tbuckley/cabot-search huggingface dataset:
Evolution of the genomic landscape of circulating tumor DNA (ctDNA) in advanced prostate cancer (aPC) over treatment and time.
Authors: David D. Stenehjem, Andrew W Hahn, Roberto Nussenzveig, Emma Carroll, David Michael Gill, Erin B. Bailey, Julia Anne Batten, Benjamin Louis Maughan, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2018)

5052 Background: While men with aPC respond to initial treatment, most will progress and require sequential therapies. Due to advances in next-generation sequencing (NGS), it is feasible to assess the tumor genomic landscape via blood or tumor tissue at different time points in treatment. Much debate exists over the concordance of tissue (tDNA) and ctDNA NGS. Some hypothesize that the genomic landscape of aPC evolves with treatment and time; however, there is a paucity of experimental data to support these statements. In this exploratory analysis, we compare the genomic landscape of aPC as detected by commercially available tDNA and ctDNA NGS platforms at different points during the course of disease. Methods: Men with aPC from the Huntsman Cancer Institute, University of Utah with matched tDNA NGS using FoundationOne (Foundation Medicine, Cambridge, MA) and ctDNA NGS using G360 (Guardant Health, Inc., Redwood City, CA) were included. Clinical data was collected retrospectively. Exonic regions from 69 genes covered by both platforms were included for analysis. Paired t-tests were used to assess number of genomic alterations (GAs) between testing platforms and were confirmed with nonparametric testing. Number of alterations was assessed by time and number of treatments between tDNA and ctDNA testing by multivariate nonparametric trend tests. Results: 101 men with aPC who had matched tissue and ctDNA NGS were included. In men with no new treatments and ≤ 1 year between tests, a similar number of GAs were detected in both tests (2.0 vs. 2.2, p=0.78). In contrast, men with ≥ 1 new treatment between tests had significantly more GAs after treatment (5.0 vs. 2.4, p=0.005). Total number of GAs was correlated with number of new treatments between testing (p=0.003) and not time between testing (p=0.76). Conclusions: In these hypothesis-generating data, the genomic landscape of aPC evolves with subsequent therapies. These data suggest that, in addition to baseline tumor genomic profiling, a contemporary tumor genomic profile at the time of disease progression may optimize guidance towards subsequent therapy selection.
Prospective study on oral alkalization in patients receiving high dose methotrexate.
Authors: Daniel Reed, Jeremy Michael Sen, Kathlene DeGregory, Louise Ming-Wai Man, Michael Kenneth Keng
Journal: Journal of Clinical Oncology (2018)

e18804 Background: High-dose methotrexate (MTX), used in protocols for treatment and prevention of central nervous system disease in multiple types of cancer, requires intravenous (IV) hydration and monitoring of urine output and pH parameters. Traditionally IV sodium bicarbonate (bicarb) is used, but it has been on shortage. As there are limited data on oral (PO) alternatives, this prospective study evaluated the use of PO bicarb and acetazolamide to alkalinize urine. Methods: A multidisciplinary team at the University of Virginia was formed. Retrospective chart review of 34 patient encounters from 5/2016-4/2017 were reviewed to establish our baseline cohort of IV bicarb use. We studied patient encounters from 5/2017-10/2017 with the intervention of using PO bicarb in combination with acetazolamide for urine alkalization. The primary outcome was time to MTX administration and secondary outcomes included length of stay (LOS), incidence of acute kidney injury (AKI), MTX clearance, and bicarb utilization. A statistical process control chart (XmR chart) depicted time to MTX and LOS and chi-squared test was used for incidence of AKI and MTX clearance in the two cohorts. Results: Our baseline median time to MTX was 11.6 hours. A total of 68 patient encounters underwent urine alkalization intervention of PO bicarb and acetazolamide. No disease and treatment regimen differences were found between the two patient cohorts. Median time to MTX was decreased to 8 hours and median length of stay was decreased from 3.15 to 3.02 days. Incidence of AKI were similar between cohorts with 11.7% and 14.7% patients in IV and PO cohorts, respectively (p = 0.68). 26.5% patients in the PO cohort experienced delayed clearance versus 13.3% patients in the IV cohort (p = 0.31). Total estimated IV bicarb saved by PO alkalization was 87,265 mEq (1,745 vials). Conclusions: PO bicarb and acetazolamide for urine alkalization appears safe and allowed continued treatment with MTX despite the IV bicarb shortage. Our study demonstrated a novel way to faster MTX initiation and decreased LOS, which did not significantly increase AKI and delay MTX clearance. Results of this study will lead to a prospective trial using outpatient alkalization.
Combining ipilimumab (ipi) and nivolumab (nivo) in advanced melanoma following progression on a PD-1 inhibitor (SWOG S1616).
Authors: Ari M. Vanderwalde, Michaella Latkovic-Taber, Siwen Hu-Lieskovan, Kenneth F. Grossmann, Jeffrey Alan Sosman, Danae Campos, Michael Wu, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

