tbuckley/cabot-search huggingface dataset:
P04.86 Correlation between activated infiltrating neutrophils and MGMT methylation in patients with diffuse malignant gliomas (MGs)
Authors: M Simonelli, M Massara, P Persico, A Capucetti, E Lorenzi, E Lugli, A Dipasquale, M Nibali, M Rossi, L Bello, M Locati, R Bonecchi
Journal: Neuro-Oncology (2018)

Different immunotherapeutic strategies are currently under clinical evaluation in the context of neuroncology. However, a critical barrier to an effective antitumor immunity is still represented by the wide array of immunosuppressive forces exhibited by malignant gliomas (MGs). The present study aims to perform a comprehensive analysis of infiltrating and circulating leukocyte subsets (lymphocytes, macrophages, dendritic cells, neutrophils) in patients with MGs, identifying the immunological profile of the different histo-molecular subtypes, exploring the functional changes during and after anticancer therapies. Here we report first preliminary data on infiltrating and circulating neutrophils. Patients with a clinical-radiological diagnosis of malignant diffuse glioma referring to the NeuroOncological Surgery Unit of the Humanitas Research Hospital between January 2017 and March 2018 were prospectively enrolled in the study. Fresh tumor tissue specimens were collected the day of surgery; peripheral blood samples (PBS) were collected at baseline and then prospectively every two months during active anticancer treatments and then every six months during follow-up. The analysis of the frequency as well as phenotypic and functional characterization of tumor associated neutrophils (TANs) and of circulating neutrophils were performed by flow cytometry. Data were correlated with histology and the molecular markers isocitrate dehydrogenase (IDH) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. As per May 2018, 26 out of 84 patients (MG specimens and PBS) plus PBS of 4 healthy donors were analyzed. 12 had IDH wt GBM (n=7 MGMT methylated; n=5 MGMT unmethylated), 5 IDH mut GBM (n=5 MGMT unmethylated), 4 IDH mut anaplastic astrocytoma (n=3 MGMT methylated; n=1 MGMT undetermined), 4 IDH mut anaplastic oligodendrogliomas (n=4 MGMT methylated). TANs represented 5% (SD= 2,67%) of all CD45+ tumor disaggregated single cell suspensions. No statistically significative differences were found comparing the percentage of TANs (CD45+CD11b+CD66b+CD16+) among different histo-molecular subgroups. However, an increased percentage of activated TANs (CD62LnegCD16high) were found in samples from IDH wt GBM patients with methylated MGMT promoter compared to unmethylated ones (p=0,005). Increased percentages of activated neutrophils were found in PBS from IDH wt GBM patients compared to healthy donors (p=0,005). An increased number of activated TANs are present in MGMT methylated IDH wt GBM patients compared to unmethylated. IDH wt GBM patients seem to have higher percentages of circulating activated neutrophils compared to healthy donors. Correlation between different subpopulations of TANs, treatment response and clinical outcome will be presented at the meeting.
The cost and cost-effectiveness of a pediatric cancer unit (PCU) in the context of universal health coverage (UHC): A report from the Childhood Cancer 2030 Network.
