tbuckley/cabot-search huggingface dataset:
Risk prediction based on post induction bone marrow response and genomic profile: A new way to stratify stage M neuroblastoma patients?
Authors: Stefan Fiedler, Ruth Lydia Ladenstein, Ulrike Poetschger, Reza Abbasi, Ales Vicha, Shifra Ash, Alberto Garaventa, Godfrey Chi Fung Chan, Walentyna Balwierz, Marek Ussowicz, Deborah Tweddle, Gudrun Schleiermacher, Georg Mann, Alem Gabriel, Marta Jeison, Jerzy Klijanienko, Martina Morini, Dominique Valteau Couanet, Inge M Ambros, Peter F Ambros
Journal: Journal of Clinical Oncology (2018)

10550 Background: So far, and apart from minor adaptations, high-risk neuroblastoma patients have been treated uniformly by not taking biological features of the tumor into consideration. To mend this oversight and address the lack of biological data, we evaluated the prognostic relevance of a combined analysis of genomic aberrations of tumor cells and minimal residual disease (MRD) of stage M neuroblastoma patients. Methods: Diagnostic/post-induction bone marrow (BM) samples from 115 (83 fulfilled all criteria) stage M patients enrolled in the HR-NBL1/SIOPEN high-risk neuroblastoma trial were automatically searched for GD2/CD56/DAPI positive disseminated tumor cells (DTCs), which provided excellent sensitivity and specificity. Information on somatic copy-number aberrations (SCNAs), MYCN amplification, aberrations in ATRX, TERT, and PTPRD genes from 139 patients was generated by high-density single-nucleotide polymorphism (SNP) arrays. Results: The 3-year event-free survival (EFS) of 184 patients was 39±4% with a 3-year cumulative incidence of relapse (CIR) of 56±6% (median observation time: 55.5 months). BM-MRD negative patients had a 3-year EFS of 67±9% (CIR:39±7%), whereas non-clearing patients had only 27±7% EFS (CIR:71±7%) (p = 0.001). Genomic analysis found a higher relapse incidence in patients whose tumors showed a gain/loss on chromosome 1q and/or aberrations in the TERT and/or PTPRD genes. Patients lacking these genomic markers and with BM clearing had the most favorable outcome (3-year EFS 92±7%) whilst those with two or more of the above mentioned genomic markers and positive BM-MRD fell into the ultra-high risk group (3-year EFS of 0%; p = < 0.001). Conclusions: Combination of BM-MRD monitoring and genomic analysis enables early risk assessment and merits further evaluation.
Adverse event (AE) management in patients (pts) with relapsed and refractory multiple myeloma (RRMM) taking pomalidomide (POM) plus low dose-dexamethasone (LoDEX): A pooled analysis from 3 clinical trials.
Authors: Philippe Moreau, Meletios A. Dimopoulos, Paul G. Richardson, David Samuel DiCapua Siegel, Antonio Palumbo, Michele Cavo, Paolo Corradini, Katja Weisel, Michel Delforge, Peter O'Gorman, Kevin W. Song, Lars Axel Sternas, Teresa Peluso, Kevin Hong, Jennifer Herring, Xin Yu, Mohamed H. Zaki, Jesus San Miguel
Journal: Journal of Clinical Oncology (2016)

8031 Background: Pts with RRMM who are heavily pretreated often have advanced disease and comorbidities, increasing their susceptibility to AEs. The management of AEs is important to ensure that pts remain on the therapy for as long as needed to receive a clinical benefit. In this analysis, safety data from 3 POM + LoDEX clinical trials (Richardson Blood 2014; San Miguel Lancet Oncol 2013; Dimopoulos ASH 2015) were pooled to better characterize the safety profile of POM + LoDEX and management of AEs. Methods: The 3 trials enrolled pts with ≥ 2 prior therapies, including lenalidomide and bortezomib, who had progressed on or within 60 days of their last therapy. Pts received POM 4 mg/day on days 1-21 of each 28-day cycle and LoDEX 40 mg (20 mg for those > 75 years of age) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Grouped AE terms were used for analysis. Results: A total of 1088 pts from the 3 trials were included in the safety population. The most common grade 3/4 AEs were neutropenia (56%), infections (34%), anemia (32%), and