i>: Prevalence of Key Cardiovascular Disease Risk Factors for Million Hearts 2022 — United States, 2011–2016
Authors: Hilary K. Wall, Matthew D. Ritchey, Cathleen Gillespie, John D. Omura, Ahmed Jamal, Mary G. George
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Despite decades-long reductions in cardiovascular disease (CVD) mortality, CVD mortality rates have recently plateaued and even increased in some subgroups, and the prevalence of CVD risk factors remains high. Million Hearts 2022, a 5-year initiative, was launched in 2017 to address this burden. This report establishes a baseline for the CVD risk factors targeted for reduction by the initiative during 2017-2021 and highlights recent changes over time.Risk factor prevalence among U.S. adults was assessed using data from the National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, and National Health Interview Survey. Multivariate analyses were performed to assess differences in prevalence during 2011-2012 and the most recent cycle of available data, and across subgroups.During 2013-2014, the prevalences of aspirin use for primary and secondary CVD prevention were 27.4% and 74.9%, respectively, and of statin use for cholesterol management was 54.5%. During 2015-2016, the average daily sodium intake was 3,535 mg/day and the prevalences of blood pressure control, combustible tobacco use, and physical inactivity were 48.5%, 22.3%, and 29.1%, respectively. Compared with 2011-2012, significant decreases occurred in the prevalences of combustible tobacco use and physical inactivity; however, a decrease also occurred for aspirin use for primary or secondary prevention. Disparities in risk factor prevalences were observed across age groups, genders, and racial/ethnic groups.Millions of Americans have CVD risk factors that place them at increased risk for having a cardiovascular event, despite the existence of proven strategies for preventing or managing CVD risk factors. A concerted effort to implement these strategies will be needed to prevent one million acute cardiovascular events during the 5-year initiative.
Abstract 17838: Discordance Between Findings in Publications and FDA Reviews for New Drug Approvals in Cardiovascular Disease and Diabetes, 2005-2013
Authors: Adam T Phillips, Nihar Desai, Harlan Krumholz, Joseph Ross
Journal: Circulation (2016)

The US Food and Drug Administration (FDA) approves new drugs based on studies that demonstrate safety and efficacy. Selective publication and outcome reporting was previously described but not evaluated since the 2007 FDA Amendment Act (FDAAA) mandated registration and reporting of all clinical studies included in applications for FDA approval. Our objective was to determine publication status and ClinicalTrials.gov registration for studies submitted to the FDA in support of new drug approvals from 2005-2013 in cardiovascular disease and diabetes, and compare outcome reporting in the FDA reviews with those in the published literature. A publicly available FDA database was searched to identify all new drug approvals. For each study used to support efficacy, we searched PubMed and ClinicalTrials.gov to determine publication and registration status, respectively, and calculated overall rates and stratified these rates by study characteristics. For all published studies, we compared FDA and peer-reviewed publ...
Dynamic process of circulating tumour DNA (ctDNA) profiling as a predictor of efficacy of pemetrexed combined platinum chemotherapy in advanced lung adenocarcinoma.
Authors: Ying Han, Xiaohong Han, Zhe Wang, Wen Luo, Wenyuan Zheng, Wumin Dai, Huang Yu, Jiarui Yao, Zhishang Zhang, Di Wu, Yuankai Shi
Journal: Journal of Clinical Oncology (2017)

e23048 Background: Pemetrexed combined platinum is recommended as first line chemotherapy regimen for non-squamous non-small cell lung cancer. However, the efficacy is variable for individuals. Methods: We conducted a prospective study with 52 consecutive patients enrolled who were histologically confirmed advanced or metastatic lung adenocarcinoma, of whom, 32 had their plasma samples collected both baseline and follow-up when efficacy evaluation. We used a next-generation sequencing to assess the dynamic change of ctDNA across 87 plasma samples. Results: 34 blood samples from 61.5% of patients demonstrated smoking status is an infavorable factor to drug efficacy ( p= 0.02, fisher’s exact test, two-sided). Simultaneously, we found positive correlation between decreased mutation burden and chemotherapy sensitivity (the mean mutation rates of pre chemotherapy, PD, PR, SD and SDA were 4.5, 6.3, 2.1, 1.6 and 2.4, respectively, p= 0.004, one way ANOVA test, two-sided).The mean mutation rates with T &gt; G substitution mutation of pre and post chemotherapy were 1.5 and 0.6 ( p= 0.014, Mann-Whitney U test, two-sided). 34.4% (11/32) individuals harbor those mutation pre chemotherapy, 6 out of them were characterized by DNA repair signatures, of which 83.3% (5/6) cases were positively related to platinum sensitivity. In addition, T &gt; G substitution was still detected from 5 patients at cycle 2, 60% (3/5) individuals were characterized by DNA repair signatures and 2 out of them had better platinum-based chemotherapy response.Neoplastic cells carrying a specific set of somatic mutations were sensitive to platinum treatment, including USP9X (pre vs post chemotherapy: 10.3% vs 0%), ZRSR2 (pre vs post chemotherapy: 6.9% vs 0%) and PIK3C2G (pre vs post chemotherapy: 10.3% vs 0%). Nonetheless, persistence of gene ROBO2 (pre vs post chemotherapy: 10.3% vs 4.6%) may be correlated with tumorigenesis. Conclusions: Dynamic monitoring of ctDNA mutation status may be contributed to advanced or metastatic lung adenocarcinoma patients stratification and prediction for pemetrexed combined platinum as first line chemotherapy regimen.
Prevalence of clinically relevant drug-drug interactions in patients enrolled in NCTN clinical trials.
Authors: Lauren A Marcath, Taylor D Coe, Emily K Hoylman, Bruce G. Redman, Daniel Louis Hertz
Journal: Journal of Clinical Oncology (2018)

