tbuckley/cabot-search huggingface dataset:
Cardiac outcomes in childhood cancer survivors (CCS): A population-based study.
Authors: Ashna Khanna, Priscila Pequeno, Sumit Gupta, Paaladinesh Thavendiranathan, Husam Abdel-Qadir, Douglas Lee, Paul C. Nathan
Journal: Journal of Clinical Oncology (2018)

10561 Background: CCS are at an elevated risk for cardiac morbidity due to cancer treatments such as anthracycline chemotherapy and thoracic radiation. Morbidities include congestive heart failure (CHF), arrhythmias, valve abnormalities, pericarditis, and coronary artery disease (CAD). However, cohort-based studies have focused primarily on CHF risk. We conducted a population-based study to determine the incidence of all types of cardiac disease in CCS. Methods: Using a provincial pediatric cancer registry, we identified all children < 18 years of age at cancer diagnosis who were treated at a pediatric cancer center in Ontario, Canada between 1987- 2010, and who survived ≥5 years from diagnosis. Each CCS was matched to population controls in a 1:5 ratio by age, sex and geographic region. The index date was 5 years after cancer diagnosis. Administrative health datasets were linked to determine the incidence of CHF, arrhythmias, valve disorders, pericardial disease, CAD (including myocardial infarction), and cardiac-related death using established algorithms. Cumulative incidence of cardiac events was calculated in both cohorts, accounting for competing risks of non-cardiac death and adult cancer events. Results: We studied 7,354 CCS (median diagnosis age 6 years, IQR 2-12) and 36,647 matched controls. During median follow-up of 11 years (IQR 5-17) from index, 2.5% of survivors vs. 0.8% of controls experienced ≥1 cardiac event. At 15 years from index, the cumulative incidence of any cardiac disease was 3.7% (95% CI 3.2-4.3%) in survivors and 1.2% (95% CI 1.1-1.4%) in controls (HR 3.3, CI 2.8-3.9, p < 0.0001). Among survivors, the 15-year cumulative incidence of morbidities was: CHF (2.0%, CI 1.6-2.4%), arrhythmias (1.5%, CI 1.2-1.9%), valve disorders (0.5%, CI 0.3-0.7%), pericardial disease (0.5%, CI 0.3-0.7%), and CAD (0.2%, 95% CI 0.1-0.4%). The 10-year incidence of cardiac-related death was 0.1% (CI 0-0.2%) vs < 0.01% (CI 0-0.03%) in controls. Conclusions: CCS are at elevated risk for multiple types of cardiovascular disease. Their absolute risk at 15-year follow-up is low, but is expected to increase as they age. Follow-up care of CCS should assess and manage general cardiovascular risk rather than limiting to CHF.
Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis
Authors: Federico Oldoni, Damiano Baldassarre, Samuela Castelnuovo, Alice Ossoli, Mauro Amato, Julian van Capelleveen, G. Kees Hovingh, Eric De Groot, Andrea Bochem, Sara Simonelli, Simone Barbieri, Fabrizio Veglia, Guido Franceschini, Jan Albert Kuivenhoven, Adriaan G. Holleboom, Laura Calabresi
Journal: Circulation (2018)

Lecithin:cholesterol acyltransferase (LCAT) is the sole enzyme that esterifies cholesterol in plasma. Its role in the supposed protection from atherogenesis remains unclear because mutations in LCAT causing fish-eye disease (FED) or familial LCAT deficiency (FLD) have been reported to be associated with more or instead less carotid atherosclerosis, respectively. This discrepancy may be associated with the loss of cholesterol esterification on only apolipoprotein AI (FED) or on both apolipoprotein AI- and apolipoprotein B-containing lipoproteins (FLD), an aspect that has thus far not been investigated.Seventy-four heterozygotes for LCAT mutations recruited from Italy and the Netherlands were assigned to FLD (n=33) or FED (n=41) groups and compared with 280 control subjects. Subclinical atherosclerosis was assessed with carotid intima-media thickness.Compared with control subjects, total cholesterol was lower by 16% (-32.9 mg/dL) and 7% (-14.9 mg/dL) and high-density lipoprotein cholesterol was lower by 29% (-16.7 mg/dL) and 36% (-20.7 mg/dL) in the FLD and FED groups, respectively. Subjects with FLD displayed a significant 18% lower low-density lipoprotein cholesterol compared with subjects with FED (101.9±35.0 versus 123.6±47.4 mg/dL; P=0.047) and control subjects (122.6±35.0 mg/dL; P=0.003). Remarkably, all 3 intima-media thickness parameters were lower in subjects with FLD compared with FED and control subjects (accounting for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids). After additional correction for nationality and ultrasonographic methods, average and maximum intima-media thickness remained significantly lower when subjects with FLD were compared with those with FED (0.59 versus 0.73 mm, P=0.003; and 0.87 versus 1.24 mm, P<0.001, respectively). In contrast, the common carotid intima-media thickness (corrected for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids) was higher in subjects with FED compared with control subjects (0.69 versus 0.65 mm; P=0.05), but this significance was lost after adjustment for nationality and ultrasonographic machine.In this head-to-head comparison, FLD and FED mutations were shown to be associated with decreased and increased atherosclerosis, respectively. We propose that this discrepancy is related to the capacity of LCAT to generate cholesterol esters on apolipoprotein B-containing lipoproteins. Although this capacity is lost in FLD, it is unaffected in FED. These results are important when considering LCAT as a target to decrease atherosclerosis.
Combination of cellular immunotherapy and rituximab-based regimens in patients with diffuse large B cell lymphoma: A pilot cohort study.
Authors: Jiu Wei Cui, Yudi Liu
Journal: Journal of Clinical Oncology (2018)

