tbuckley/cabot-search huggingface dataset:
Children’s Oncology Group (COG) clinical trials as exemplars of pragmatism in clinical research.
Authors: Nupur Mittal, Anil George, Lizette Leanos, Paul Kent
Journal: Journal of Clinical Oncology (2017)

e18188 Background: In 2016, President Obama announced the “Moonshot Cancer Initiative” to advance cancer research. One of the key components of this initiative is promoting enrollment in pragmatic clinical trials and data sharing. As described in 2009 by Thorpe et al, using the 9-domian PRECIS-2 tool, a ‘pragmatic’ trial, as opposed to an ‘explanatory’ trial used to confirm a physiologic hypothesis, is one in which the intervention can be immediately applied into real-world clinical practice (J of Clin Epi:2009). In the US, 60%-90% children are enrolled on COG research trials. State-of-the-art treatment for a child is derived from superior therapy identified in prior trials which then serves as the standard arm of subsequent phase-III trials and becomes the de facto practice guideline and ‘standard of care’ .To accomplish this goal, COG shares its data among the 242 member institutions.Our objective is to assess “pragmatism” in COG trials. Methods: We analyzed the 158 COG phase III clinical trials between 2006-2016 for all 9 domains of the PRECIS-2 (Table 1) and graded them from 1-5 (most explanatory to most pragmatic). Results: Out of 152 phase III clinical trials on the COG website, 138 (91%) scored 5/5 for all 9 PRECIS pragmatic domains and 148 (98%) scored &gt;4. The scoring for all 9 domains is in table 1. Conclusions: COG provides nearly all children in the United States access to pragmatic phase III research as outlined in the Moonshot Goals. Goal of merging evidence-based standard care accessible to all and conducting well- designed clinical research to identify the best therapies has been accomplished by COG and should serve as an example to other cancer organizations. 9 domains of PRECIS-2 to assess pragmatism in clinical trials. [Table: see text]
On enabling early detection of cancer via DNA-based signatures in liquid biopsy.
Authors: Bahram Ghaffarzadeh Kermani
Journal: Journal of Clinical Oncology (2018)

e24262 Background: Early detection of cancer has been in the spotlight, due to its promise to radically change the course of treatment of this disease. If cancer is detected at early stages, the probability of having positive outcome is significantly higher than detecting it at late stages, i.e., the current state-of-the-art. While circulating tumor cells (CTCs) provide a viable method for liquid biopsy, a major challenge with them for earlier stages of cancer has been their low sensitivity. However, with the technological advances made in this field, higher sensitivities are now reported to be achievable. Once the CTCs are isolated, if the cells are sequenced and specific cancer signatures are found, then the problem of early detection could become addressable. Methods: The focus of this work is on finding sensitive and specific signatures for identification of cancer. Previously, we reported on a molecular signature for early detection of breast cancer, based on whole genome sequencing (WGS) data. Here, we report on different WGS-based signatures, tested on a small representative set of real-patient, tissue-based data from the International Cancer Genome Consortium (ICGC). Results: Our preliminary results suggest that a sensitivity rate of ~90% would be possible as the upper limit (i.e., not including the sensitivity of the CTC detection) for the detection of cancer at Stages I or II, for a limited number of cancer types, e.g., breast, prostate and pancreatic cancer. While these signatures were found using tissue-based data, they are expected to remain valid when applied to CTCs, despite the sources of noise that are attributed to CTCs, namely allele dropout (ADO) and additional false positives/negatives. The observations were verified on a few late-stage CTCs --to be repeated once early-stage CTCs are available. Conclusions: In summary, this preliminary study supports the claim that a CTC-based liquid biopsy technique using WGS has the promise to provide a reliable platform for early detection of cancer. In addition to the isolated signatures found in this study and the previous study, the combination of these signatures via machine learning techniques could result in a yet more sensitive and specific early predictor for a subset of cancer types.
The importance of serum and fluid Vascular Endothelial Growth Factor (VEGF) level and fluid/serum VEGF ratio in the differential diagnosis of Malign Pleural Mesothelioma (MPM).
Authors: Muhammet Ali Kaplan, Yakup Duzkopru, Refik Ulku, Cetin Tanrikulu, Mehmet Kucukoner, Serdar Onat, Abdurrahman Abakay, Zuhat Urakci, Fatih Meteroglu, Zeynep Oruc, Abdurrahman Isikdogan
Journal: Journal of Clinical Oncology (2016)

