tbuckley/cabot-search huggingface dataset:
Mixed methods examination of diverse patients’ experiences with precision oncology.
Authors: Lynne I. Wagner, Mollie Canzona, Janet A. Tooze, Kathryn E. Weaver, Kelsey Shore, Lauren Peters, William J. Petty, Mercedes Porosnicu, Wei Zhang, Boris Pasche
Journal: Journal of Clinical Oncology (2018)

e22148 Background: Tumor molecular profiling holds great promise for improving outcomes, however patients’ comprehension and decision processes have not been examined. Methods: Purposive sampling was used to recruit non-Hispanic white (NHW) and African American (AA) cancer patients (85% participation rate) after consent for tumor sequencing. Qualitative interviews were conducted in-clinic or via telephone, then patient-reported outcomes (PRO) measures were administered. Interviews were audio-recorded, transcribed, and analyzed using thematic content analysis. Results: Participants (N = 34; 14 NHW urban, 10 NHW rural, 10 AA urban) were 56% male, a mean of 60.7 years, with lung (41%), gastrointestinal (32%), head and neck (21%), or thyroid (3%) cancer or cancer of unknown primary (3%). Qualitative: Analysis and tabulation of interview themes found limited comprehension of molecular profiling (24/34), expectation of cure (14/34), and “information overload” (24/34) when molecular profiling was discussed. 5/10 AA patients’ discussed medical mistrust, converging with a trend for higher medical mistrust on PROs among AA compared to NHW (25.4 vs 22.3, SD = 9.3). PROs: Only 45% reportedly understand “molecular profiling,” 50% understand the purpose of molecular profiling, and the mean estimated probability of a targetable result was 70.1/100 (SD = 20.8). Extending life, maximizing or improving QOL, identifying effective treatment and helping future patients were the most common reasons for molecular profiling. Conclusions: Findings from this pilot yielded descriptions of precision oncology using patients’ words and warrant further exploration. Findings underscore the need to educate patients on molecular profiling to support decision-making, align expectations, and mitigate distress and decisional regret. PRO (n = 22) Mean SD Health literacy (3-15) 8.7 1.9 PROMIS-29 (T-scores) Physical function 41.9 7.5 Anxiety 55.5 8.7 Depression 50.7 8.6 Reasons for profiling: (1-5 scale) Extend life 4.9 0.3 Maximize QOL 4.9 0.3 Improve QOL 4.8 0.4 Help future patients 4.6 0.9 Find effective tx 4.5 0.8 Avoid side effects 4.4 1.0 Avoid ineffective tx 4.0 1.2 Family encouraged testing 2.5 1.6 Only option 2.0 1.3 Medical Mistrust Scale 23.3 9.2
Effect of the loss of NF1 in breast cancer on pathway activation.
Authors: Abde M. Abukhdeir, Matthew S. Najor, Satnam Brar, Sanja Turturro, Liam Portt, Timothy Yung, Melody A. Cobleigh
Journal: Journal of Clinical Oncology (2018)

e24284 Background: The neurofibromatosis gene (NF1) is a negative regulator of the Ras protein and is lost in ~20% of breast cancers, leading to constitutive activation of Ras. Few studies have explored the functional consequences of NF1 loss in breast cancer. Therefore, we created a cellular model for the loss of NF1 in breast cells in order to identify novel therapies that would target NF1 null breast cells. Methods: The CRISPR CAS9 system was used to create an isogenic cellular system by knocking out (KO) NF1 through targeted disruption of both NF1 alleles. Immunoblotting confirmed loss of the protein and was used to identify changes in cellular signaling that resulted from the loss of NF1. Results: Loss of NF1 endowed cells with a more transformed phenotype, including EGF growth independence and anchorage-independent growth. We observed increased activation of MAPK and activated Rho GTPase. The MEK inhibitors trametinib and PD0325901 (IC50= 0.25 nM and 0.16 nM, respectively) inhibited growth of NF1-null, but not parent cells. We explored inhibitors of other proteins in the MAPK signaling pathway, including the Raf inhibitors sorafenib and vemurafenib and the dual MAP3K1/MAP2K4 inhibitor LY2228820. However, these compounds did not selectively inhibit growth of NF1-null cells, suggesting that Raf and MAP3K1/MAP2K4 are not vulnerable targets in NF1-null cells. Vincristine and zoledronic acid can indirectly affect Rho GTPase function. NF1-null cells were more sensitive to both as single agents (IC50= 1.1 nM and 6.9 μM, respectively) than parental cells. We also tested multiple combinations of these drugs and observed benefits from several combinations that exceeded single agent use. Similar sensitivity was not observed to docetaxel or ixabepilone. Conclusions: Our results suggest that loss of NF1 results in a transformed phenotype. The NCI MATCH program currently lists the MEK inhibitor trametinib as the drug of choice for any tumor harboring mutant NF1. Our results provide the first evidence that this drug could be efficacious in breast cancers. Additionally, we provide evidence that other drugs and drug combinations may be more effective, warranting further exploration.
Abstract 17380: End-tidal Carbon Dioxide During Resuscitation is Associated With CPR Depth and Ventilatory Rate
Authors: Joseph Tonna, Cabe R Clark, Benjamin R Fogg, Scott Youngquist
Journal: Circulation (2015)