e15044 Background: Preclinical studies showed that antibody-dependent cell-mediated cytotoxicity mediated by CD56+natural killer (NK) cells contributed to the activity of rituximab (R) in patients (pts) with diffuse large B-cell lymphoma (DLBCL). We investigated the efficacy and safety of combination of cellular immunotherapy (CIT) and R-based regimens. Methods: Eligible pts should be newly diagnosed as DLBCL, be at least 18 years, and have a life expectancy ≥ 3 months during January 2010 and May 2017 in the First Hospital of Jilin University. Pts were treated with the combination therapy (study group, SG) or R-based regimens alone (control group, CG). Autologous peripheral blood mononuclear cells were collected by apheresis, and were induced into NK, γδT, or CIK cells, then the expanded immunocytes were infused back into pts after 14 days culture ex vivo. One course of CIT contained six times of infusion. The primary endpoint was progression free survival (PFS), the secondary endpoints were overall survival (OS) and safety. Results: In the SG, there are 20 pts with median age of 58 (33-80) years old, while 47 pts in CG with median age of 57 (21-87) years old. The median follow-up time was 36 months. The characteristics including age, sex, performance status, Ann Arbor stage, IPI score, serum lactate dehydrogenase, extranodal sites and chemotherapy courses had no significant difference between the two groups. But pts presenting with B symptoms were more in the CG than those in SG (X2= 5.376, P = 0.020). The 3-year PFS rates of the study and control group were 83.1% and 69.9%, respectively. And the 3-year OS rates of the study and control group were 87.7% and 75.4%, respectively. Compared with CG, the improvement in 3-year PFS was 13.2% (13-13.4) for SG, and OS rate improved by 12.3% (12.1-12.5) after combination with CIT.Among the pts receiving CIT, one patient had skin rash. Conclusions: Combination of CIT and R-based regimens was well tolerated and showed a great potential to improve the PFS and OS of the pts with newly-diagnosed DLBCL. This study provided a novel strategy for the treatment of DLBCL, and it is worthwhile to study this combination strategy in multi-center randomized clinical trials.
Phase II clinical trial with long-term infusion of anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 (IL2) in patients with high risk neuroblastoma.
Authors: Holger N. Lode, Dominique Valteau-Couanet, Sascha Troschke-Meurer, Carla Manzitti, Juliet Gray, Victoria Castel, Isaac Yaniv, Hans Loibner, Nikolai Siebert, Evgenia Glogova, Ulrike Poetschger, Ruth Ladenstein
Journal: Journal of Clinical Oncology (2016)

