tbuckley/cabot-search huggingface dataset:
Giving voice to patients: Understanding treatment preferences of patients with multiple myeloma (MM).
Authors: Caroline McKay, Eric Maiese, Joseph Chiarappa, Laura Sarokin, M. Janelle Cambron-Mellott, Martine Maculaitis, Nicole Alunni, Noopur S. Raje
Journal: Journal of Clinical Oncology (2019)

e18302 Background: Findings from few studies examining preferences for MM treatment are limited in application, as they are largely missing the voices of patients (PTs). The present qualitative study elucidates PT preferences, the perceived trade-offs they are willing to make, and how these may differ by line of therapy (LOT). Methods: Semi-structured phone interviews were conducted with MM PTs (front-line [FL] = 11, early relapse 1- 2 prior-lines [1/2PL] = 10) recruited via purposive sampling from targeted panels and PT groups, April-May 2018. A discussion guide was developed and a trained interviewer conducted 1-hour interviews on the diversity and valence of factors influencing how PTs evaluate potential regimens and how preferences vary by experience (i.e., LOT). Interviews were audio recorded and transcribed, responses coded, and content analysis performed to identify key themes emerging from textual data. Results: The sample was 42% male, mean age 64 years, with mean 58 months since diagnosis. Three key themes were identified. Firstly, treatment decision-making, revealed that trust in one’s health care provider (HCP) was a potent influence on treatment choice. Whereas FL PTs reported often only one option is offered and rely on HCP to make decisions, 1/2PL PTs consider other sources of information and engage in more shared decision-making. Secondly, expectations about treatment, illustrated that HCPs discuss important factors, e.g., efficacy and tolerability, in general terms with FL PTs and provide more details to 1/2PL PTs. Lastly, “ top of mind” factors that influenced treatment decisions, effectiveness, followed by side effects, emerged as the greatest influences on preference, although 1/2PL PTs reported less concern with side effects than FL PTs. Relatedly, quality of life was described as salient; the lived experience of treatment was often mentioned within the context of side effects. Conclusions: The way PTs construct, prioritize, and communicate about treatment when assessing “benefit-risk” is a dynamic process, based on where PTs are in their treatment journey. By examining treatment preferences grounded in PTs’ lived and changing experiences with MM, the findings may contribute to better PT-HCP engagement through treatment decision-making and improve clinical care.
Progastrin, a novel ubiquitous cancer blood biomarker for early detection and monitoring.
Authors: Benoit You, Eric Assenat, Olivier Glehen, Delphine Maucort-Boulch, Lea Francoise Payen, Vahan Kepenekian, Marie Dupuy, Pierre Liaud, Thibault Mazard, Gwenael Ferron, Maud Flaceliere, Julien Soulé, Veronique Saywell, Winston Tan, Laurent Villeneuve, Marc Ychou, Fanny Beloin, Manish Kohli, Dominique Joubert, Alexandre Prieur
Journal: Journal of Clinical Oncology (2019)

3037 Background: The successes of recent publications on “multi-tumor” circulating markers highlight the relevance of novel universal diagnostic cancer serum biomarkers. Since the Wnt/ß-catenin/Tcf4 pathway, activated in many tumors, induces the GAST Gene encoding progastrin synthesis, we hypothesized that progastrin, easily measurable in the blood, might be a “multi-tumor” diagnostic biomarker. Methods: Progastrin levels were measured in the blood samples of 1319 patients with 12 different cancer origins, and compared to those of 557 asymptomatic 18-75 years old blood donors. Moreover the longitudinal kinetics of progastrin concentrations were serially assessed during treatments in 168 patients with ovarian cancers enrolled in the randomized CHIVA trial (NCT01583322, GINECO), 191 patients with peritoneal involvement from gastro-intestinal cancers enrolled in BIG-RENAPE trial (NCT03787056), and in 95 HCC patients. The progastrin was measured using an ELISA test developed by ECS Progastrin (Prilly, Switzerland). Results: Compared to healthy blood donors, progastrin was found at higher concentrations in the plasma of cancer patients: median 4.47 vs 0.20 pM, P &lt; 0.0001; diagnostic discriminative power, ROC analysis AUC = 0.86 (95% CI, 0.83-0.89; P &lt; 0.0001). Progastrin levels were found elevated in all cancer groups, regardless of disease stages, and of pathology origins: ROC AUCs ranged from 0.71 to 0.93, all P &lt; 0.0001 (Table). The longitudinal progastrin changes during treatments, suggest relationships to tumor burden, and potential monitoring value. Conclusions: Progastrin is a novel ubiquitous cancer biomarker, easily detectable in the blood using an affordable ELISA test (CancerRead Lab test(R)). It may change the future paradigms about screening (in particular for populations at higher or lower risks of cancer), cancer diagnostic &amp; monitoring. [Table: see text]
A novel preclinical model of cholangiocarcinoma based on human aberrant FBXW7 expression.
Authors: Jingxiao Wang, Haichuan Wang, Michele Peters, Ning Ding, Silvia Ribback, Kirsten Utpatel, Matthias Evert, Antonio Cigliano, Frank Dombrowski, Xinhua Song, Antonio Cossu, Meng Xu, Li Che, John Dozier Gordan, Diego Calvisi, Xin Chen
Journal: Journal of Clinical Oncology (2019)