TPS9597 Background: We hypothesize that patients with advanced melanoma who progress on anti-PD-1 therapy upfront may respond to the addition of the CTLA-4 inhibitor ipi to continue PD-1 inhibition (with nivo), and that responses would occur at a rate higher than would be expected from switching to ipi alone. We surmise that this would occur because melanomas primarily refractory to PD-1 antibodies may not have a sufficient pre-existing T cell infiltrate, which can be corrected by adding treatment with ipi, as CTLA-4 blockade increases new intratumoral T cell infiltration. Methods: This is a Phase 2, prospective open-label study of ipi +/- nivo in patients with advanced melanoma refractory to a PD-1 inhibitor. The primary endpoint of the study is progression free survival. Secondary objectives include the difference in T-cell infiltrate in biopsies of patients with response and no-response to therapy; objective response rate; overall survival; and toxicity. Key eligibility criteria include unresectable melanoma; disease progression while on prior PD-1 agents or after stopping with no intervening therapy; no confirmed partial or complete response to prior anti-PD1 agents; no prior receipt of CTLA-4 inhibitor; Zubrod performance status 0-2; no active brain metastases; no history of autoimmune pneumonitis or colitis requiring steroids or interruption of therapy; and adequate organ function. Prior receipt of BRAF/MEK inhibitors is permitted. Subjects are randomized 1:3 to ipi 3mg/kg q3wk x4 doses or ipi with nivo 1mg/kg q3wk x4 doses followed by nivo 240mg q2wk (21 planned on ipi; 63 on ipi+nivo). Tumor biopsy and blood for correlative studies are taken prior to enrollment and at Day 28-35 on study. Tumor assessments are performed every 12 weeks for 1 year and treatment is continued while clinical benefit persists with a final survival follow-up at 2 years. The combination will be considered superior to single-agent ipi if PFS is doubled from 3 to 6 months with one-sided alpha of 0.1 and power of 0.9. As of January 2018, 5 of 84 planned subjects have enrolled. Clinical trial information: NCT03033576.
P04.11 Profound sensitivity of glioblastoma cells to apoptosis induction by TG02, a novel oral multi-cyclin-dependent kinase inhibitor
Authors: E Le Rhun, C von Achenbach, B Lohmann, M Silginer, H Schneider, K Meetze, E Szabo, M Weller
Journal: Neuro-Oncology (2018)

TG02 is a novel multikinase inhibitor targeting cyclin-dependent kinases (CDK) -1, -2, -5, -7 and -9 and thought to act mainly via CDK-9 inhibition-dependent depletion of short-lived oncoproteins such as MCL-1 or c-MYC. We studied the activity of TG02 in 9 human long-term glioma cell lines (LTC) and 5 glioma-initiating cell lines (GIC) using various cell death assays in vitro and in the ZH-161 GIC model in vivo. TG02 exhibits strong anti-tumor cell activity with EC50 concentrations in the nanomolar range. Median survival in the ZH-161 model was prolonged by TG02 from 28 to 33 days (p=0.056). Neither constitutive CDK levels nor those of MCL-1 or c-MYC correlated with sensitivity to TG02. Cdk-9 or cdk-5 gene silencing alone did not fully reproduce the effects of TG02. C-myc gene silencing inhibited cell growth, but did not affect TG02 activity. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, and the pan-caspase inhibitor, zVAD-fmk, or BCL-2 or MCL-1 gene transfer moderately attenuated TG02-induced cell death; still, electron microscopy revealed cell death to be essentially apoptotic. TG02 activity was independent of O6-methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL-1, loss of c-MYC, or senescence. TG02 is a highly potent anti-glioma agent in vitro that appears to induce cell death mainly in an apoptotic, but largely caspase-independent manner. Clinical evaluation of TG02 in glioblastoma is warranted.
Hearing Care Access?
Authors: Nicholas S. Reed, Frank R. Lin, Amber Willink
Journal: JAMA (2018)