e20086 Background: VEGF is one of the parameters that has been studied in differential diagnosis of malign fluids. This study is aimed to evaluate applicability of serum, fluid VEGF level and fluid to serum VEGF ratio in the diagnosis of MPM. Methods: The patients with pleural effusion over age of 18, between period of 2011 and 2015 were included in the study. They were separated into three groups: group 1: mesothelioma patients, group 2: other malignancies and group 3: benign etiologies. Group 1 and 2 were accepted as malign group. For evaluate fluid/serum VEGF ratio In all groups, fluid, serum VEGF levels and ratio of fluid/serum VEGF level were studied. Results: 20 cases with mesothelioma, 44 cases with other malignancies and 20 cases with benign etiologies were included in this study. No statistically significant difference were found according to serum VEGF levels for all groups, (group 1: 437±324 pg/ml, group 2: 354±223 pg/ml, group 3: 373±217 pg/ml, p:0.836), while fluid VEGF levels showed statistically significant difference (group1: 3359±700 pg/ml, group 2: 2175±435 pg/ml, group 3: 1092±435 pg/ml, p:0.041). Ratio of fluid to serum VEGF levels showed no statistical difference between malign (group 1 and group 2) and benign (group 3) groups. (8.83±1.29 vs. 4.57±1.07, p:0.059), but showed statistically significant difference between mesothelioma and benign groups. (12.11±1.68 vs. 4.57±1.07, p:0.044). Conclusions: VEGF can be an applicable parameter in the differential diagnosis of malign fluids, especially malign pleural mesothelioma. Further studies need to be done to support the applicability of fluid/serum VEGF ratio as a promising parameter for differential diagnosis of the malign fluids. However these parameters should be evaluate with others parameters that using for differantial diagnosis malign fluids.
Performance of two immunoafinity-based methods for CTC detection and molecular characterization in advanced colorectal cancer.
Authors: Santiago Cabezas-Camarero, Virginia De la Orden-García, Silvia Veganzones-de-Castro, Beatriz Mediero-Valeros, Manuel Enrique Fuentes-Ferrer, Antonio Carlos Sánchez Ruiz, Mariano Provencio, Enrique Aranda, Javier Sastre Valera, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2018)

e15648 Background: Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value as a source of molecular data is still unclear. Methods: We compared CellSearch (Janssen Diagnostics, LLC) and IsoFlux (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; N = 34). Secondly, we used castPCR to study KRAS status in CTC isolated with IsoFlux and compared it with that of the primary tumor in patients from group 1 and in patients KRAS wild-type (KRASWT) with progressive disease (group 2; N = 22). Results: Median number of CTC detected with CellSearch was 1 (range: 0-78) and with IsoFlux was 8 (range: 0-419), showing a modest correlation (r = 0.345, P = 0.036), which improved in the presence of lung metastases (r = 0.805, P = 0.016). A Bland-Altman plot showed a poor agreement between the two enumeration systems, particularly when IsoFlux recovered high CTC counts (≥11 CTC). After a median follow-up since CTC collection of 25 months (range: 1-35) CellSearch ≥ 3 vs < 3 CTC (HR 1.15, 95% CI 0.38-3.51, Harrell's C = 0.53) and IsoFlux ≥ 11 CTC (HR 1.47, 95% CI 0.58-3.75, Harrell's C = 0.58) were established as the best cutoff points for predicting survival in group 1. Although not statistically significant, median survival was shorter at higher CTC levels with both systems (CellSearch ≥ 3 vs < 3 CTC: 22 vs 25.7 m, P = 0.61; IsoFlux ≥ vs < 11 CTC: 22 vs 26.6 m, P = 0.18). Using castPCR we found KRAS mutations in CTC in 16 out of 26 patients from both groups (Group 1: 12/18; Group 2: 4/8). KRAS-mutant CTC using castPCR matched the primary tumor in 6/16 cases studied with conventional RT-PCR methods. When using castPCR in both the primary tumor and CTC, KRAS mutated status coincided in 9/16 cases. Conclusions: IsoFlux seems more efficient than CellSearch in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the minimum of CTC for castPCR-based genetic analyses. These results should be confirmed in a larger sample.
TCT-432 FANTOM II trial: Safety &amp; Performance Study of the Fantom Sirolimus-Eluting Bioresorbable Coronary Scaffold – 24-Month Follow-up Clinical Outcomes Final Results
Authors: Georgios Bouras, Alexandre Abizaid, Matthias Lutz, Didier Carrie, Joachim Weber-Albers, Darius Dudek, Louise Gambone, Jeffrey Anderson, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2018)
Induction of mortality and malformation in Xenopus laevis embryos by water sources associated with field frog deformities.
Authors: J G Burkhart, J C Helgen, D J Fort, K Gallagher, D Bowers, T L Propst, M Gernes, J Magner, M D Shelby, G Lucier
Journal: Environmental Health Perspectives (1998)