Introduction: End-tidal carbon dioxide (ETCO2) has been proposed as a physiologic marker of blood flow during CPR. Hypothesis: We hypothesized that ETCO2 values would be associated with initial rhythm, witnessed status, impedance threshold device (ITD) use, CPR quality measures and ventilatory rates (VR). Methods: Chest compression (CC) metrics, VR, and ETCO2 values from prehospital resuscitation attempts were averaged over each 1 min of resuscitation. When return of spontaneous circulation (ROSC) was identified, as evidenced by the cessation of CC and measurement of a blood pressure, we censored 1 min prior to the termination of CC to reduce the measurement of unrecognized ROSC physiology. Mixed effects models were used for analysis. Results: Monitor data from N=102 adult prehospital resuscitation attempts was available for analysis, providing 1,079 (1-min) epochs for analysis (median of 8 min/case, IQR 4-14). ETCO2 appeared at a median of 9 min (IQR 6-12) into resuscitation, measured from an endotracheal tube (78%), laryngeal tube (21%), and bag valve mask (1%). Median VR was 9 breaths/min (IQR 6-11). Average initial ETCO2 was 28 (95% CI 25-31) followed by an average rise of 0.8 mm Hg/min (95% CI 0.5-1.1), regardless of ITD use, initial rhythm, or witnessed status. In univariate analysis, ETCO2 was not associated with CC fraction, rate, or release velocity but was associated with CC depth (2.7 mm Hg/inch of depth, 95% CI 0.1-5.4), and VR (quadratic response, p&lt;0.0001). Results held in multivariate analysis. In the narrow range of low VRs observed in our sample, increased VRs were associated with higher ETCO2 values between 0-17 breaths/min before falling at higher rates (FIGURE). Conclusions: Similar to others, we observed a linear association between ETCO2 and CC depth but a quadratic relationship between ETCO2 and VR during prehospital resuscitation. Improving CC depth and maintaining a VR of 10 breaths/min may optimize ETCO2 values in adults.
Advice for Indian states to ban electronic nicotine delivery systems spark criticism
Authors: Sanjeet Bagcchi
Journal: BMJ (2018)

An initiative by the Indian government to encourage states to stop the manufacture, sale, and advertisement of electronic nicotine delivery systems, including e-cigarettes, has been criticised by a nonprofit advocacy group.

Although experts in oncology, addiction medicine, and public health have welcomed the plan, the Association of Vapers India alleges that the government is protecting the tobacco industry and denying 120 million Indian smokers’ access to safer choices.12

In August, India’s Ministry of Health and Family Welfare urged states to ban the production, trade, and marketing of electronic …
Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: Phase 1b results from JAVELIN Lung 101.
Authors: Alice Tsang Shaw, Se-Hoon Lee, Suresh S. Ramalingam, Todd Michael Bauer, Michael J. Boyer, Enric Carcereny Costa, Enriqueta Felip, Ji-Youn Han, Toyoaki Hida, Brett Gordon Maxwell Hughes, Sang-We Kim, Makoto Nishio, Takashi Seto, Patrick Ezeh, Debasis Chakrabarti, Jing Wang, Andrew Chang, Luca Fumagalli, Benjamin J. Solomon
Journal: Journal of Clinical Oncology (2018)