Authors: Fernando Sanchez-Zubieta, Paola Friedrich, Benjamin Galvez-Galvez, Roberto C. Gonzalez-Lopez, Oscar Gonzalez-Ramella, Carlos Rodriguez-Galindo, Sumit Gupta, Sue Horton, Nickhill Bhakta
Journal: Journal of Clinical Oncology (2018)

e18891 Background: No costing data for comprehensive childhood cancer service delivery in an upper-middle income country (UMIC) are available. Further, there are no PCU costing data from any low or middle-income country (LMIC) with a UHC system. Building on prior work in other non-UHC LMIC, we tabulated the cost and cost-effectiveness of operating a PCU in Mexico, an UMIC with UHC. Methods: Administrative data on costs and volumes of inputs were determined for the PCU at the Hospital Civil de Guadalajara (HCG) by retrospectively determining the services used (e.g. imaging, pathology, medications) and their unit costs. Salaries of medical and non-medical personnel were multiplied by the percentage of time devoted to the care of children with cancer. Costs associated with inpatient bed use, central administration, and utilities were calculated using hospital occupancy rates and WHO-CHOICE estimates. Cost-effectiveness was estimated based on number of annual new patients diagnosed at HCG and 5-year survival. Results: The cost of pediatric cancer services at HCG, involving 165 new diagnoses, was $8.6 million in 2016. Cost by category is provided in the Table. Based on a 5-year survival of 73%, the cost per Disability Adjusted Life Year averted among patients treated at HCG was $3034 (3% discounting; accounted for early mortality and survivorship-associated late-effects), well below the WHO-CHOICE threshold of “very cost-effective” (i.e. less than the Mexican GDP/capita of $8201). The state of Jalisco (74%), federal Seguro Popular (23%) and private charities (3%) financed all non-capital expenditures. Conclusions: This is the first comprehensive cost analysis of a UMIC PCU. We found that childhood cancer services delivered by such a PCU are very cost-effective. These data and methodologies can guide policymakers and stakeholders when planning resource allocation for pediatric cancer services in Mexico and other LMIC with UHC. Category USD $ '000 % Personnel 1715 19.9 Hoteling 2232 25.8 Outpatient 517 6.0 Pathology 306 3.5 Pharmacy 1391 16.1 Radiation 74 0.9 Imaging 234 2.7 Surgery 124 1.4 Blood Bank 579 6.7 Utilities 576 6.7 Central Administration 891 10.3 Total 8638
Incidence, clearance and predictors of type-specific HPV infection among Nigerian women.
Authors: Sally Nneoma Adebamowo, Toyosi Olawande, Ayo Famooto, Eileen Dareng, Clement Adebamowo
Journal: Journal of Clinical Oncology (2016)

e17001 Background: There is a dearth of data on incidence, clearance and associated risk factors of HPV infection among Nigerian women. Methods: Women were enrolled in Nigeria from 2012 to 2013 and followed through 2015. SPF10 DEIA LiPA25 /Linear array tests were used. We computed multivariate logistic regression models adjusted for age, age at sexual initiation, number of lifetime sexual partners, body mass index (BMI), education, marital and HIV statuses. Results: A total of 728 of 1020 (71%) women were followed up for a mean duration of 13(9) months, their mean age at baseline was 37(8) years, 44% were HIV-. About 12% of the women had incident HPV and 19% cleared their HPV infections. The incident rate (IR) was 6.6/1,000 person-months (PM) for any HPV and 2.6/1,000 PM for high-risk hrHPV. In multivariate models, compared to those who were HIV-, HIV+ women had higher IRs of any HPV, IR Ratio (IRR): 8.61 (95% CI 3.89, 19.02) and hrHPV, IRR: 7.35 (95% CI 2.34, 22.55). Overweight/obese women had lower IR