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Mass spectrometry biomolecular omics profiling and imaging to dissect the initial emergence of molecular drug resistance in <i>ALK</i>-positive (ALK+) lung cancer.
Authors: Xiaoliang Wu, Zuan-Fu Lim, Satoshi Komo, Callee Walsh, Haixia Yang, Lin Zhu, Kacey Rhodes, Brandon C. Jones, Elena Pugacheva, Matthew Smolkin, Erin H. Seeley, Patrick C. Ma
Journal: Journal of Clinical Oncology (2018)

12018 Background: ALK tyrosine kinase inhibitors (TKIs) yield a significant tumor response in advanced ALK+ non-small cell lung cancer (NSCLC), that is often rapid and remarkable. Nonetheless, acquired drug resistance invariably develops. Currently, the mechanisms for the initial emergence of molecular drug resistance in the responders are still not fully understood. Methods: ALK+ H3122 and Ma-ALK001.S (patient-derived cell line) lung adenocarcinoma in vivo xenograft models were investigated under drug treatment with/without ALK-TKI (TAE684 or Alectinib) for 0, 7 and 14 days. Mass spectrometry imaging (MSI) and biomolecular profiling were carried out on FFPE or fresh frozen tissues to compare peptide/lipid/metabolite profiles among the tumors using a histology-guided MS (HGMS) approach. Full section MSI was also performed to determine the intratumoral drug distribution. Cells were subjected to both Matrix Assisted Laser Desorption/Ionization (MALDI)-MS and Laser Ablation Electrospray Ionization (LAESI)-MS profiling. Statistical analyses were performed using SCilS and MarkerLynx, respectively. Results: ALK-TKIs precision treatment engendered an early emergence of drug resistant escape in the ALK+ tumor cells within the initial 14 days of treatment. Direct MS/MS fragmentation verified that ALK-TKIs were detected within the drug-dosed tumors undergoing early drug-escape. We identified unique peptide landscape changes emerging under ALK-TKI treatment. Most significant peak differences were observed between day 0 and day 14 (677) in the H3122 group, and also between day 0 and day 14 (341) in the Ma-ALK001.S group. Interestingly, day 7 peptide signatures in these models were more similar to day 14 than to the day 0 control. Overall, biomolecular profiling (peptides, lipids and metabolites) of ALK+ lung tumor cells using combined MALDI and LAESI-MSI analysis was successful. Conclusions: MSI technology facilitates interrogation of the biomolecular changes occurring within drug persister tumor cells under precision treatment. An ALK drug resistant proteomics signature emerges as early as day 7 under precision inhibitor treatment.
Beyond survival and tumor progression: Assessing patients' (pts') function to further define clinical benefit in oncology studies.
Authors: Tom Karagiannis, Patrick Marquis, Jenny Petersen, Oren Meyers, Stephen Y. Chui, Alicyn Katherine Campbell, Sara Strzok, Farrah Pompilus, Elisabeth Piault-Louis
Journal: Journal of Clinical Oncology (2017)