Water samples from several ponds in Minnesota were evaluated for their capacity to induce malformations in embryos of Xenopus laevis. The FETAX assay was used to assess the occurrence of malformations following a 96-hr period of exposure to water samples. These studies were conducted following reports of high incidences of malformation in natural populations of frogs in Minnesota wetlands. The purpose of these studies was to determine if a biologically active agent(s) was present in the waters and could be detected using the FETAX assay. Water samples from ponds with high incidences of frog malformations (affected sites), along with water samples from ponds with unaffected frog populations (reference sites), were studied. Initial experiments clearly showed that water from affected sites induced mortality and malformation in Xenopus embryos, while water from reference sites had little or no effect. Induction of malformation was dose dependent and highly reproducible, both with stored samples and with samples taken at different times throughout the summer. The biological activity of the samples was reduced or eliminated when samples were passed through activated carbon. Limited evidence from these samples indicates that the causal factor(s) is not an infectious organism nor are ion concentrations or metals responsible for the effects observed. Results do indicate that the water matrix has a significant effect on the severity of toxicity. Based on the FETAX results and the occurrence of frog malformations observed in the field, these studies suggest that water in the affected sites contains one or more unknown agents that induce developmental abnormalities in Xenopus. These same factors may contribute to the increased incidence of malformation in native species.
An open-label, phase 2 study of nivolumab in combination with either rucaparib, docetaxel, or enzalutamide in men with castration-resistant metastatic prostate cancer (mCRPC; CheckMate 9KD).
Authors: Karim Fizazi, Charles G. Drake, David R. Shaffer, Russell Pachynski, Fred Saad, Marika Ciprotti, George Kong, Charles J. Ryan, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2018)