compared to those with normal weight for any HPV, IRR: 0.52 (95% CI 0.29, 0.92) but not hrHPV, IRR: 1.12 (95% CI 0.47, 2.64). The clearance rate (CR) was 8.9/1,000 PM for any HPV; 5.0/1,000 PM for hrHPV. In multivariate models, compared to those who were HIV-, HIV+ women had higher CRs of any HPV (CR Ratio (CRR): 3.77 (95% CI 2.24, 6.35) and hrHPV, CRR: 7.35 (95% CI 2.34, 22.55). Overweight/obese women had lower CRs compared to those who had normal weight, for any HPV, CRR: 0.56 (95% CI 0.35, 0.91) and HrHPV, CRR: 0.47 (95% CI 0.26, 0.86). No significant association was observed for age and HPV incidence or clearance. Conclusions: Our findings suggest HIV and BMI may have independent effects on HPV incidence and clearance. Type specific high-risk HPV incidence and clearance. High-Risk HPV Type Incident Rate/ 1,000 Person-Months 95% CI Clearance Rate/ 1,000 Person-Months 95% CI 16 0.30 0.08-0.77 0.37 0.12-0.87 18 0.75 0.36-1.39 1.13 0.63-1.86 31 0.45 0.17-0.98 0.45 0.16-0.98 33 0.22 0.05-0.66 0.90 0.46-1.58 35 0.07 0.00-0.42 0.83 0.41-1.48 39 0.22 0.05-0.66 0.45 0.16-0.98 45 0.15 0.02-0.54 0.45 0.16-0.98 51 0.22 0.05-0.66 0.53 0.21-1.08 52 0.83 0.41-1.49 0.90 0.46-1.57 56 0.07 0.00-0.42 0.60 0.26-1.18 58 0.15 0.02-0.54 0.30 0.02-0.77 59 0.30 - 0.37 0.12-0.89
Abstract 15345: ONO-4232, an EP4-selective Agonist, Improves Left Ventricular Diastolic Dysfunction and Ameliorates Acute and Chronic Heart Failure in Animal Models
Authors: Toshiya Kanaji, Kazuhiro Fuchibe, Masaya Takahashi, Tsutomu Shiroya
Journal: Circulation (2012)

Background: Prostaglandin E2 (PGE2) has four receptor subtypes, EP1-EP4. Among these EP2 and EP4 are known to be expressed in blood vessels and involved in vasodilation. EP4 is also reported to be a dominant receptor subtype expressed in cardiac tissue, and EP4 agonists have been shown to provide protection from cardiac ischemia/reperfusion injury. Therefore, we investigated the efficacy of ONO-4232 (ONO), an EP4-selective agonist, in experimental models of acute (AHF) and chronic heart failure (CHF). Methods and Results: (1) AHF was induced in dogs by combined volume overload, coronary ligation, and methoxamine infusion producing an elevation of LVEDP and systemic vascular resistance (SVR), increase in tau, reduction of LV dP/dt max and cardiac output (CO) in vehicle treated animals. ONO (3, 10 ng/kg/min, i.v. infusion) reduced both LVEDP and SVR and prevented the decrease in CO. Moreover, ONO significantly reduced tau, the time constant of LV relaxation, without apparent influence on LV dP/dt max. On th...
Romidepsin activity in T follicular helper(TFH)-phenotype PTCL versus non TFH treated on the same clinical trials.
Authors: Paola Ghione, Neval Ozkaya, Promie Faruque, Neha Mehta-Shah, Matthew Alexander Lunning, Jia Ruan, Natasha Galasso, Alison J. Moskowitz, Ahmet Dogan, Steven M. Horwitz
Journal: Journal of Clinical Oncology (2018)

7509 Background: Histone-deacetylase inhibitors are active agents for peripheral T-cell lymphomas (PTCL). Anecdotally, angioimmunoblastic T-cell lymphoma (AITL) may respond better to romidepsin than PTCL-NOS. The cell of origin of AITL and a subset of PTCL-NOS are understood to originate from a follicular helper T-cell (TFH). We characterized PTCL-NOS in terms of TFH phenotype and analyzed responses to romidepsin in AITL, TFH-PTCL, and non-TFH-PTCL. Methods: We analyzed 41 patients with PTCL treated with romidepsin alone or in combinations at MSKCC between 7/2012 to 1/2018. We re-reviewed the pathology of all PTCL-NOS to identify TFH-PTCL. We estimated survival with Kaplan-Meier method and differences in survival with Log-Rank. Differences between groups were estimated