e18138 Background: Little is known of the changes pts experience in day-to-day function as a consequence of cancer and/or treatment. With ongoing and future oncology drug development, gaining a greater understanding of the functional impact of these agents could help complement assessments of survival and quality of life. We set out to understand “function,” the performance of (and changes in) tasks and roles required for everyday living, and which aspects of function are most meaningful from the pts’ perspective to inform future assessment. Methods: We reviewed literature related to functional assessments used in oncology and conducted 20 1:1 semi-structured interviews to explore how pts describe their daily functioning. Results: There was no consensus on the definition of “function” (N = 40 publications). Interview participants represented a broad spectrum of clinical (e.g. eight cancer types, ECOG status 0–3 [n = 4, 7, 6, and 2, respectively], prior treatment exposure [7/20 received taxanes]) and demographic characteristics. Interview participants had difficulty defining “function;” 7/20 did not provide a definition. Pts referred to 60 unique concepts that were organized into four overarching categories: mobility, cognition, activities (basic activities of daily living, domestic life, social context, and exercise), and roles (e.g. caregiver/parent, employee, spouse/partner) within the research. Functional impairments were described as limitations in mobility and/or cognitive abilities. Interviews also revealed 47 stimuli (e.g. signs/symptoms) that were associated with changes in the aforementioned functional categories as well as 20 different adaptations (e.g. frequency, intensity, precaution/prevention, external aids, proactive behavioral changes) that were used to overcome functional impairment. Conclusions: “Function” is a complex concept; impact on mobility, cognition, and the activities and roles that comprise function are unique and depend on the type of cancer, treatment, and life situation. Results point to the assessment of mobility, cognition, activities, and roles as individual concepts for measuring function comprehensively.
Investigation of mechanisms of resistance to ipilimumab therapy with a pre-surgical trial in patients with high-risk, localized prostate cancer.
Authors: Jianjun Gao, John Francis Ward, Curtis Alvin Pettaway, Lewis Z Shi, Sumit Kumar Subudhi, Luis M Vence, Hao Zhao, Jianfeng Chen, Hong Chen, Eleni Efstathiou, Patricia Troncoso, James Patrick Allison, Christopher Logothetis, Ignacio Ivan Wistuba, Jennifer Ann Wargo, Jorge M Blando, Manuel A Sepulveda, Jing Jing Sun, Padmanee Sharma
Journal: Journal of Clinical Oncology (2017)

5081 Background: Anti-CTLA-4 therapy ipilimumab (BMS) has led to clinical benefit in patients with metastatic melanoma. However, in multiple clinical trials in patients with prostate cancer, ipilimumab has not demonstrated significant clinical benefit. To identify potential immune inhibitory pathways responsible for resistance to ipilimumab therapy, we evaluated tumor samples from a pre-surgical clinical trial and performed correlative laboratory studies. Methods: We carried out a pre-surgical clinical trial with androgen deprivation therapy (ADT), (leuprolide acetate, Tap Pharmaceuticals) plus ipilimumab in patients with localized, high-risk prostate cancer. Each patient received one injection of leuprolide (22.5 mg) on week 0 and ipilimumab (10 mg/kg) on weeks 1 and 4. Patients then underwent surgery at week 8. Tumor tissues were collected at baseline and then at surgery for flow cytometry, IHC, multiplex immunofluorescence, and gene profiling analyses. In vitro studies were carried out for functional analysis. Results: Sixteen patients completed treatment with ipilimumab plus ADT and surgery. We observed a significant increase of immune cells including T cells and macrophages into prostate tumors after ipilimumab therapy, similar to data observed in ipilimumab-treated melanoma samples. However, compared to melanoma tumors, we found higher expression of PD-L1 and VISTA inhibitory molecules on CD68+ macrophages in prostate tumors. Interestingly, PD-L1 and VISTA were expressed on distinct subset of CD68+ macrophages, with high expression of CD163, suggesting an M2 subtype. In vitro studies demonstrated that engagement of PD-L1 and/or VISTA pathways inhibited T cell responses. Co-culture with monocytes resulted in suppression of T cell function, which can be reversed with anti-VISTA blocking antibody. Conclusions: These data suggest that evolving compensatory inhibitory pathways including PD-L1 and VISTA may mediate resistance of prostate cancer to ipilimumab therapy. Concurrent blockade of other immune checkpoints such as PD1/PD-L1 and/or VISTA may be necessary to provide significant clinical benefits for patients with prostate cancer. Clinical trial information: NCT01194271.
Impact of oncologist outpatient productivity on prevalence of goals of care discussions.
Authors: Sofya Pintova, Cardinale B. Smith, Kerin B. Adelson, Jason Parker Gonsky, Natalia Egorova, Rebeca Franco, Nina A. Bickell
Journal: Journal of Clinical Oncology (2018)