9008 Background: ALK tyrosine kinase inhibitors (TKIs) are standard of care for patients (pts) with advanced ALK+ NSCLC, and preclinical data suggest potential synergistic activity with checkpoint inhibitors in NSCLC irrespective of ALK status. Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody approved in various countries for treatment of metastatic Merkel cell carcinoma, and in the US for advanced urothelial carcinoma that has progressed following platinum therapy. We report initial results from JAVELIN Lung 101 (NCT02584634), a phase 1b/2 dose-finding trial of avelumab + crizotinib (A+C) or the next-generation ALK TKI lorlatinib (A+L) in pts with advanced/metastatic ALK-negative/wildtype (ALK−) or ALK+ NSCLC, respectively. Methods: In phase 1b, pts with previously treated ALK− NSCLC received A (10 mg/kg Q2W) + C (250 mg BID) while pts with ALK+ NSCLC received A (10 mg/kg Q2W) + L (100 mg QD) (starting dose levels in each group). The primary endpoint was dose-limiting toxicities (DLTs); secondary endpoints included adverse events (AEs) and objective responses. Results: At data cutoff on Oct 27, 2017, 12 ALK− pts had received A+C and 28 ALK+ pts had received A+L. All ALK− pts had received prior anticancer therapy; ALK+ pts had received a median 2 prior ALK TKIs (range 1-3; data not reported for 1 ALK+ pt). DLTs occurred with A+C in 5 ALK− pts (41.7%): ALT and AST increase (2 pts each), febrile neutropenia, hepatitis, QT prolongation, and rash (1 pt each). No DLTs occurred with A+L in ALK+ pts. Grade ≥3 AEs of any causality occurred with A+C in 7 ALK− pts (58.3%; most common [≥10%] was ALT increase [16.7%, n = 2]), and with A+L in 15 ALK+ pts (53.6%; most common were hypertriglyceridemia [14.3%, n = 4] and GGT increase [10.7%, n = 3]). The confirmed objective response rate with A+C in ALK− pts was 16.7% (95% CI, 2.1-48.4; partial response [PR] in 2 pts), and with A+L in ALK+ pts was 46.4% (95% CI, 27.5-66.1; PR in 12 pts; complete response in 1 pt). Conclusions: A+L showed an acceptable safety profile, distinct from A+C, and promising antitumor activity in pts with ALK+ NSCLC, and will be evaluated in treatment-naive pts in phase 2. Clinical trial information: NCT02584634.
Feasibility of an induced metabolic bioluminescence imaging technique in ovarian cancer: Results of a pilot study.
Authors: Marco Johannes Battista, Kristina Goetze, Marcus Schmidt, Cristina Cotarelo, Veronika Weyer-Elberich, Annette Hasenburg, Stefan Walenta, Wolfgang Mueller-Klieser
Journal: Journal of Clinical Oncology (2016)

e17093 Background: The precise determination of energy metabolites is challenged by the heterogeneity of their distribution, their rapid changes after surgical resection and the architectural complexity of malignancies. Induced metabolic bioluminescence imaging (imBI) allows to determine energy metabolites in tissue sections and to localize these as consecutive sections were stained with H&E. Here, we report whether the determination of ATP and lactate is feasible in suspicious peritoneal lesions in ovarian cancer (OC) using imBI. Methods: Patients with suspected advanced OC were enrolled in this prospective, pilot study. During surgery, samples of peritoneal metastases were resected and transferred in liquid nitrogen within 30 seconds. ATP and lactate concentrations were measured using imBI. Furthermore, the expression of monocarboxylate transporter (MCT)-1 and MCT-4 was determined by immunofluorescence staining. The correlations between lactate and MCT-1 as well as lactate and MCT-4 were calculated by the Spearman rank correlation coefficient. Results: 16 patients were screened, 12 finally entered the study. In all 12 cases high concentrations of ATP suggested that energy metabolism was not altered by the surgical and transport procedures (mean ± SD, 0.69 μmol/g ± 0.33). Final histological assessment revealed a benign peritoneal lesion in one case, which subsequently served as a benign reference. The concentration of lactate was remarkably higher in the 11 OC cases (mean ± SD, 23.03 μmol/g ± 8.86) compared to the benign reference (6.54 μmol/g ± 1.84). Lactate concentrations strongly correlated with MCT-1 (rho = 0.734, p = 0.007), but not with MCT-4 (rho = 0.315, p = 0.319). Conclusions: These results show that surgical and transport procedures and imBI are feasible in OC and encourage further effort to elucidate the role of lactate, MCT-1 and MCT-4 in OC.
Discontinuation of everolimus due to unrelated adverse events in cancer patients.
Authors: Sherise C Rogers, Christine Ann Garcia, Shenhong Wu
Journal: Journal of Clinical Oncology (2016)