10562 Background: A new delivery method of anti-GD2 antibody ch14.18/CHO by long term infusion (LTI) may improve the toxicity profile but maintain effective immune modulation and clinical activity in patients (pts) with high risk relapsed/refractory neuroblastoma (NB). Methods: 124 pts were enrolled into an open label SIOPEN Phase II clinical trial (EudraCT 2009-018077-31) to receive up to 5 cycles of 6x106 IU/m2 sc IL2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2 oral 13-cis-RA (d19-32)(APN311-202). Primary efficacy endpoints were antibody ( > 1µg/ml) and NK-cell levels. Toxicity endpoint was i.v. morphine free antibody delivery after 5 days of cycle 1 in > 80% patients. Secondary endpoints were increased ADCC levels over baseline, Fc gamma receptor (FCGR) polymorphisms, objective clinical responses and progression free as well as overall survival. Results: All per protocol treated patients met primary efficacy endpoints. This translated into an increase in ADCC in all evaluable patients. Toxicity observed in this trial was improved compared to standard delivery methods of anti-GD2 antibodies. Objective clinical response rate observed in this trial was 40%. The survival update of the cohort revealed a 2-y OS of 64±6% (mean OS 2.7± 0.2 y, median PFS 3.7 y (95% CI: 2.0-3.7 y)) and a 2-y PFS of 53 ± 6% (mean PFS 2.0 ± 0.2 y, median PFS 2.3 y (95% CI: 1.2-3.3 y)). This result is clearly superior to historical controls not treated with ch14.18/CHO (p < 0.001), indicating clinical efficacy of the treatment. In this cohort, we found 63/124 pts with low affinity FCGR alleles (FCGR2A-H131R/R and/or FCGRA3A-V158 F/F). These patients showed lower EFS and OS rates compared to 59/124 patients with high affinity FCGR polymorphisms (p < 0.05). These findings underline FCGR mediated ADCC as mechanism of action of this treatment modality. Conclusions: Results of this Phase II study show efficacy, clinical activity and improved toxicity profile of a new delivery method of ch14.18/CHO and underline ADCC as the mechanism of action. Clinical trial information: NCT01701479.
Efficacy of bevacizumab in second-line versus first-line treatment of metastatic colorectal cancer: Results from a new methodological approach based on the ITACa strategy trial.
Authors: Elisabetta Petracci, Emanuela Scarpi, Alessandro Passardi, Giovanni Luca Frassineti, Annibale Biggeri, Dino Amadori, Oriana Nanni
Journal: Journal of Clinical Oncology (2017)

3546 Background: Cancer trials collecting information on subsequent treatment lines offer an invaluable opportunity to gain a deeper understanding of therapeutic strategies. Still in the oncological literature, evidence comes from studies ignoring whole patient history. The few studies that consider more than one line of treatment often analyze data for each line separately. Methods: Data from the ITACa strategy trial investigating the role of bevacizumab (B) in first- and second-line of treatment in metastatic colorectal cancer patients (mCRC) were analyzed. The trial consisted of two arms with treatment crossover: chemotherapy (CT) plus B followed by CT alone vs CT alone followed by CT+B. The primary end-point was Progression-Free Survival (PFS). Our aim was to evaluate if the efficacy of B was greater or smaller in first- or second-line treatment. Survival analysis for repeated events taking into account of potential selection bias was performed. Indeed, patients starting a second-line treatment are a selected subgroup of patients initially enrolled. Results: Of the 370 patients in the intention-to-treat population, 175 (47.3%) received second-line treatment. Considering all available information from randomization to first and eventual second progression and accounting for the potential selection bias, the average effect of B in terms of PFS resulted in an HR = 0.80 [95% CI 0.68-0.95]. When evaluating the differential effect of B in first- and second-line, we found that the addiction of B to CT in first-line provided 10% (95% CI -28%; +12%) risk reduction (HR = 0.90, 95% CI 0.72–1.12) respect to CT alone and the addiction of B to CT in second-line provided 36% (95% CI -51%; -16%) risk reduction (HR = 0.64, 95% CI 0.49-0.84) respect to chemotherapy alone. Conclusions: The ITACa trial enabled us to analyze data in a unified framework considering first- and second-line treatment together. Results highlight an advantage of B when administered in combination with second-line chemotherapy, suggesting the best strategy for its administration. Clinical trial information: NCT01878422.
In vitro and xenograft anti-tumor activity, target modulation and drug synergy studies of PV-10 against refractory pediatric solid tumors.
Authors: Lucy Swift, Chunfen Zhang, Tanya Maria Trippett, Aru Narendran
Journal: Journal of Clinical Oncology (2018)