e15624 Background: Pre-clinical models that mimic human genetic events occurring in intrahepatic cholangiocarcinoma (iCCA) are limited. The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types. Methods: Firstly, we determined the FBXW7 mutation frequency (n = 120) and mRNA expression (n = 87) in a collection of human iCCA. Based on the preliminary findings in human data, we generated a mouse model by hydrodynamic tail vein injection of activated/myristylated (myr-)AKT with Fbxw7ΔF, a dominant negative form of Fbxw7. Subsequently, we investigated the role of established targets of Fbxw7, namely Notch2, Yap, and c-Myc in this novel mouse model and in human CCA cell lines. Results: FBXW7 mRNA expression is almost ubiquitously downregulated (71/82; 86.6%) in human iCCA specimens, while only 0.8% of samples showed FBXW7 somatic mutations. In vivo, co-expression of AKT and Fbxw7ΔF triggered the development of iCCA lesions and mice were euthanized by 15 weeks post-injection due to high tumor burden. At the molecular level, a strong induction of FBXW7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-Myc was consistently confirmed as a FBXW7 target in human CCA cell lines. Interestingly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 delayed cholangiocarcinogenesis in the same model. Furthermore, in human iCCA specimens, a strong, inverse correlation between the expression levels of FBXW7 and c-Myc was observed. Conclusions: Downregulation of FBXW7 is almost ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice. This pre-clinical mouse model could be used to test novel therapeutics targeting c-Myc, Notch2, and/or Yap.
Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.
Authors: Juliet Richman, Alistair E. Ring, Mitchell Dowsett, Ivana Sestak
Journal: Journal of Clinical Oncology (2019)

514 Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]
Characteristics and treatment of rheumatologic adverse events associated with immune checkpoint inhibitors: A multicentric prospective cohort study.
Authors: Amine Mouamnia, Renaud Desbarbieux, Laurent Mortier, Arnaud Scherpereel, Sylvain Dubucquoi, René-Marc Flipo, Peggy Philippe, Bernard Cortet, Marie-Helene Vieillard
Journal: Journal of Clinical Oncology (2019)

e14133 Background: To characterise the specific rheumatologic immune-related adverse events (irAEs) in patients with cancer treated by immune checkpoint inhibitors (ICI), and to propose a treatment flowchart of irAEs. Methods: A multicentric prospective study was performed to characterise the irAEs. Results: From December 2016 to December 2018, 39 patients were referred to the Department of Rheumatology. There were 22 men and 17 women. The middle age was 64,72 years old. The average time to continue ICI treatment after the onset of the irAEs was 3 months. 24 patients were followed for a melanoma, 10 for non-small cell lung cancers and five patients for various other neoplasia (glioblastoma, urothelial carcinoma, Merkel cell carcinoma, esophageal carcinoma, renal cell carcinoma). 43% had inflammatory pain (n = 17), whose 17% had arthritis (n = 7). The diagnosis was polymyalgia rheumatica for 10 patients, eosinophilic fasciitis for one patient, erosive Rheumatoid arthritis for one patient, non-erosive Rheumatoid arthritis for one patient. The other patients (57 %) had mechanical rheumatological involvement. Treatment of irAEs was glucocorticoids for 7 patients with a satisfying response, methotrexate for 1 patient, and sulfasalazine for one patient. The non-inflammatory pain was treated by antalgics and physiotherapy. The ICI was stopped (due to irAEs) for only one patient. Conclusions: In the light of these findings, a logigram of management is proposed and is being validated on a larger prospective cohort. irAEs is a good example of collaboration between oncologist and rheumatologist to improve the patients’ quality of life.
Case 19-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Lot B. Page, Robert B. Colvin
Journal: New England Journal of Medicine (1986)