e14020 Background: The mTOR (mammalian target of rapamycin) inhibitor everolimus, a targeted agent used widely in cancer patients, is often discontinued due to serious adverse events. It is challenging to differentiate between adverse events related and unrelated to everolimus therapy, as these effects may be due to the drug itself, or confounding factors such as the underlying cancer, comorbidities, and concurrent medications. To assess the scope of this issue, a meta-analysis of randomized controlled trials was performed to examine the risk of everolimus discontinuation due to unrelated adverse events. Methods: A PubMed search was performed to identify all randomized controlled clinical trials where everolimus was compared to placebo with or without concurrent therapies in cancer patients. Eligible clinical trials reported a discontinuation rate due to adverse events for the everolimus group (related and unrelated to everolimus) and the placebo control group (unrelated to everolimus). A random- or fixed effects model was used to determine summary incidences, relative risks and 95% confidence intervals. Results: A total of 15 RCTs were eligible for analysis, including a total of 5,631 patients (everolimus: n = 3366, control: n = 2265). The incidences of everolimus discontinuation was 12.3% (95% CI: 9.5-15.8%) due to all adverse events and 4.7% (95% CI: 3.1-7.0%) due to unrelated adverse events. Adverse events unrelated to everolimus contributed to discontinuation at a relative risk of 0.39 (95% CI: 0.28-0.54). Subgroup analysis showed discontinuation risk due to unrelated adverse events varied significantly with cancer types (P < 0.001). The lowest risk was seen in renal cell cancer (RR = 0.12, 95% CI: 0.03-0.46), and highest seen in angiomyolipoma associated with tuberous sclerosis (RR = 4.0, 95% CI: 0.75-21.2). Risk of discontinuation due to unrelated adverse events did not vary significantly with dose (P = 0.84) or its combination with other agents (P = 0.49). Conclusions: There is a substantial risk of everolimus discontinuation due to unrelated adverse events in cancer treatment. Serious efforts should be made to differentiate between related and unrelated adverse events before stopping therapy.
TCT-351 Descriptive analysis of consecutive adverse angiographic and clinical events in pooled Italian series of Magnesium Bioabsorbable Metallic Scaffold Magmaris TM
Authors: Stefano Galli, Sarah Troiano, Altin Palloshi, None Claudio Rapetto, Massimo Leoncini, Paolo Mario Ravagnani
Journal: Journal of the American College of Cardiology (2018)
Effect of Acute Mitral Insufficiency of Various Degrees on Mean Arterial Blood Pressure, Coronary Blood Flow Cardiac Output and Oxygen Consumption
Authors: Renéwégria, Gerhardmuelheims, Robertjreissaty, Jironakano
Journal: Circulation Research (1958)

In anesthetized dog, acute mitral insufficiency of variable severity results in an increase in coronary blood flow and myocardial oxygen consumption. The increase in oxygen consumption is interpreted as meaning either that the left ventricle expends a significant amount of energy in regurgitating blood into the left atrium during mitral insufficiency, or that mitral insufficiency induces a decrease of the efficiency of the left ventricle or both.
MATCH-R development of preclinical models from patient with acquired resistance to targeted therapy
Authors: L. Bigot, O. Deas, G. Lang, F. André, S. Caro, L. Friboulet, Y. Loriot, J.-G. Judde, B. Besse, J.-C. Soria
Journal: Annals of Oncology (2018)

Background: Advances in molecular oncology and cancer genetics in the last 15 years have defined many of the key driving oncogenes in human cancer. Despite these successes it is now apparent that tumour cells adapt and develop acquired resistance to these targeted inhibitors so that disease progresses within 5-7 months. Methods: In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Active Resistance) models is planned over 5 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. To favor successful xenograft establishment, the first two passages were performed without drug treatment, which was applied from the third passage on. Results: As of June 2018, 48 PDX models have been successfully obtained from 137 patients (global take rate =30%). The take rates are 21% for prostate cancer (12/57), 26% for lung adenocarcinoma (15/58), 100% for bladder cancer (9/9), 8% for cholangiocarcinoma (1/12), and 55% for tumor from other origin (11/20). With regard to resistance to targeted therapy, we obtained 9 baseline models, 9 models resistant to FGFR inhibitor, 4 resistant to ALK inhibitor, 7 resistant to 3rd generation EGFR inhibitor, 2 resistant to Enzalutamide (AR inhibitor). Preliminary analyses indicate that PDX mimic the clinical scenario observed in the matched patient (10/12 models recapitulate the pharmacological response of the original biopsy). Conclusions: The generation of PDX models from patients who develop acquired resistance to targeted therapies is feasible. Preliminary analyses suggest that PDX models mimic the clinical scenario supporting the relevance of these models. Legal entity responsible for the study: Gustave Roussy. Clinical trial identification: NCT02517892. Funding: Lombard Odier. Disclosure: All authors have declared no conflicts of interest.
Pretreatment FDG-PET metrics to predict survival in locally advanced non-small cell lung cancer treated with definitive thoracic radiotherapy or concurrent chemoradiotherapy.
Authors: Tatsuya Yoshida, Hiroaki Kuroda, Kosuke Tanaka, Yuko Oya, Junichi Shimizu, Yoshitsugu Horio, Takeshi Kodaira, Yukinori Sakao, Yasushi Yatabe, Toyoaki Hida
Journal: Journal of Clinical Oncology (2016)