with Mann Whitney and Fisher’s Exact tests. Results: Patients characteristics are in the table. Median FU was 43.6 months. Patients received romidepsin after at least one line of prior therapy (range 1-5) as single agent in 21 (11 TFH, 10 non-TFH), or combination in 20 (13 TFH, 7 non-TFH) with duvelisib, lenalidomide or lenalidomide+carfilzomib. Three PTCL-NOS were TFH, 2 PTCL-NOS were re-classified as AITL. Romidepsin therapies had 58% ORR in TFH compared to 30% in non-TFH (p = 0.11). Median time-to-progression was 6 months for TFH vs 2months for non-TFH (p = 0.0046, HR 0.31, 95% CI 0.14–0.70). Six patients sufficiently responded to romidepsin to proceed to alloSCT (5 TFH, 1 non-TFH). Conclusions: Our results suggest that romidepsin, and combinations, may have superior activity in TFH-PTCL compared to non-TFH. If this observation is confirmed in prospective studies, it could help in the development of subtype-specific PTCL therapy. TFH(n = 24) Non TFH(n = 17) p Gender (M/F) 10 (42%)/14 (58%) 4 (23%)/13 (77%) 0.32 Age 67 years (36–75) 58 years (32–83) 0.21 Median prior therapies 1 (1-5) 1 (1-5) NS Median time-from-diagnosis, months 8 (3-38) 9 (3-67) 0.91 Ann Arbor I-II 4 (16%) 2 (12%) 0.99 III-IV 20 (84%) 15 (88%) IPI at romidepsin start 0-2 9 (37%) 7 (41%) > 0.99 3-5 15 (63%) 10 (59%) Response ORR CR ORR CR Overall 14 (58%) 7 (29%) 5 (30%) 2 (12%) 0.11 Single agent (n = 21) 4 (36%) 1 (9%) 1 (10%) 1 (10%) 0.31 Combinations (n = 20) 10 (77%) 6 (46%) 4 (57%) 1 (14%) 0.61
Descriptive analysis of 2419 patients with brain metastases of solid cancers: A real life cohort.
Authors: Anna Sophie Berghoff, Sophie Schur, Lisa Fuereder, Brigitte Gatterbauer, Karin Dieckmann, Georg Widhalm, Johannes A. Hainfellner, Christoph Zielinski, Peter Birner, Rupert Bartsch, Matthias Preusser
Journal: Journal of Clinical Oncology (2016)

2072 Background: Profound knowledge of the baseline characteristics and the clinical course of brain metastases (BM) patients is the basis for reasonable clinical trial planning. Methods: A detailed chart review analysis of 2419 BM patients (50.5% male, 49.5% female, median age 59 years) patients treated for BM of solid cancers at the Medical University of Vienna between 1990 and 2011 was performed. Results: Primary tumor was lung cancer in 43.2%, breast cancer in 15.7%, melanoma in 16.4%, renal cell carcinoma in 9.1%, colorectal cancer in 9.3% and unknown in 1.4% patients. Rare primary tumor types included genito-urinary cancers (4.1%), sarcomas (0.7%), gastro-esophageal cancer (0.6%) and head and neck cancers (0.2%). A singular BM was present in 48.7% of patients, 2-3 BM in 27.7% and 23.5% presented with > 3 BM. Multiple BM were most frequently observed in breast cancer (30.6%) and least frequently in colorectal cancer (8.5%; p < 0.001). Time from primary tumor to BM diagnosis was shortest in lung cancer (median 11 months; range 1-162) and longest in breast cancer (median 44 months; 1 – 443; p < 0.001). Recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) scores showed significant correlation with overall survival (both p < 0.001, log rank test). Evaluation of the disease status in the last 2 months prior to patient death showed intracranial progression in 35.9%, extracranial progression in 27.5% and combined extra-and intracranial progression in 36.6% of patients. Conclusions: Our data highlights the heterogeneity in presentation and clinical course of BM patients in the everyday clinical setting and may be useful for rational planning of clinical studies.
Molecular architecture simulation and reverse engineering techniques to uncover clinically applicable novel therapeutic targets in B-lymphoma cells.