e18819 Background: Oncology patients are at high risk of clinically relevant drug-drug interactions (DDIs) due to high rates of polypharmacy. DDIs in patients enrolled in clinical trials can adversely affect patient safety, study drug outcomes and validity. The study objective was to determine the prevalence of clinically relevant DDIs involving study drugs in patients enrolled in NCTN clinical trials at the University of Michigan Comprehensive Cancer Center (UMCCC). Methods: All patients enrolled in NCTN trials of commercially available medications at UMCCC from January 2013 to August 2017 were included. Patient’s concomitant medication lists at the enrollment date, or at the next available date, were collected from UMCCC electronic medical records. Medication lists were screened using Lexicomp, and all major/contraindicated (level D or X) DDIs involving study agents were recorded. Flagged interactions were reviewed by a pharmacist and PharmD student for clinical relevance. Discordant decisions were discussed until reaching consensus. A clinically relevant interaction was defined as a DDI that would warrant a medication change to ensure patient safety at enrollment. Results: One hundred thirty patients enrolled in 35 NCTN trials were included. Patients were taking 6.7 concomitant medications on average (median: 6, range: 0-21). Lexicomp detected at least one level D or X DDI in 23.8% of patients (31/130). Ten percent of all patients (13/130) had at least one clinically relevant DDI, and of the patients with clinically relevant DDI 46.2% (6/13) had DDI that affected the safety or efficacy of the study agent. Conclusions: These findings confirm a high prevalence of clinically relevant DDI involving study agents in patents enrolled in NCTN trials. More consistent and stringent DDI screening is needed during enrollment to reduce DDI prevalence to enhance patient safety and clinical trial data validity. Additionally, emphasis should be placed on DDI screening for trials likely to have DDI, such as if study drugs are strong inhibitors or inducers of CYP450 enzymes.
Prognostic impact of ezrin expression in Ewing sarcoma.
Authors: Thomas Cash, Hong Yin, Courtney McCracken, Zhi Geng, Steven G. DuBois, Bahig M. Shehata, Thomas Arthur Olson, Howard M. Katzenstein, Cynthia Wetmore
Journal: Journal of Clinical Oncology (2016)

10545 Background: Ezrin is a membrane-cytoskeleton linker protein that has been associated with metastasis and poor outcomes in a variety of human cancers including osteosarcoma and high-grade soft tissue sarcomas. The prognostic value of ezrin expression in Ewing sarcoma is unknown. The purpose of this study was to determine whether there is a relationship between ezrin expression and outcome in patients with Ewing sarcoma. Methods: The cohort included 53 newly diagnosed Ewing sarcoma patients treated at Children's Healthcare of Atlanta (n= 31) and UCSF Benioff Children's Hospital (n= 22) between 2000 and 2011. Patients received alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide given at two- or three-week intervals, and local control with either surgery, radiation, or both. The intensity and proportion of cells with ezrin immunoreactivity were assessed in diagnostic tumor tissue using a semi-quantitative scoring system. Relevant clinical data were obtained by chart review. Patient characteristics were compared using Wilcoxon rank sum, Fisher exact, and chi-square tests. Event-free survival (EFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Ezrin expression was detected in 72% (38/53) of tumor samples. There was no difference in the clinical characteristics between patients whose tumor showed the presence or absence of ezrin expression, including the proportion of patients with metastasis (24% vs. 27%; P = 1.0). This was also true when tumors were analyzed by high (3+) vs. low/no (0-2+) ezrin positivity and high (3+) vs. low/no (0-2+) ezrin intensity. There was no difference in the 5-year EFS between patients whose tumor showed high vs. low/no ezrin positivity (P = 0.76) as well as cytoplasmic vs. non-cytoplasmic ezrin expression pattern (P = 0.38). Patients whose tumor sample showed high ezrin intensity had a significantly better 5-year EFS when compared to patients with low/no ezrin intensity (78% vs. 53%; P = 0.03). Conclusions: Ezrin expression can be detected in the majority of Ewing sarcoma tumor samples. Intense ezrin expression may be correlated with a favorable outcome, however further investigation with a larger cohort is needed to validate this finding.