10557 Background: Children with refractory malignancies who fail conventional treatment protocols endure significant morbidity and mortality. Therefore, studies to identify tolerable and effective therapeutic agents are urgently needed. PV-10 (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a novel therapeutic that in adult tumors induces direct cytotoxicity and stimulates tumor specific immune activation via immunogenic cell death, and is the subject of ongoing clinical study in combination with checkpoint inhibition (NCT02557321). Our studies aim to identify the potential of PV-10 in future clinical trials for refractory pediatric malignancies. Methods: A panel of cell lines derived from relapsed pediatric neuroblastoma, Ewing sarcoma, rhabdomyosarcoma and osteosarcoma (n = 20) were treated with increasing concentrations of PV-10 and cell viability was measured by alamar blue assay. Target modulation and induction of cell death pathways were investigated by western blots. The activity of PV-10 in combination with either radiation or a panel of chemotherapeutic agents was measured by cell survival assays and time-lapse microscopy. Mouse xenografts of pediatric solid tumors were injected with PV-10 and tumor growth dynamics were quantified by bioluminescence imaging. Results: PV-10 induced cell death in all pediatric solid tumor cell lines (IC50: 20-100 mM) with a measurable therapeutic-window. Western blot analyses showed dose dependent activation of caspases 3, 7 and 9 and PARP cleavage, indicating induction of apoptosis. Drug combination studies showed synergy with DNA damaging agents (including radiation) and agents that target mitosis and cytokinesis such as vincristine and inhibitors of Plk1 and Aurora A kinase. Xenograft studies showed significant reduction of tumor burden in treated mice by comparison to control animals, with corresponding increase in overall survival. Conclusions: Our studies provide pediatric solid tumor directed pre-clinical data for the activity, mechanisms of action, drug synergy and in vivo activity of PV-10, to support the formulation of an early phase clinical trial in this population.
EGFR alterations in gliosarcoma: A single institution experience.
Authors: Ashley Woods, Lindsey Lowder, Soma N/A Sengupta, Stuart Neill
Journal: Journal of Clinical Oncology (2018)

e14022 Background: Epidermal growth factor receptor (EGFR), is overexpressed or mutated on a variety of malignancies, most notably non-small cell lung cancer, colorectal cancer and Glioblastoma (GBM). Glioblastoma is the most aggressive primary brain tumor, and has an EGFR alteration frequency of 35-50%. Gliosarcoma, a histologic variant of IDH wild-type GBM, has a lower frequency of EGFR alterations (4-8%). Methods: Currently, there is no standardized technique for the detection of EGFR alteration in GBM and detection varies on the methodology used. We characterized EGFR alterations in gliosarcoma using an Oncoscan, a DNA copy number/single nucleotide polymorphism array using formalin fixed paraffin embedded tissue. Results: A retrospective search for
The influence of decision aids on prostate cancer screening preferences: A randomized survey study.
Authors: Kyle Tsai, Adam Benjamin Weiner, Shilajit Kundu, Mary-Kate Keeter, David Victorson, Edward M. Schaeffer, William Catalona
Journal: Journal of Clinical Oncology (2018)

5085 Background: Shared decision making between a patient and caregiver is important when discussing prostate cancer (PCa) screening. Decision aids (DAs) are tools intended to facilitate this process and improve patient participation through education, yet little is known about how DAs affect screening preferences. We administered an online survey study to determine how different DAs impact the decision to undergo or recommend a loved one undergo PCa screening. Methods: Using ResearchMatch, an online, study recruitment registry, participants matched for age, race, and gender were randomized to one of six different major professional society’s free, online DA on PCa screening. We compared pre- and post-DA responses. The primary outcome was change in participant likelihood to undergo or recommend a loved one undergo PCa screening on a scale of 1 (unlikely) to 100 (extremely likely). Secondary outcomes included change in participant comfort with PCa screening based on the average of six, five-point Likert-scale questions. Results: Median age was 53 years for the 1,336 participants, and 50% were men. Randomized groups did not differ significantly by race, age, gender, income, marital status, or education level. Likelihood to undergo or recommend PCa screening decreased from 83 to 78 following DA exposure (p < 0.001). Reviewing the DAs from the Center for Disease Control or American Academy of Family Physicians did not alter likelihood (both p > 0.2), while reviewing the DA from the United States Preventive Services Task Force was associated with the largest decrease (-16.0, p < 0.001). Participants reported increased comfort with the decision-making process for PCa screening from 3.5 to 4.1 (out of 5, p < 0.001) following exposure to a DA. Conclusions: In this online survey, after exposure to most DAs from major professional societies, participants were less likely to undergo or recommend their loved one undergo PCa screening. DAs improved participant comfort with the PCa screening shared decision-making process. These results illustrate how different DAs may disparately influence men and their loved ones about the tradeoffs of PCa screening.
Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma
Authors: Amit Sud, Hauke Thomsen, Giulia Orlando, Asta Försti, Philip J. Law, Peter Broderick, Rosie Cooke, Fadi Hariri, Tomi Pastinen, Douglas F. Easton, Paul D. P. Pharoah, Alison M. Dunning, Julian Peto, Federico Canzian, Rosalind Eeles, ZSofia Kote-Jarai, Kenneth Muir, Nora Pashayan, Daniele Campa, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Elke Pogge von Strandmann, Anthony J. Swerdlow, Andreas Engert, Nick Orr, Kari Hemminki, Richard S. Houlston
Journal: Blood (2018)
OS3.6 Development and validation of a DNA methylome-based predictor of meningioma recurrence and meningioma recurrence score
Authors: F Nassiri, Y Mamatjan, S Suppiah, J Badhiwala, S Mansouri, S Karimi, P Harter, P Baumgarten, M Weller, M Preusser, C Herold-Mende, F Sahm, A von Deimling, G Zadeh, K Aldape
Journal: Neuro-Oncology (2018)