thrombocytopenia (26%). AEs were managed by dose modifications and/or supportive care (Table). The rate of grade 3/4 venous thromboembolic events was low (2%). Peripheral neuropathy (PN) of any grade occurred in 17% of pts; 1% experienced grade 3/4 PN. AEs leading to POM dose reductions or interruptions occurred in 24% and 66% of pts, respectively. AEs leading to discontinuation of POM were infrequent (7%). Conclusions: In this large pooled safety analysis, POM + LoDEX showed an acceptable safety profile in pts with RRMM. AEs were manageable, and discontinuations due to AEs were uncommon. Clinical trial information: NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010). POM + LoDEX (N = 1088) Dose management Median average POM dose (range), mg 4.0 (1.6-4.2) ≥ 1 dose reduction, % 24 For neutropeniaa 8 For thrombocytopeniaa 5 For infectionsa 4 Median time to AE onset (range), daysa Neutropenia (n = 693) 20.0 (1.0-591.0) Thrombocytopenia (n = 393) 15.0 (1.0-498.0) Infections (n = 748) 41.5 (1.0-493.0) Supportive care, % Anti-infective 88 Red blood cell transfusion 45 Granulocyte colony-stimulating factor 17 Platelet transfusion 14 a Grouped AE terms.
Randomized comparison of pazopanib (PAZ) and doxorubicin (DOX) in the first line treatment of metastatic soft tissue sarcoma (STS) in elderly patients (pts): Results of a phase II study (EPAZ).
Authors: Viktor Grünwald, Annegret Kunitz, Markus Kajo Schuler, Patrick Schoffski, Hans-Georg Kopp, Sebastian Bauer, Bernd Kasper, Lars H Lindner, Jens-Marcus Chemnitz, Martina Margrit Crysandt, Alexander Stein, Bjoern Steffen, Gerlinde Egerer, Silke Zimmermann, Annika Karch
Journal: Journal of Clinical Oncology (2018)

11506 Background: The systemic treatment standard of advanced, inoperable STS in elderly pts is single agent DOX. We tested the hypothesis whether PAZ has comparable efficacy to DOX in elderly STS pts, while offering better tolerability. Methods: Key inclusion criteria: age ³60 years, no prior systemic treatment for STS, progressive disease, ECOG 0-2, adequate organ function. DOX 75 mg/m2 q3wks for a total of 6 cycles or PAZ 800 mg OD continuously were given after 1:2 randomization. ECOG 2 and liposarcoma histology were used for stratification. The primary endpoint was progression free survival (PFS) in the per protocol (PP) population. A non-inferiority design was applied with an upper limit of the 95% confidence interval (CI) of less than 1.8. Key secondary endpoints were neutropenia and febrile neutropenia in hierarchical order. EORTC QLQ-C30 was utilized to measure quality of life. Cox regression analysis, ANCOVA and Kaplan-Meier curves were applied (NCT01861951). Results: Between 10/2012 and 03/2016, 39 pts were randomly assigned to DOX and 81 to PAZ. The median follow-up was 11.8 months (mo). The median age was 71 years (range: 60-88). In the PP population, DOX vs. PAZ achieved a PFS of 5.3 vs. 4.4 mo (HR 1.00; 95%CI 0.65-1.53; P = .993), respectively. The incidence of neutropenia CTC grade 4 and neutropenic fever in patients were 56% and 10% for DOX and 0% and 0% for PAZ, respectively. OS was 14.3 vs. 12.3 mo. (HR 1.083; 95%CI 0.68-1.72; P = .735) for the intention to treat population. Most frequent AEs for DOX were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for PAZ fatigue (58.0%), nausea (43.2%) and diarrhea (43.2%). Similar outcome was reported for global EORTC QLQ-C30 measures. Conclusions: This study showed that PAZ was non-inferior compared to DOX, rendering PAZ a putative therapeutic option in the first line treatment of STS of pts above 60 years of age. The distinct AE profile may be used to council pts and tailor therapy to individual needs. Clinical trial information: NCT01861951.Outcome of primary and key secondary endpoints DOX PAZ HR 95%CI P value PFS 5.3 mo 4.4 mo 0.998 0.650-1.533 0.993 Neutropenia grade 4 56% 0% - - < 0.0001 Febrile neutropenia 10% 0% - - 0.003
MYD88 L265P mutation and CDKN2A loss as early mutational events in primary central nervous system lymphomas.