Presentation of CaseAn 18-year-old Caucasian man was admitted to the hospital because of hypertension.He was well until eight years earlier, when hypertension was found. Five years before admission a renal angiographic examination, performed elsewhere, showed stenosis of the superior mesenteric and left renal arteries and the infrarenal portion of the abdominal aorta. A percutaneous transluminal angioplasty of the left renal artery was performed on two occasions, with transient improvement in the caliber of the vessel and the blood pressure. During the year before admission the patient's hypertension worsened progressively, and he began to experience frequent headaches that responded . . .
SP0086 ASSESSMENT: HOW TO PERSONALIZE SECONDARY FRACTURE PREVENTION?
Authors: Daniel Prieto-Alhambra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The existing armamentarium of therapeutic options to minimise fracture risk is growing. Different therapies have different properties, and can be used for different patient targets. <h3>Objectives:</h3> To discuss data on short-term fracture risk following an index fracture, and on the short-term efficacy of different therapies. <h3>Methods:</h3> Narrative review of recent literature. <h3>Disclosure of Interests:</h3> Daniel Prieto-Alhambra Grant/research support from: Grants from Amgen, UCB Biopharma and Servier outside the submitted work, Consultant for: UCB Biopharma, Speakers bureau: Amgen
Modeling of pharmacodynamic (PD) biomarkers (BM) related to CDK4/6 inhibition and exploratory BM-response (progression free survival [PFS]) analyses in patients with advanced breast cancer.
Authors: Yanke Yu, Yuan Liu, Diane Dan Wang
Journal: Journal of Clinical Oncology (2019)

e14528 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) approved for advanced breast cancer (ABC). In a clinical trial, the expression levels of PD BMs related to PAL effect, including thymidine kinase (TK) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues, were measured at both baseline and post-treatment in patients with ABC treated with PAL plus letrozole (LET). Pharmacokinetic (PK)/PD modeling was conducted previously to characterize the longitudinal change of pRb and Ki67. The PK/PD was further evaluated for TK and exploratory analyses were conducted to evaluate the relationship between PFS and all three BMs. Methods: The present analyses used data from a Phase 1 study evaluating the PK, PD, safety and efficacy of PAL plus LET in 26 Chinese women with ABC. A 2 compartment model was used to describe the PK of PAL. A precursor-dependent indirect response model was developed to describe the TK time course after PAL treatment. PAL effect was modeled as I max inhibitory model. Cox proportional hazard model was used to assess the correlation of PFS with three BM metrics (baseline BM, simulated lowest BM and maximum BM change in Cycle 1). Results: The BM data included 194 TK observations from 26 patients. The PK/PD models adequately described the longitudinal change of TK, and showed PAL caused TK reduction. The estimated IC 50 value was 49.5 ng/mL, similar to those for pRb and Ki67. The BM-response analyses for PFS showed that correlation was found for TK. There was a significant correlation between PFS and baseline TK (BTK) and minimum TK (MTK) in Cycle 1. A longer PFS was associated with lower BTK and lower MTK. A trend for longer PFS with higher maximum TK change in Cycle 1 was observed although the relationship was not statistically significant. Conclusions: PAL exposure had significant correlation with the reduction of all three BMs. Longer PFS was associated with lower BTK and MTK. Due to the small sample size (N = 26), this analyses result need to be confirmed in a larger study.
OCT Risk Factors for Development of Late Age-Related Macular Degeneration in the Fellow Eyes of Patients Enrolled in the HARBOR Study
Authors: Marco Nassisi, Jianqin Lei, Nizar Saleh Abdelfattah, Ayesha Karamat, Siva Balasubramanian, Wenying Fan, Akihito Uji, Kenneth M. Marion, Kirstie Baker, Xiwen Huang, Elizabeth Morgenthien, Srinivas R. Sadda
Journal: Ophthalmology (2019)
The combination of the NT157 and sorafenib as a new therapeutic option for hepatocellular carcinoma.
Authors: Hui Guo, Yu Wang, SZ Yu, WY Li
Journal: Journal of Clinical Oncology (2019)

