tbuckley/cabot-search huggingface dataset:
Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma.
Authors: Suthee Rapisuwon, Sapna Pradyuman Patel, Richard D. Carvajal, Leonel Fernando Hernandez-Aya, Katy K. Tsai, Sunandana Chandra, Ming Tony Tan, Adil Daud, Jeffrey Alan Sosman, Michael B. Atkins
Journal: Journal of Clinical Oncology (2020)

TPS10089 Background: Treatment of primary ocular melanoma is often very effective, with local recurrence rates of &lt; 5%. However, distant recurrence is as high as 50% depending on features of the primary tumor. These data emphasize the need for effective adjuvant therapy for patients with locally treated ocular melanoma. Several adjuvant treatments have been developed for patients with high-risk cutaneous melanoma, including ipilimumab and nivolumab monotherapies and an ongoing trial is exploring the nivolumab/ipilimumab combination (CA209-915), but patients with high-risk ocular melanomas have been excluded from these trials. As yet there is no approved adjuvant treatment for high-risk ocular melanoma patients. Methods: We are conducting a Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma. This study aims to generate efficacy and safety data for adjuvant this regimen in patients with locally treated high-risk ocular melanoma with 3-year risk of relapse &gt; 50%. The primary endpoint is 3-year relapse-free survival rate. Secondary endpoints are median relapse-free survival, median overall survival, 3-year overall survival rate and safety. All patients will receive nivolumab 240mg IV every 2 weeks plus ipilimumab 1mg/kg IV every 6 weeks. Subjects may receive up to 25 doses of nivolumab and 8 doses of ipilimumab. The accrual goal is 50 patients across all participating institutions. Subjects treated in this study will be matched with controls selected from a contemporaneously collected OM registry, “contemporaneous control” in order to better assess efficacy. Control subjects will be from institutions not participating in this trial, will otherwise meet the trial eligibility criteria and will be further matched with trial participants for various demographic and risk factors to the extent possible. The study is enrolling in 6 comprehensive cancer centers in the US. Clinical trial information: NCT3528408.
Exercise trends among previously non-exercising breast cancer survivors: Analysis of an ethnically diverse sample.
Authors: Sonal Oza, Victoria Susana Blinder, Christina Tran, Sujata Patil, Francesca Gany, Nicole Roberts, Lewis J. Kampel, Manmeet Malik, Ting Bao
Journal: Journal of Clinical Oncology (2019)

e23048 Background: Exercise is associated with improved symptoms and breast cancer (BC) survival. Little is known about personal and social factors that determine exercise participation in diverse BCS. The study seeks to characterize exercise trends and distinguish factors associated with initiating exercise among pre-diagnosis employed, non-exercising, ethnically and socioeconomically diverse BCS. Methods: BCS were recruited from academic and community medical centers. Women with stage I-III BC were surveyed during and 4 months post-completion of active treatment (surgery +/- chemo +/- radiation). The primary outcome was exercise initiation 4 months post treatment. Variables were self-reported except for clinical cancer variables, which were abstracted from the medical record. Results: Our sample (n = 494) included 22% black, 20% Chinese, 8% Korean, 27% Latina, and 21% non-Latina white women (3% other). 56% were born outside of the US; 30% reported an income &lt; 200% of the federal poverty level (FPL). 72% of BCS exercised the year before diagnosis; 28% did not. Significant correlates (p &lt; 0.05) of NOT exercising pre-diagnosis included lack of post-secondary education, Chinese or Korean ethnicity, lack of alcohol consumption, and lower acculturation level, resilience, and income. Among 138 non-exercisers, 63% reported exercising at follow-up. Significant correlates of exercise initiation are listed in table. In a multivariable model that included age, acculturation, job loss, insurance status, chemo-, and radiotherapy (RT), receipt of RT was significantly associated with exercise initiation (OR 3.1, 95% CI 1.4-7.1). Conclusions: A BC diagnosis may be an impetus to initiate exercise among previously sedentary, employed women. Patients who undergo radiotherapy appear to be more likely to start exercising. Additional research is needed to understand why some patients initiate exercise while others do not. [Table: see text]
Effect of GPR87 on cell proliferation via KRAS signaling pathway in p53-mutant lung cancer cells.
Authors: Takayuki Nakano, Nariyasu Nakashima, Dage Liu, Xia Zhang, Natsumi Matsuura, Shintaro Tarumi, Sung soo Chang, Tetsuhiko Go, Yoshiyuki Kakehi, Hiroyasu Yokomise
Journal: Journal of Clinical Oncology (2019)