Authors: Aneel Paulus, Sharoon Akhtar, Ansu Kumar, Neeraj Singh, Shireen Vali, Taher Abbasi, Sikander Ailawadhi, Asher Chanan-Khan
Journal: Journal of Clinical Oncology (2016)

e23169 Background: Most cancers follow a polygenic mode of progression to ensure their survival; not defined by a single aberration but through multiple abnormalities acting in concert. Existing molecular profiling techniques are unable to account for this; thus, the clinical benefit derived has been marginal. Advances in parallel computing and machine learning algorithms may overcome limitations of current profiling tools. Here, we report on a novel predictive technology capable of constructing a digital avatar, based on collation of salient tumor cell genomic/cytogenetics as well as predicting drug sensitivity, which we validated experimentally in lymphoma cells for potential clinical translation. Methods: WES, cytogenetic and karyotype data from a patient-derived IgM-secreting B-lymphoplasmacytic lymphoma cell line (IgM-LPL, RPCI-WM1) was used in simulation/validation experiments. FDA approved and select experimental drugs (n~150) were simulated on the avatar. Validation studies measuring cell proliferation (MTS assay), apoptosis (Annexin-V staining), cell cycle and protein profiling (immunoblotting) were conducted. Results: Numerous aberrations including MYD88L265P mutation, absence of CXCR4 mutations and chromosomal abnormalities were configured in a predictive model. Several pathways were predicted as oncogenic drivers in the RPCI-WM1 avatar and drug screening simulations predicted for heightened lymphoma cell sensitivity towards tozasertib (AURK inhibitor), binimetinib (MEK inhibitor)- but resistance towards ribociclib (CDK4/6 inhibitor). These predictions were experimentally validated where RPCI-WM1 cells demonstrated an IC50 of ~10nM, ~100nM and > 1100nM towards tozasertib, binimetinib and ribociclib, respectively. Conclusions: Our preclinical proof of concept study in IgM-LPL cells demonstrates abilities of a novel technology to simulate prominent genomic features and resulting oncogenic pathways and predict sensitivity to therapeutic agents. In vitro validation and modeling studies show high correlation and prospective studies to validate this robust technology in a clinical setting are currently underway.
Vitamin D deficiency in older cancer patients with solid tumors, effect on overall survival.
Authors: Beatrice Jara-Almonte Edwards, Xiaotao Zhang, Linda Pang, Ming Sun, Yunlong Geng, Ann-Marie Hedberg, Debu Tripathy, Richard Champlin, Uday R. Popat, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2018)

e22038 Background: Vitamin D deficiency is endemic in the American population. Estimates of Vitamin D deficiency are lacking in older cancer patients. Methods: Single site, retrospective cohort study, 2013-2016. Patients who were referred for geriatric assessment in the Program for Healthy Aging at MD Anderson Cancer Center were evaluated with standardized geriatric scales. Bone health assessment was ordered in all patients as per National Osteoporosis Foundation guidelines. Patients were provided treatment for identified geriatric issues, vitamin D and bone health disorders. Patients were followed for up to 3 years (6 months-3 years). Analysis: descriptive, univariate, multivariate and survival analysis Results: Four hundred and fifty-seven patients with solid tumor or hematologic malignancies completed geriatric assessment (mean age 77.7 ± 6.9), with equal gender distribution. Three hundred and two had bone density and 396 had Vitamin D testing. Bone health disorders were present in 77% of tested individuals. Vitamin D insufficiency (25(OH) D < 30 ng/ml) and deficiency (25(OH) D < 20ng/ml) were identified in 195 (49 %) and 82 patients (21 %) of tested individuals. On follow-up, 153 (33%) patients died. Univariate analysis revealed that Vitamin D deficiency was a risk factor for overall survival (OS) in solid tumors, HR = 1.80 (95% CI = 1.08, 2.99, p = 0.02). We did not identify collinearity of vitamin D deficiency with other risk factors for OS. This association was not seen in hematologic malignancies. Conclusions: Vitamin D deficiency is common in older cancer patients and is associated with overall survival in older cancer patients with solid tumors. Prospective studies are needed.