The greatest clinical challenge faced in meningioma is the inability to predict recurrence for individual patients, limiting the ability to select patients who would benefit from adjuvant radiation therapy to prevent recurrence. In this multi-center cohort study, we utilized global epigenome DNA methylation profiles from human tumor samples to generate and validate a methylome-based predictor of recurrence-free survival (RFS) in individual patients to guide decision making regarding adjuvant treatment. Cox modeling of individual probes was used for feature selection in a training set (N=228 patients) which was then applied to two independent validation sets (N=54; N=140 patients). Gene-expression analysis was correlated to DNA methylation profiles using two published microarray datasets (GSE16581; GSE9438). Finally, penalized Cox modeling was used to generate a 5-year meningioma recurrence score based on a nomogram that integrated our validated methylome-based predictor with established clinical factors. The methlyome-based predictor was independently associated with RFS in each of the two validation sets, after adjusting for tumor grade and extent of resection (EOR; HR 4.0, 95%CI 1·4 - 11·5, P = 0·01 and HR 2·3, 95%CI 1·4 - 3.8, P = 0·002). Using a 5-year RFS metric, the methylome-based predictor performed favourably compared to a grade-based predictor in both validation cohorts (ΔAUC =15%; ΔAUC=12%). Functional annotation of the included probes implicated the homeobox gene family. A nomogram constructed using the validated methylome-predictor with WHO grade and EOR demonstrated greater predictive performance than a nomogram using clinical factors alone (ΔAUC = 7·7%) and resulted in two different risk groups with distinct recurrence patterns (P < 0·001). The methylome-based predictor and meningioma recurrence score developed and validated in this study provide important prognostic information not captured by established clinical factors. The meningioma recurrence score represent the first combined molecular and clinical prognostic tool that is individualized for patients with meningiomas, and hence an advance towards precision medicine in meningiomas
Analysis of the HLA-I genotypes in patients with solid tumours who were treated with anti-HER therapy.
Authors: Javier López-González, Cristina Morales-Estevez, Facundo Alberti-Vargas, Juan de la Haba-Rodriguez, Rafael Gonzalez-Fernandez, Maria Teresa Cano, Ignacio Porras, Maria Jose Ortiz, María Auxiliadora Gómez-España, Barbara Manzanares-Martin, Alberto Moreno, Enrique Aranda
Journal: Journal of Clinical Oncology (2016)

e14505 Background: Better outcomes have been reported with the addition of Cetuximab and Trastuzumab to traditional chemotherapy schemes in colorectal, breast, head and neck cancer. Cetuximab (IgG1 chimeric monoclonal antibody whose specific target is the epidermal growth factor receptor EGFR) and Trastuzumab (Antibody G1 humanized monoclonal Ig that binds selectively to Her2 receptor) have an additional mechanism: antibody-mediated cytotoxicity (ADCC), showing that ADCC mediated by Trastuzumab and Cetuximab induces specific cellular immune response. This ADCC is mediated by NK cells. We try to analyse the different HLA genotypes in our series of metastatic cancer patient treated with these Mabs, and their impact on the evolution of the disease and the treatment efficacy. Methods: 116 patients from Reina Sofia University Hospital of Cordoba, treated with monoclonal antibody (Trastuzumab or Cetuximab) have been selected (55 colorectal, 39 breast and 22 head and neck) during the treatment. A sample of peripheral blood was collected; the extraction and purification of DNA, and performing HLA typing of class I alleles (HLA-BW4, HLA-BW6, HLA-C1, HLA-C2, HLA-C04) were performed. Clinical and histological treatment and evolution data of each patient were collected. This study was approved by the ethical committee of the Reina Sofia University Hospital (HURS). Results: In our study, patients who show HLA-B allele W4W4 have better time to treatment failure (TTF), median 16.06 months IC 95% (14.00-18.13), p = 0,019. A non-significant trend was observed in patients genotyped as HLA-C2C2 to have a worse TTF, 7.93 months IC 95% (6.10-9.75), compared to HLA C1C1 (P = 0.099). HLA C04 allele appears to be associated to worse TTF in breast cancer subgroup; 14.20 months IC 95% (3.43-24-69) p = 0.133. Conclusions: Different genotypes of HLA class I alleles could have been associated with time to treatment failure. Prospective studies are necessary to validate HLA alleles as biomarkers.