e14713 Background: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCRs) family and suggested to contribute to the viability of human tumor cells including lung cancer cell. The mechanism of GPR87 in promote cell proliferation is still not yet well understand. p53 was reported to take an important role in keeping cell viability of GPR87-expressing cells. However, most of lung cancer cells possess p53 mutation. In the present study, several reported signal pathway were investigated in lung cancer cells. Methods: Two p53 mutant GPR87-overexpressing lung cancer cell H358 and PC9 lung cancer cell was investigated. An adenoviral vector that encoded a short hairpin siRNA targeting the GPR87 gene (Ad-shGPR87) was constructed. Real-time RT-PCR was performed to evaluate gene expressions and westen blotting analysis for protein expression. MTT assay was used to evaluate the cell viability. Results: Ad-shGPR87 effectively inhibited the GPR87 expression and significantly reduced the percentage of viable cells in GPR87-overexpression H358 and PC9 cell. Regading the signal pathway, there was no p53 expression in H358 cell and no changes in PC9 cell. However, both cells showed a significant decrease in KRAS and c-Myc gene expression 5 days after Ad-shGPR87 transfection. On the other hand, after Ad-shGPR87 transfection, Akt and Cyclin-D1gene expression decrease slightly in H358, but not in the PC9 cell. Conclusions: Theses result show that GPR87 may promoting cell proliferation through several signaling pathways and that the active in p53 mutant cell may linked to KRAS pathway in lung cancer cell.
Impact of Oncology Care Model (OCM) reporting requirements on quality of care.
Authors: Emily Castellanos, Abigail Orlando, James Hamrick, Xinran Ma, Gillian O'Connell, Neal J. Meropol, Blythe J.S. Adamson
Journal: Journal of Clinical Oncology (2019)

6620 Background: The OCM is a voluntary Center for Medicare and Medicaid Innovation alternative payment model pilot program. As of Oct 2017, OCM practices are required to report the biomarker status for NSCLC pts. Our objective was to assess the effect of OCM reporting on quality of care in aNSCLC. Methods: We developed a decision-analytic model to compare the likelihood of receiving biomarker testing and corresponding appropriate therapy. We populated the model using real-world data from pts (n=7,075) at OCM sites (n=45) and non-OCM sites (n=105) in the Flatiron Health electronic health record (EHR)-derived database. The pre-period control included pts diagnosed with aNSCLC from Jan 1, 2011 - Dec 31, 2015; the post-period included pts diagnosed Oct 2017 - Nov 2018. For OCM vs non-OCM sites, we estimated probabilities and unadjusted odds ratio (OR) of biomarker testing (EGFR, ROS1, or ALK) and subsequent delivery of appropriate therapy, defined as use of a biomarker-guided tyrosine kinase inhibitor (TKI) for positive pts, or non-TKI therapy for negative pts. Results: No differences in rates of biomarker testing or delivery of appropriate therapy were detected between OCM and non-OCM practices prior to the reporting requirement. In the post-period, OCM was associated with higher odds of biomarker testing and appropriate therapy (Table). Conclusions: To our knowledge, this is the first study of the association of OCM reporting requirements with downstream quality of care. Our results suggest that OCM documentation and reporting requirements are associated with modestly higher quality of care for pts with aNSCLC. Ongoing sensitivity analyses will determine the relative contribution of provider and practice characteristics to these findings. Careful measurement of the impact of reporting requirements is essential to measure the impact of payment reform interventions and inform policy. [Table: see text]
Cost effectiveness (CE) of blinatumomab (BLIN) versus inotuzumab ozogamicin (INO) in adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) with no more than one prior salvage therapy (S0/S1) from a United Kingdom health care perspective.
Authors: Thomas E. Delea, Xinke Zhang, Jordan Amdahl, Diana Boyko, Franziska Severin, Marco Campioni, Ze Cong
Journal: Journal of Clinical Oncology (2019)