e15610 Background: Sorafenib, which was the only choice of systemic therapy in the past ten years in HCC. But sorafenib alone achieves limited efficacy. Reversing sorafenib resistance was difficulty for oncologist. Based on previous study, we investigated whether NT157 augmented antitumor activity of sorafenib and underlying mechanisms. Methods: HCC cell lines and xenografts were employed to determine antitumor activity of NT157 combined with sorafenib and explore underlying mechanisms. Results: NT157 inhibited proliferation and induced apoptosis in dose and time dependent manner in HCC cells. HCC tumor was efficiently inhibited by NT157 in vivo. Mechanistic investigations elucidated NT157 induced phosphorylation of IRS1 by ERK pathway, and blockade of Stat3 pathway was independent of ERK pathways. NT157-activated p-ERK committed them to degradation by proteasome. CCL20 and CXCL8 were selected as efficacy markers by sequence, which effectively and minimal invasively predict efficacy. No major toxicity of liver, kidney and hemogram was observed, but SII (systemic immune-inflammation = N*P/L) was much lower, implying NT157 may influence immune and inflammatory reaction. Combination of NT157 and sorafenib increased percentage of apoptotic cells, c-caspase3 and PARP. Besides, sorafenib can reverse transient elevation of p-ERK by NT157, which may be potential mechanism of two drugs performing synergy. In vivo tumor volume and weight decreased in combination group compared with monotherapy. NT157 decreased p-AKT, which was overexpressed in resistant cell, implying NT157 may reverse sorafenib resistance by inhibiting AKT. To explore mechanism of sorafenib resistance in HCC, we established sorafenib-resistant HCC cell. Combination of two drugs inhibited cell viability, increased the percentage of apoptotic cells and activated of caspase3 and PARP cleavage in resistant cell. Conclusions: Our findings demonstrate NT157 displays potent antitumor effect in HCC via blockade IRS1 and STAT3 pathways. Combination of NT157 and sorafenib has potential therapeutic effect, even in sorafenib-resistant HCC cell. These findings identify a novel therapeutic strategy for HCC using a combination of NT157 and sorafenib.
Temozolomide versus irinotecan-temozolomide for children with relapsed and refractory high risk neuroblastoma (RR-HRNB): Results of the BEACON-Neuroblastoma randomized phase 2 trial—A European Innovative Therapies for Children with Cancer (ITCC) - International Society of Pediatric Oncology Europe Neuroblastoma Group (SIOPEN) trial.
Authors: Lucas Moreno, Veronica Moroz, Cormac Owens, Jennifer Laidler, Dominique Valteau-Couanet, Marion Gambart, Victoria Castel, Natasha Van Eijkelenburg, Aurora Castellano, Karsten Nysom, Nicolas U. Gerber, Genevieve Laureys, Ruth Lydia Ladenstein, Guy Makin, Sucheta Vaidya, Estelle Thebaud, Pamela Kearns, Andrew DJ Pearson, Keith Wheatley
Journal: Journal of Clinical Oncology (2019)