Authors: Michael White, Priscilla Kaliopi Brastianos, Tracy Batchelor, Naema Nayyar, Corey Gill, Matt Lastrapes, Mia Bertalan, Alex Kaplan, Meghan D'Andrea, Ivanna Bihun, Andrew Kaneb, Jorg Dietrich, Judith Ferry, Maria Martinez-Lage Alvarez, Anita Giobbie-Hurder, Darrell R. Borger, Fausto J Rodriguez, Matthias Holdhoff, Daniel P. Cahill, Scott L. Carter
Journal: Journal of Clinical Oncology (2018)

e14041 Background: The genetic alterations that define PCNSL are beginning to be identified, and the genomic evolution that conveys susceptibility or resistance to treatment in recurrent disease is unknown. Methods: We performed whole-exome sequencing on 36 PCNSL patients and 1 patient with EBV-positive disease. Targeted MYD88 sequencing was performed on a validation cohort consisting of 28 patients with PCNSL. We also performed whole-exome sequencing and phylogenetic analysis of 4 paired cases of recurrent PCNSL. IHC for PD-L1 was performed on 43 patient specimens. Results: Combined whole-exome and targeted sequencing identified MYD88 mutation in 58% (43/64) of patients, CDKN2A/CDKN2B bi-allelic loss in 44% (16/36), and CD79b mutation in 61% (22/36). CD79b mutation was associated with improved overall survival. Copy number analysis found frequent copy loss, with few areas of amplification. We did not identify amplification of PD-1/PD-L1, and IHC for PD-L1 revealed 3+ expression in 30% (13/43) specimens. Phylogenetic analysis of paired primary and recurrent specimens identified MYD88 and CDKN2A/CDKN2B loss as important early clonal events. Conclusions: PCNSL is characterized by frequent mutations within the BCR and NFkB pathways, as well by frequent regions of copy-loss. This is the first study showing that CDKN2A loss is an early event in the evolution of PCNSL. PD-L1 was not amplified and was highly expressed in 30% of samples. CD79b mutation may serve as a promising prognostic marker that needs to be explored further. Whole-exome sequencing of PCNSL tumors provides insight into the defining genetic attributes of this disease, and potentially informs rational treatment decisions.
Randomized double-blind placebo-controlled biomarker modulation study of vitamin d in premenopausal women at high risk for breast cancer (SWOG S0812).