e18359 Background: To estimate Incremental CE Ratio (ICER) of BLIN vs INO in adults with R/R S0/S1 ALL based on matching-adjusted indirect comparison (MAIC) of TOWER and INO-VATE trials from a UK healthcare perspective. Methods: CE was estimated by a partitioned-survival model with outcomes based on published aggregate data from INO-VATE (cutoff: 01/05/2017) and individual patient data from TOWER weighted to match patients in INO-VATE using MAIC. Five analyses were conducted based on alternative approach for the MAIC (anchored through Standard of Care [SOC] vs unanchored), proportional hazard (PH) assumptions, and reference overall survival (OS) distributions. Rates of complete remission and HSCT, utilities, duration of therapy, and use of subsequent therapies also were MAIC adjusted. Due to inconsistent definitions of event-free survival (EFS) between the trials, EFS was assumed to be equal for BLIN and INO complete responders. Costs were estimated from published sources and included those of medicine and administration, key adverse events, HSCT, salvage therapy, and terminal care. Utilities were based on EORTC-8D values derived from EORTC QLQ-C30 assessments in TOWER. A 50-year time horizon was used. Results: In all analyses, BLIN was more costly and more effective than INO. The ICER for BLIN vs INO ranged from £4,014 to £13,371 per QALY. Conclusions: For various approaches for conducting MAIC of BLIN vs INO, BLIN was highly cost effective vs INO in R/R ALL adults with S0/S1 from a UK healthcare perspective. [Table: see text]
Prediction of EGFR-TKI efficacy in non-small cell lung cancer patients by metabolomics and genomics.
Authors: Lei Zhang, Rongrong Luo, Lin Wang, Jiarui Yao, Di Wu, Zhishang Zhang, Xiaohong Han, Yuankai Shi
Journal: Journal of Clinical Oncology (2019)

e20627 Background: Metabolites and somatic mutations involved in EGFR-TKI efficacy remains unclear in non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutation (EGFRsm+). Here we performed a joint analysis of metabolomics and genomics data to identify metabolites and somatic mutations as biomarkers for EGFR-TKI efficacy. Methods: Metabolomic profiling of plasma samples (n = 43) from NSCLC patients with EGFRsm+, consisting of cohort A (n = 30) and B (n = 13), was conducted using UPLC or rapid separation LC-MS/MS. The 13 matched FFPE samples in cohort B were also used in the targeted sequencing below. FFPE samples (n = 18) from NSCLC patients with EGFRsm+ were subjected to targeted sequencing. According to progression free survival (PFS), all patients were assigned a status of poor (PFS≤42 weeks) and good responders (PFS &gt; 42 weeks). A joint analysis of metabolomics and genomics data was adopted to identify biomarkers for EGFR-TKI efficacy. Results: The partial least squares discrimination analysis mothod was performed to establish a prediction model responsible for separation of good and poor responders in cohort A, comprising 27 metabolites with variable importance in projection score (VIP) &gt; 1.5. Based on the prediction model, the ROC analysis demonstrated the sensitivity of 0.8, the specificity of 0.75, and the area under the ROC curve (AUC) of 0.7 in cohort B. The Welch’s t test method identified 15 significant metabolites ( P &lt; 0.05) in cohort A. With the criteria of VIP &gt; 1.5 and P &lt; 0.05, four metabolites, 3-Methyl-L-Histidine, LysoPE(18:2(9Z,12Z)/0:0), Histamine, and SM(d18:1/16:0), were detected as potential biomarkers. To further validate them, associations of these metabolites and somatic mutations were explored in 13 patients with both metabolomics and genomics data available using the Welch’s t test. The results revealed patients with either CTCF R415X or PTK2B G491X had significantly lower Histamine level compared with those without either mutation (both P &lt; 0.05), and significantly increased level of SM(d18:1/16:0) was observed in patients with either GATA2 P250A or MAGI1 S763X (both P &lt; 0.05). Intriguingly, worse PFS was showed in patients with any mutation of GATA2 P250A ( P = 0.02), CTCF R415X ( P = 0.002), PTK2B G491X ( P = 0.002), and MAGI1 S763X ( P = 0.0007). Conclusions: Our joint analysis identified two plasma metabolites and four somatic mutations as biomarkers for EGFR-TKI efficacy. The present findings may provide insights into molecular mechanisms of EGFR-TKI efficacy. Further validation in prospective studies was warranted.
Abstract P026: Associations of Biomarkers of Endothelial Dysfunction with Hyperglycemia and Insulin Resistance in Hispanic/Latino Youths: Results From the Hispanic Community Children’s Health Study/Study of Latino Youth (SOL Youth)
Authors: Christina M Parrinello, Mercedes R Carnethon, Linda C Gallo, Robert C Kaplan, Carmen R Isasi
Journal: Circulation (2016)