e20038 Background: Whether fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) metrics predict the clinical outcome in locally advanced non-small cell lung cancer (NSCLC) has not been well established. In this study, we investigated the association between the survival and pretreatment FDG-PET metrics, including the standardized uptake value (SUV), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) in locally advanced NSCLC treated with definitive thoracic radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Methods: A total of 95 unresectable stage III NSCLC patients who underwent whole-body FDG-PET/CT (BIOGRAPH 40 TruePoint w/TrueV) prior to treatment, and received definitive thoracic RT or CCRT consisting of platinum doublet chemotherapy in first-line setting were retrospectively reviewed. Results: Seventy-two patients (76%) were male, median age was 67 (range 41-85), and 85 (89%) received CCRT. Forty-five (47%) patients had adenocarcinoma, 28 (29%) squamous cell carcinoma, 13 (14%) other histology. The frequency of EGFR mutations, ALK rearrangements, and KRAS mutations was 19%, 1%, 6%, respectively. Overall response rate was 77.2%, and median progression-free survival (PFS) and median survival time (MST) were 10.8 and 32.9 months. PFS and MST significantly differed by TLG high ( > 320) and low (320 ≥ ) groups, not SUV, MTV. High TLG was associated with shorter survival (PFS: 8.1 vs. 14.3 months, P< 0.001, and overall survival (OS): 21.9 vs. 66.1 months, P< 0.001). Multivariate analysis showed that high TLG was an independent predictive factor for shorter PFS and OS [PFS: HR 2.37, 95% confidence interval (CI): 1.33-4.30, P< 0.01; OS: HR 3.01, 95% CI: 1.45-6.52, P< 0.01-. Conclusions: TLG, which combines the volumetric and metabolic information of FDG-PET/CT, can predict PFS and OS in locally advanced NSCLC patients treated with definitive thoracic RT or CCRT. Baseline metabolic tumor burdens measured with TLG will be of great help in predicting survival time in locally advanced NSCLC patients.
Racial/ethnic disparities in skeletal-related events among women treated with bisphosphonate therapy for bone metastasis secondary to breast cancer.
Authors: Zhong Zheng, Lu Chen, Ji-Hyun Lee, Melanie Royce, Thomas Schroeder, David Y. Lee
Journal: Journal of Clinical Oncology (2018)

e13092 Background: Bone metastases is a major cause of morbidity in metastatic breast cancer patients. Skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, and surgery/radiation required for treatment of bone metastasis, can adversely impact the quality of life. Bisphosphonates (BP) have been shown to be effective in delaying the time to occurrence of the first SRE as well as decreasing subsequent SREs. However, whether these effects are uniformly seen across all populations is not well known. This study aims to determine if any difference in SREs exists by race/ethnicity, and list any confounding factors that might modify this effect. Methods: We retrospectively collected data on breast cancer patients with bone metastasis treated with BP from 2000 to 2010. Incidence of SRE and time to SRE from initiation of BP were compared among patients of different race/ethnicity using the Kaplan-Meier curve and log-rank test. Patient characteristics including but not limited to age, receptor status, type of BP received, presence of SREs prior to BP therapy, were analyzed using univariate logistic regression analysis. Results: Medical records of 82 patients were reviewed and 76 were eligible. Of the 76 analyzed, 41 have reportable SREs while on BP. These include 40.9% of all Hispanic, 58.3% of all American Indian (AI), and 63.9% of all Non-Hispanic White (NHW). Within one year of initiating BP, 39% of AI developed an SRE compared to 8% and 21% of NHW and Hispanic, respectively (p = 0.026, p = 0.265). In the univariate logistic regression analysis, having an SRE prior to BP therapy was an independent risk factor for developing SRE during BP therapy (OR: 2.67, 95% CI: 1.04 – 6.85; p = 0.042). In this cohort, AI had the highest SRE rate prior to BP therapy at 66.7% compared to 36.4% for Hispanic and 62.9% for NHW, respectively. Conclusions: AI patients are more likely to have an earlier onset of SREs at year one compared with NHW while on BP therapy. Studies have shown an increased risk of osteoporosis among AI and therefore fracture. Future studies should identify reasons for the racial/ethnic disparities in SREs and suggest methods to prevent early onset of SREs in AI.