Authors: Katherine D Crew, Garnet L Anderson, Dawn L. Hershman, Mary Beth Terry, Parisa Tehranifar, Danika L Lew, Monica Yee, Eric Allen Brown, Sebastien S. Kairouz, Nafisa Kuwajerwala, Therese Bartholomew Bevers, John E. Doster, Corrine Zarwan, Laura Kruper, Lori M. Minasian, Leslie G. Ford, Banu Arun, Marian Neuhouser, Powel Brown
Journal: Journal of Clinical Oncology (2018)

1550 Background: Observational studies have reported an inverse association between vitamin D status and breast cancer risk. We examined whether high-dose vitamin D supplementation among high-risk premenopausal women reduces mammographic density (MD), a strong predictor of breast cancer risk. Methods: We conducted a multicenter randomized double-blind placebo-controlled trial among premenopausal women at high risk for breast cancer [5-year Gail risk score ≥1.67%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)] and with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤32 ng/mL. Subjects were randomized 1:1 to 1 year of vitamin D3 20,000 IU/week or matching placebo. All received standard-dose vitamin D 600 IU/day. The primary endpoint was change in MD from baseline to 1 year as assessed by the Cumulus technique. Secondary endpoints were serial blood biomarkers [25(OH)D, 1,25(OH)D, parathyroid hormone, insulin-like growth factor (IGF)-1, IGF binding protein-3] and MD change at 2 years. Results: Among 208 subjects registered from December 2011 to April 2014, median age was 44.6 years (range, 21-50); 84% were white; 33% had a baseline serum 25(OH)D < 20 ng/mL; 78% had a high baseline MD. At 1 year, we observed a significant mean change in serum 25(OH)D in the active vs. placebo group (+18.9 vs. +2.8 ng/mL, p < .01), but non-significant change for IGF-1 (-9.8 vs. -1.8 ng/mL, p = 0.28). Mean absolute change in MD at 1 year and 2 years after randomization was -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6%, respectively, for the placebo arm (p > 0.05). At 1 year, MD correlated with serum IGF-1 and IGF-1/IGFBP-3 (p < .01). High-dose vitamin D3 was well-tolerated. Conclusions: Changes in MD at 1-2 years were small and did not significantly differ between high-dose and standard-dose vitamin D. Longer exposure may be required to detect a difference. The relationship between vitamin D, IGF-1, and MD are hypothesis-generating. Understanding the relationship between vitamin D and biomarkers of breast cancer risk may inform future clinical trials. Clinical trial information: NCT01097278.
The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial
Authors: Ben O'Leary, Rosalind J. Cutts, Yuan Liu, Sarah Hrebien, Xin Huang, Kerry Fenwick, Fabrice André, Sibylle Loibl, Sherene Loi, Isaac Garcia-Murillas, Massimo Cristofanilli, Cynthia Huang Bartlett, Nicholas C. Turner
Journal: Cancer Discovery (2018)

CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor-positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy.
TCR inhibitory molecule as a promising allogeneic NKG2D CAR-t cell approach.
Authors: David Edward Gilham, Alexandre Michaux, Eytan Breman, Sébastien Mauen, Jennifer Bolsée, Fanny Huberty, Jérôme Marijsse, Benjamin Violle, Céline Jacques-Hespel, Céline Marchand, Nancy Ramelot, Thuy N'Guyen, Julien Houssa, Sophie Agaugue
Journal: Journal of Clinical Oncology (2018)

e15042 Background: Most CAR T cell therapy relies on autologous cells with potential limitation in quality of the cells. Cells derived from an allogeneic healthy donor may be more consistent in quality but their use raises two issues: the elimination of the donor T cells due to the host versus graft (HvG) response, and graft versus host disease (GvHD) due to the recognition of non-self molecules expressed on recipient cells by the T Cell Receptor (TCR) of donor cells therefore leading to potential safety concerns for the recipient. HvG can be controlled by pre-conditioning of the patient. However, to avoid GvHD, TCR signalling of the donor T cells could be inhibited by means of the expression of a truncated form of CD3z called TIM (TCR inhibitory molecule). Theobjective of that study was to assess TIM functionality in human primary T cells in combination with an NKG2D-based CAR Methods: Peripheral blood mononuclear cells from healthy donors were transduced with the appropriate vectors with subsequent enrichment of transduced cells by magnetic selection. The purified CAR T cell populations were expanded and tested for CAR functionality and reduced allo-response. Results: T cells engrafted with the TIM showed a significant reduction in IFNgamma secretion after mitogenic stimulation and in mixed lymphocyte reactions when compared to control T cells. Moreover, no xeno-GvHD was seen in NSG mice treated with human TIM T cells. When TIM was co-expressed with an NKG2D specific CAR (CYAD-101), CYAD-101 cells displayed reduced allo potency whilst maintaining potent NKG2D-specific in vivo anti-tumor activity against established orthotopic colorectal tumors. Preliminary results indicate that TIM acts as a dominant negative inhibiting several actors of the TCR signaling pathway. Conclusions: The TIM reduces GvHD yet does not interfere with NKG2D-CAR mediated anti-tumor activity offering an attractive allogenic CAR T cell therapy. The clinical development of CYAD-101 will be further pursued in a phase I trial to assess the safety and clinical activity of multiple doses administered with standard chemotherapy in patients with unresectable metastatic colorectal cancer.