Background: Endothelial dysfunction may contribute to the long-term development of diabetes and cardiovascular disease (CVD). However, little is known about the correlates of biomarkers of endothelial dysfunction in youths, which is significant because early markers of endothelial damage might signal high future CVD risk and could be reversible. Methods: We included 1,318 participants from the Hispanic Community Children’s Health Study/Study of Latino Youth (SOL Youth) (2012-14) aged 8-16 years with complete data who were fasting ≥8 hours. We calculated unadjusted Pearson correlations for e-selectin and PAI-1, biomarkers of endothelial dysfunction, with sociodemographic and clinical variables. We conducted multivariable logistic regression and used predictive margins to obtain prevalence ratios (PRs) and 95% CIs for the association of quartiles of e-selectin and PAI-1, separately and in combination with one another, with fasting glucose≥100 mg/dL, HbA1c≥5.7%, and HOMA-IR≥2.6. Results: Higher levels of e-selectin and PAI-1 were associated with higher body mass index, systolic blood pressure, and dyslipidemia (P&lt;0.05 for all). After adjustment for sociodemographic and clinical variables, higher levels of PAI-1 were associated with elevated fasting glucose and HOMA-IR, and higher levels of e-selectin were associated with elevated HOMA-IR ( Figure ). Associations were relatively unchanged when including both e-selectin and PAI-1 in the same model. Adjusted PR and 95% CI for Q4 of e-selectin with HOMA-IR was 1.36 (1.13, 1.60); and for Q4 of PAI-1 with fasting glucose and HOMA-IR were 2.50 (1.16, 3.85) and 1.59 (1.26, 1.91), respectively. Conclusions: Biomarkers of endothelial dysfunction were independently associated with insulin resistance in Hispanic/Latino youths. Since the endothelium may help regulate insulin secretion, these biomarkers may be useful in risk stratification and prediction of diabetes and CVD in this population.
Gemtuzumab ozogamicin (GO) induces activation of Bak/Bax, depolarization of mitochondria and activation of caspase-3 in GO-sensitive AML cells
Authors: Petra Haag, Kristina Viktorsson, Marita Lindberg, Lena Kanter-Lewensohn, Rolf Lewensohn, Leif Stenke
Journal: Cancer Research (2008)