10001 Background: BEACON-Neuroblastoma is a randomized Phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a 2x2 factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT), with or without bevacizumab. Here we report the results of the irinotecan randomization (T vs. IT), which had a probability-based Bayesian design. Primary endpoint was best overall response (complete or partial) during the first 6 courses, by RECIST for measurable disease patients and International Neuroblastoma Response Criteria for evaluable disease patients for which overall response rate (ORR) was calculated. Results: From 2013 to 2018, 61 patients were randomized to treatment with T and 60 to IT. Median age was 5.8 years. 85 and 36 had measurable and evaluable disease respectively; 55 and 66 had refractory and relapsed disease; 22 had MYCN amplification. Baseline characteristics were balanced between the arms. Response data was not yet available for 2 patients on T. Response was not assessable for 17 patients (did not have treatment or stopped early) who were considered non-responders. The ORR was 24% for T and 17% for IT (risk ratio (RR) = 0.70, 95% credible interval 0.32 to 1.44). The probability that the RR for ORR was &gt;1.0 was 17%, meaning that IT did not show greater activity than T. There was no interaction between treatment with/without bevacizumab (heterogeneity test, p=0.7). 27 (44%) T and 35 (58%) IT patients had grade ≥3 toxicities as per CTCAE v4.0. Diarrhea occurred in no patients on T and 7 (12%) on IT; hematological toxicities included anemia (6 T, 4 IT), neutropenia (14 T, 22 IT) and thrombocytopenia (14 T, 11 IT). Conclusions: Irinotecan does not improve the response rate when added to temozolomide in RR-HRNB, but does increase diarrhea. Longer follow-up is needed before assessing whether it impacts progression-free or overall survival. Number of responses by treatment arm. Clinical trial information: NCT02308527. [Table: see text]
Longitudinal toxicity analysis with novel summary metrics of lenalidomide maintenance in follicular lymphoma in ECOG-ACRIN 2408.
Authors: Gita Thanarajasingam, Amylou C. Dueck, Paul J Novotny, Thomas Matthew Habermann, Ranjana H. Advani, Randy D. Gascoyne, Thomas E. Witzig, Andrew Quon, Erik Ranheim, Brad S. Kahl, Andrew M. Evens, Fangxin Hong
Journal: Journal of Clinical Oncology (2019)

6511 Background: Conventional adverse event (AE) analysis (ToxC) focuses on incidence of grade (gr) 3+ toxicities, and fails to capture AE time profile. Novel metrics that reflect chronic low gr and overall AE burden are needed. We applied the Toxicity over Time (ToxT) approach to ECOG-ACRIN 2408 to depict time-dependent toxicity of lenalidomide (L) with rituximab maintenance (MR) in follicular lymphoma (FL), and we developed a novel summary metric of symptomatic AE burden, the maximum gr over time (MGOT). Methods: In E2408, high risk FL patients (pts) were randomized (1:2:2) to: A) bendamustine-rituxumab (BR) x 6 then MR x 2 years (yrs) vs B) BR-bortezomib x 6 then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + L x 1 yr (MRL). Analysis included 3 laboratory and 5 symptomatic AEs of highest incidence during maintenance on arms A and C. Treatment-related AEs of any gr were analyzed by ToxC and ToxT. Repeated measures, time-to-event (TTE) and area under the curve (AUC) analyses capture trends over time in ToxT. MGOT combines the 5 symptomatic AEs. Results: 104 randomized pts (30 MR, 74 MRL) were included. For the laboratory AEs, by ToxC, neutropenia incidence was significantly higher in MRL (84%) than MR (47%, p &lt; .001). ToxT additionally shows neutropenia does not worsen over time (10/14/20% gr 1/2/3+ at c1, 6/21/12% gr 1/2/3+ at c12). For the symptomatic AEs, ToxC indicates 2% gr 3+ GI AEs. However, gr 1-2 GI AEs are more common on MRL (59%) than MR (26%, p &lt; .001). ToxT AUC captures a higher burden of GI AEs over time on MRL(2.8) vs MR(1.4, p = .002). TTE depicts sooner GI AE onset in MRL (10% vs 0% gr 2+ GI by day 50, p = 0.03). Bar charts of incidence and grade by cycle illustrate this improves over time (34/7/4% gr 1/2/3+ at c1, 13/0/0% gr 1/2/3+ at c12). ToxT MGOT analyses demonstrate earlier time to gr 2+ symptomatic AE on MRL vs MR (63% vs 31% by day 50, p &lt; .001) and suggest that overall AE burden over time is higher for patients on MRL(AUC 18.2) than MR(11.8, p &lt; .001). Conclusions: ToxT depicts AE time profile and can guide AE interventions. Summary metrics suggest that symptomatic AEs occur earlier and their burden over time is higher on MRL. We are implementing ToxT in patient-reported AE data to better characterize pt tolerability.