Abstract 16047: Novel Association of Polymorphic Genetic Variants With Baseline PR Interval in Patients With Atrial Fibrillation: New Directions From a Prospective Study (DECAF)
Authors: Sanghamitra Mohanty, Amelia W Hall, Prasant Mohanty, Chintan Trivedi, Luigi Di Biase, Rong Bai, Amin Al-Ahmad, Rodney Horton, John David Burkhardt, Javier Sanchez, Jason Zagrodzky, Shane Bailey, G. J Gallinghouse, Patrick Hranitzky, Vishwanath R Iyer, Andrea Natale
Journal: Circulation (2015)

Background: Prolongation of the PR interval in the electrocardiogram (ECG) is known to be associated with increased risk of atrial fibrillation (AF). We examined the association of selected single nucleotide polymorphisms (SNPs) with PR interval in AF patients. Methods: Four hundred AF patients undergoing catheter ablation were prospectively enrolled at our center. DNA extraction and genotyping for 16 AF-related SNPS from blood samples were performed using Qiagen QiaAMP kit and TaqMan assay respectively. A total of 371 DNA samples were available for genotyping. Multivariate linear regression analyses (after adjusting for age, gender, BMI, AF type) were applied to test allelic association (for minor allelic frequency) with baseline PR interval. PR interval duration in millisecond (ms) was derived from 12-lead ECGs recorded at the time of patient enrollment. Results: Three hundred seventy-one AF patients (67% male, 62±12 year, left atrial size 45.3±7 mm, 64% non-paroxysmal) undergoing catheter ablation were included in the analysis. Two SNPs, rs3807989 and rs7193343 were identified to have significant association with baseline PR interval. For rs3807989 (7q31), median [interquartile range] of PR interval durations were 174 (149-202), 169 (145-194), 162 (137-184) ms for AA, AG, GG (risk allele: A) respectively. The regression analysis for rs3807989 in a dominant model, showed significant allelic association (regression coefficient (beta) 9.8 [95% CI 1.58 to 18.02], p=0.019) with prolonged PR interval. For rs7193343, median [interquartile range] of PR interval durations were 169 (144-194), 162 (142-184), 154 (128-186) ms for CC, CT, TT (risk allele: T) respectively. When considering the effect of rs7193343 fitted with an additive model, significant inverse association with PR interval was observed (beta -7.4 [95% CI -14.23 to -2.63], p=0.032). Conclusion: We identified two novel genetic markers located near developmental genes CAV1 and ZFHX3 to be associated with PR interval; rs3807989 correlated directly with prolonged PR duration while rs7193343 demonstrated inverse correlation with the phenotype. Defining the etiology of this differential association will provide important insight into underlying AF mechanisms.
A pilot study of NY-ESO-1<sup>c259</sup> T cells in subjects with advanced myxoid/round cell liposarcoma (NCT02992743).