2767  Although most patients with acute myeloid leukemia (AML) show an initial response to high dose chemotherapy, a majority will develop resistance and relapse within 1-2 years. The conjugated antibody gemtuzumab ozogamicin (GO) constitutes a novel therapeutic approach with promising effects, as a single drug or in combination with anthracyclins, also in refractory AML patients. Consisting of a monoclonal CD33 antibody coupled to a toxin, calicheamicin, GO enters the cell after binding to the CD33 antigen, preferentially expressed on myeloid cells. Intracellularly, calicheamicin is released and cause site-specific DNA double-strand breaks (dsb). Although GO has been proposed to induce apoptosis through caspase-3 activation, the more precise cellular and molecular mechanisms behind the response, and resistance, to GO are still largely unknown. With the final aim to identify potential applicable biomarkers related to the clinical outcome of GO treatment, we have investigated in vitro effects of GO, and of calicheamicin alone, on AML cell lines (HL-60, NB-4 and KG1a) and AML primary cells with focus on pro-apoptotic signalling. All cells were confirmed to be CD33 pos by flow cytometry. Following a 24-72 h incubation with GO or calicheamicin at clinically relevant concentrations (10-500 and 0.3-15 ng/ml, respectively) HL-60, NB-4 and the primary AML cells displayed a clear dose and time dependent decrease in cell viability, whereas the KG1a cells appeared resistant even at high concentrations (1000 and 30 ng/ml, respectively). With respect to pro-apoptotic signalling, GO treatment was found to induce mitochondrial depolarization followed by caspase-3 activation in HL-60 and NB-4 cells. In contrast, KG1a showed slight depolarization of mitochondria in response to GO-treatment and caspase-3 was activated only at high GO or calicheamicin concentrations (1000 and 30 ng/ml, respectively). Conformational changes in the pro-apoptotic Bcl-2 proteins Bak and Bax, which occur prior to mitochondrial depolarization, were observed in HL-60 and NB-4 cells, while no significant Bak/Bax activation could be observed in the GO-resistant KG1a cells. Moreover, activation of the stress activated protein kinases (SAPK) JNK and p38 were observed in HL60 cells. In contrast, no activation of p38 or JNK kinases was found in the GO-resistant KG1a cells.  In conclusion, we show that GO, at clinically relevant concentrations, induce pro-apoptotic signalling which involve activation of pro-apoptotic Bak/Bax and SAPK signalling and subsequent mitochondrial depolarization and caspases-3 activation. Conversely, GO consistently failed to induce these pro-apoptotic signalling changes in GO-resistant KG1a leukemic cells. Our findings may highlight possible resistance mechanisms in AML which may be of clinical importance to treat AML.
Phase I (safety assessment) of durvalumab (MEDI4736) with focal sensitizing radiotherapy in platinum resistant ovarian, primary peritoneal or fallopian tube epithelial carcinoma.
Authors: Anna Tinker, Peter Lim, Christina Aquino-Parsons, Paul Hoskins, Daniel Khalaf, Stephanie Lheureux, Kathy Han, Mitchell Liu, Julian J Lum
Journal: Journal of Clinical Oncology (2019)

TPS5604 Background: Radiation (RT) of malignant neoplasms can induce immunogenic tumor cell death, alter the tumor micro-environment and enhance recruitment of anti-tumor T cells. Co-administration of focal RT and an immune checkpoint-inhibiting agent may overcome immune-suppressive signals and potentiate systemic responses. A phase I study is underway to assess the safety of RT combined with PD-L1 inhibition in patients with recurrent epithelial ovarian/fallopian tube/peritoneal carcinomas (OV). Methods: Women with platinum resistant epithelial OV, ECOG PS 0/1 and ≤ 2 lines of treatment in the platinum-resistant setting are eligible. 1 lesion evaluable by RECIST criteria (v 1.1) and 2 additional lesions suitable for RT (minimal treatment volume 4cc) are required. Pre- and on-treatment biopsies for correlative studies are mandatory. The primary objectives are to assess the safety and tolerability of the focal RT combined with the immune checkpoint inhibitor, durvalumab (D), as defined by dose-limiting toxicities (DLTs), and to define the maximum tolerated RT dose and treatment schedule. The secondary objectives are to evaluate the clinical activity of focal RT and D [RECIST (v 1.1), GCIG CA-125, and immune-related response criteria], progression free survival and overall survival. D 1500 mg delivered intravenously every 28 days = one cycle. RT to the 2 selected target lesions is delivered 24-36 hours prior to the infusion of D. The RT starting dose-level is 24Gy (in 4 fractions) per lesion (given Days -1, 1 and 28 of Cycle 1 and Day 1 of Cycle 2). A 3+3+3 design will permit more extensive exploration of toxicity if DLTs are observed (Table). Investigator assessed DLTs are defined by CTCAE v. 4.03 and include the following: any grade ≥3 adverse event suspected to be related to D or RT (necrosis or recall reactions at previously irradiated sites, RT induced bowel perforation, any unexpected grade 3 or greater toxicity at the site of RT), any grade ≥2 allergic or autoimmune event that involves vital organ function, and any other grade 3 allergic or autoimmune events that do not resolve to grade 1 before the next scheduled dose of D. Treatment may continue up to 12 months. Enrollment began August 2018. To date, no DLTs have been observed at dose level 1 (n= 3) and enrollment is ongoing. Clinical trial information: NCT03283943. [Table: see text]