QoL of pediatric-inspired compared to hyper-CVAD regimens for newly diagnosed AYA patients with Ph-ALL: A modeling analysis.
Authors: Ellen Hooper, Xingdi Hu, Peggy L Lin, Daniel J. DeAngelo
Journal: Journal of Clinical Oncology (2017)

e22002 Background: The treatment of acute lymphoblastic leukemia (ALL) requires 2+ years of intensive multi-agent chemotherapy, with significant impact on quality of life (QoL). While treatment protocols exist for adolescent / young adult (AYA) patients, there is limited evidence on the QoL impact for patients treated with pediatric-inspired protocols, which include asparaginase, versus regimens such as Hyper-CVAD. Objective: To compare the QoL impact of pediatric-inspired vs Hyper-CVAD regimens in the 1 st -line treatment of AYA patients with Ph- ALL using disease simulation. Methods: A 6-state Markov model was developed to simulate total life-years and quality-adjusted life-years (QALYs) for AYA ALL patients receiving 1 st line pediatric-inspired or Hyper-CVAD regimens. Modeled health states were: no first complete remission (no treatment/non-response to 1 st line), first complete remission, first relapse, second complete remission, second relapse, and death. Model inputs for CR, EFS, OS, AEs, and health utility were obtained from literature. Weibull function was fitted to extrapolate survival and QALY over time. Results: Compared with Hyper-CVAD, the pediatric-inspired protocol resulted in increased life-years and QALYs at years 5, 10 and through a lifetime horizon. Benefits were mainly driven by more favorable progression-free survival and OS of patients in pediatric-inspired protocols compared to hyper-CVAD. Conclusions: This disease simulation model suggests that pediatric-inspired protocols for newly diagnosed AYA patients with Ph- ALL may increase QoL, as measured by QALYs, compared to Hyper-CVAD. Future long-term follow-up studies are needed to confirm these findings. [Table: see text]
Identifying and understanding how to address the gaps in care experienced by adolescent and young adult cancer patients at UIHC.
Authors: Erin Michele Mobley, Kristin Foster, William W. Terry
Journal: Journal of Clinical Oncology (2017)

e18238 Background: Cancer survival rates for adolescents and young adults (AYAs) have not improved at the same rate as other age groups. According to the National Cancer Institute, these patients may fall into a gap between pediatric and adult practices. In an effort to counteract the decreased survival rates of AYAs, the Stead Family Children’s Hospital and the Holden Comprehensive Cancer Center joined forces to develop an AYA cancer program at the University of Iowa Hospitals and Clinics. Methods: The target population included patients aged 13-31 treated for malignancy in one of the following diseases or disease sites: central nervous system, leukemia, lymphoma, neuroendocrine, sarcoma, thyroid, and other. Four focus groups were held to identify and describe gaps in care, as well as provide suggestions for program development. A convergent-parallel mixed-methods design was used. Qualitative data were derived from focus group discussion and selected free-response survey questions, while quantitative data were derived from objective survey questions. Both quantitative and qualitative analyses were conducted to gain targeted feedback from participants. Results: Across the four focus groups, the number of participants ranged from 8 – 19 (n = 24). Topics discussed included: communication, treatment experience, overall AYA program; finances, work, school, late effects; relationships, emotions, spirituality; and body image, infertility, sexuality, risky behavior, and suicide. The results of the analyses found three unique domains that are important to AYAs across the cancer continuum: autonomy, communication, and relationships. The three primary domains make the AYA population different from traditional adult or pediatric populations. The surveys corroborated the focus group discussion findings. Conclusions: Information obtained from these analyses have been used to inform specific projects within the development of the AYA program to address patient-identified gaps. For AYAs, the importance of autonomy, communication, and relationships should be considered when developing an AYA program, as well as for potential policy or health services research utilization in the future.