Authors: Sandra P. D'Angelo, Mihaela Druta, George D. Demetri, David A. Liebner, Scott Schuetze, Arun S. Singh, Neeta Somaiah, Brian Andrew Van Tine, Breelyn A. Wilky, Karen Chagin, Tim Pulham, Malini Iyengar, Elliot Norry, Arundathy N. Bartlett-Pandite, Rafael G. Amado
Journal: Journal of Clinical Oncology (2017)

TPS3097 Background: Myxoid/round cell liposarcomas (MRCLS) account for 6-10% of soft tissue sarcomas. Although a chemosensitive tumor, metastatic MRCLS has a poor prognosis and is inevitably fatal. More effective, durable and less toxic therapies are needed. NY-ESO-1 is a cancer/testis antigen that is expressed in 80-90% of MRCLS tumors. This study will evaluate the safety and efficacy of genetically engineered affinity enhanced autologous NY-ESO-1 c259 T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 in MRCLS. Methods: This open label phase I/II non-randomized pilot study will evaluate efficacy (overall response rate by RECIST v1.1, time to response, duration of response, progression free survival, overall survival), safety, and translational research endpoints. Patients must meet these criteria: ≥ 18 yrs old; HLA-A*02:01, *02:05 or *02:06 positive; have advanced (metastatic or inoperable) MRCLS expressing NY-ESO-1 at 2+/3+ intensity in ≥30% of tumor cells by IHC; measurable disease; prior systemic anthracycline therapy; have ECOG status 0 or 1; and adequate organ function. Initially, ten patients are planned to be enrolled, with potential to enroll an additional 5 patients. Patients who do not receive the minimum cell dose or who do not receive the T-cell infusion may be replaced. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259 TCR, and 1– 8 × 10 9 transduced T-cells are infused intravenously on Day 1 after lymphodepletion with fludarabine 30 mg/m 2 /day and cyclophosphamide 600 mg/m 2 /day on days -7 to -5. Response is assessed at 4, 8, 12 and 24 weeks, and then every 3 months until confirmation of progression of disease. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02992743.
Abstract 13748: A Disintegrin and Metalloproteinase 17 Deletion in Smooth Muscle Cell Transiently Suppresses Angiotensin II Mediated Hypertension
Authors: Mengcheng Shen, Jude Morton, Sandra T Davidge, Zamaneh Kassiri
Journal: Circulation (2016)

Introduction: A disintegrin and metalloproteinase-17 (ADAM17) proteolytically releases membrane-bound growth factors and cytokines. Hypertension is associated with remodeling, hypertrophy and hyperplasia of smooth muscle cells (SMCs). ADAM17 has been reported to mediate Angiotensin II (Ang II)-induced SMC hypertrophy. We investigated the role of smooth muscle cell ADAM17 in Ang II-induced hypertension. Hypothesis: Smooth muscle cell ADAM17 deficiency suppresses Ang II-induced hypertension. Methods: SMC-specific ADAM17-deficient mice ( Adam17 flx/flx /SM22Cre ; Adam17 SMC-Cre ), and littermate controls ( Adam17 flx/flx ) received Ang II or saline (Alzet pumps, 1.5 mg/kg/d; 4 wks). Blood pressure was measured in conscious mice before and 4 wks after Ang II infusion (Telemetry). Vascular function (vasoconstrictor/dilator response), circumferential wall stress/strain were assessed in second order mesenteric arteries ex vivo at 2 wks after Ang II/saline infusion. SMCs were isolated from either genotype (enzyme dispersal method). SMC proliferation (BrdU incorporation), migration (scratch assay) and apoptosis (Annexin V/7-AAD staining, Flow Cytometry) were assessed (±Ang II). Activation of signaling pathways (phospho/total EGFR, Akt and ERK1/2), HB-EGF were assessed by Western blot. Results: Adam17 SMC-Cre mice exhibited suppressed hypertension in the 1 st week of Ang II infusion (reduced systolic, diastolic &amp; MAP). However, by the 2 nd week, systolic and diastolic BP rose to similar levels as Adam17 flx/flx mice and remained similar. Ex vivo analyses revealed similar acute vasoconstrictor/dilator responses, and comparable wall stiffness in both genotypes; but the Ang II-induced increase in wall thickness was not observed in Adam17 SMC-Cre group. ADAM17-deficient SMCs showed reduced Ang II-induced proliferation, migration, and activation of HB-EGF and ERK1/2. A time-course study revealed delayed Ang II-mediated EGFR activation in ADAM17-deficient SMCs (@24 hrs vs 30 min). End organ damage, hypertrophy and fibrosis in the heart and kidneys, were comparable. Conclusions: ADAM17 deficiency in SMCs causes a transient reduction in Ang II-induced hypertensive response, possibly due to delayed activation of the EGFR pathway.