10106 Background: Oncologists report that time required to conduct goals of care (GoC) discussions impede its practice, yet, little data is available to support this widely held belief. We studied the impact of oncologists’ productivity on their ability to have meaningful GoC discussions. Methods: At community, academic, municipal and rural hospitals, we recruited & randomized solid tumor oncologists & their newly diagnosed advanced cancer patients with < 2 year prognosis to participate in a RCT, testing a coaching model of communication skills training. Patients were surveyed after the post-imaging visit where GoC discussion was expected. We measured quality of GoC discussions by patients’ rating how well their physician talked about goals. We measured productivity by work revenue value units (wRVUs) per hour for each day the oncologist saw the study patient post-imaging. Analyses were done with Kruskal-Wallis and Wilcoxon tests. Results: We enrolled 22 oncologists and 221 productivity days were assessed. The highest median productivity was observed in the Community hospital. In all four sites participating in this study, no significant difference in productivity was observed between visit days where quality GoC discussion took place vs no quality GoC discussion occurred. A multivariate analysis controlling for intervention group, hospital, patient and oncologist characteristics, found no relationship between productivity and conduct of high quality GoC discussion. Conclusions: The prevalence of high quality GoC discussion reported by advanced cancer patients was high among the four institutions in this study. Despite concerns about time constraints, productivity was similar regardless of whether or not a quality GoC discussion took place . Clinical trial information: NCT02374255.Hospital N = 221 Prevalence of High Quality GoC Discussion Productivity Median Productivity Quality GoC Discussion Occurred (+) Productivity No Quality GoC Discussion Occurred (-) p value Community 77% 4.3 (1.7-9.9) 4.3 (1.7-9.9) 3.8 (2.7-6.0) 0.69 Academic 80% 3.6 (0.4-7.5) 3.6 (0.9-6.4) 3.8 (2.3-7.5) 0.45 Municipal 70% 3.0 (0.7-6.1) 2.9 (0.7-6.1) 3.1 (3.0-3.2) 0.62 Rural 62% 2.9 (1.4-6.0) 3.0 (1.7-6.0) 2.9 (1.4-4.1) 0.48 p = 0.1 p < 0.001
Next Generation Sequencing (NGS) and patient pathways: What is the impact on clinical decision?
Authors: S. Coquerelle, M. Darlington, M. Michel, M. Durand, J. Gutton, I. Borget, S. Baffert, P. Marino, L. Perrier, I. Durand-Zaleski
Journal: Annals of Oncology (2018)

Background: Patient stratification, through the use of personalized medicine tools, is supposed to optimize patient care, reduce toxicities and increase the risk-benefit balance as well as decreasing healthcare costs. However, few studies have assessed the impact of Next Generation Sequencing (NGS) on clinical decision making. We evaluated whether information on mutational profiles modified clinical practice and care for patients with non-metastatic and metastatic cancer in an observational impact study. Methods: This study was a multicentric observational decision impact analysis conducted in seven sequencing platforms and 117 hospitals working with these platforms. The platforms were certified by the French National Cancer Institute (INCa). All NGS analyses performed between October 2013 and September 2016 for adult patients treated for lung, colorectal cancer or melanoma, both metastatic and non-metastatic, were included. We excluded analyses on constitutional mutations, somatic mutations for other cancers or NGS analysis with exclusive research purpose. Patients' pathways and referral patterns were obtained from NGS prescription forms and interviews with biomolecular biologists and clinicians. We extracted anonymized data on NGS results from the platforms. Results: 1213 patients from more than 117 centres were analyzed. Even if panels used were relatively homogeneous - less than 20kb (97%) and commercial kits (80%) -, we observed significant variability among practices. Depending on the initial structure of care and on the platform to which it was related, patients benefited from an NGS analysis at diagnostic (2 platforms) or later on (5 platforms), of a review of the medical file by a multidisciplinary meeting or not and of an unequal access to medical innovation on the national territory. Conclusions: We observed an important variability among practice on national territory. Thus patient equality of treatment is questionable. In a healthcare and economic perspective, important topics still need to be assessed to get a better understanding of the global impact of NGS. Among the outstanding questions: how can disutility of care, such as avoided complications and toxicities, limitation of diagnostic wavering, be evaluated? Funding: INCa. Disclosure: All authors have declared no conflicts of interest.