TPS3126 Background: Although multiple new agents have been approved for mCRPC over the last decade, median survival remains unsatisfactory at ~12-35 months. Immunotherapy targeted solely at programmed death-1 (PD-1)/PD-1 ligand-1 (PD-L1) interactions has shown limited evidence of antitumor activity in patients (pts) with prostate cancer, likely due to the immunologically "cold" nature of the tumor and low PD-L1 expression on tumor cells. However, if existing prostate cancer treatments can trigger an adaptive immune response, attracting infiltrating immune cells and increasing tumor PD-L1 expression, there is a rationale for combination with anti-PD-1/PD-L1 inhibitors to improve outcomes. The current phase 2 study will evaluate combinations of the PD-1 inhibitor nivolumab with either rucaparib (PARP inhibitor), docetaxel, or enzalutamide (androgen receptor inhibitor) in men aged ≥18 years with mCRPC (NCT03338790). Methods: Key inclusion criteria: Histologic confirmation of adenocarcinoma of the prostate, evidence of metastatic disease, ongoing androgen deprivation therapy, and evaluable tumor biopsy. Key exclusion criteria: Active brain metastases, active malignancy in prior 3 years (except apparently cured locally-curable cancers), and major surgery ≤14 days before treatment assignment. Pts will be assigned to nivolumab + rucaparib, nivolumab + docetaxel, or nivolumab + enzalutamide based on prior systemic treatment history and the presence/absence of measurable disease and homologous recombination deficiency (HRD). Nivolumab, rucaparib, and enzalutamide treatment will continue until disease progression/unacceptable toxicity (nivolumab treatment ≤2 years); docetaxel will be given for ≤10 cycles. Co-primary endpoints: Objective response per Prostate Cancer Clinical Trials Working Group 3 criteria and prostate-specific antigen response in HRD+ pts and all treated pts; secondary endpoints: Overall survival, progression-free survival, and response kinetics in HRD+ pts and all treated pts, and safety/tolerability in all treated pts. Enrollment began December 2017 with a target of ~300 pts. Clinical trial information: NCT03338790.
P01.081 Can psychological profile change during RT and influence survival in patients affected by high grade gliomas? Final report of a prospective study
Authors: L Dinapoli, S Chiesa, R Gatta, F Beghella Bartoli, G Sabatino, T Zinicola, F Catucci, A Olivi, V Valentini, M Balducci
Journal: Neuro-Oncology (2018)
Differences in global toxicity burden among patients and care providers during initial chemotherapy for breast cancer.
Authors: John Christopher Rowland, Dawn L. Hershman, Kevin Kalinsky, Katherine D. Crew, Ying Kuen Cheung, Shing Mirn Lee
Journal: Journal of Clinical Oncology (2017)

e21649 Background: To better assess the safety of new drugs in cancer clinical trials, a measure of the overall toxicity burden is essential. We propose a novel tool for eliciting an overall toxicity burden score from physicians, nurses and patients, and compare these scores at baseline and after initial chemotherapy. Methods: Sixty patients starting therapy for breast cancer were enrolled prospectively from 2013 to 2015. Before and after starting therapy (cycle 2 day 1), a global toxicity burden score (TBS) was elicited from each patient using a scale from 0 to 10 based on the burden of their disease and therapy on their daily life, with 10 indicating more burden. After toxicities were collected using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), the treating physician and nurse completed an identical questionnaire independently. Baseline TBS, and pre- and post-treatment differences in TBS, number of CTCAE reported and overall health from the EORTC QLQ-C30 (higher indicating better health) were compared using paired t-tests. Results:Out of the 59 evaluable patients, the average age was 54 years, 1 was male, 55% were white, 41% Hispanic, 16% stage III or IV, and 59% received adjuvant therapy. Patients reported higher TBS at baseline compared to clinicians (mean (SD): patients = 3.10 (2.78), nurses = 1.26 (1.55), physicians = 0.90 (1.33); p &lt; 0.001). Moreover, while post-treatment patient reported outcomes were worse, they were not significantly different (mean difference (SD): TBS = 0.27 (2.74) p = 0.48; overall health status = -5.13 (21.53) p = 0.09). However, the number of toxicities and clinicians’ TBS increased significantly post-treatment (mean difference (SD): number of toxicities = 3.61 (2.71) p &lt; 0.001; physicians = 1.65 (1.47) p &lt; 0.001; nurses = 1.58 (1.41) p &lt; 0.001). Conclusions: The proposed tool for eliciting overall toxicity burden is simple and suggests that clinicians underestimate disease burden at baseline, and while the increase in number of toxicities after treatment is reflected in increased clinician reported burden, it is less apparent in patient reported outcomes. Future research should evaluate new measures of burden and toxicities over time.
Evolution in epithelial ovarian cancer (OC) trials: Improving accuracy by design.
Authors: Michelle K. Wilson, Victor Rodriguez-Freixinos, Katherine Karakasis, Tony Panzarella, Amit M. Oza
Journal: Journal of Clinical Oncology (2016)

5534 Background: In OC intermediate endpoints (IEP) such as progression free survival (PFS) are used to assess benefit in randomized controlled trials (RCTs) but surrogacy for overall survival (OS) has not been shown. This study explores how choice of IEP, trial design and reporting of RCTs in OC has evolved. Methods: A systematic review of MEDLINE and EMBASE identified RCTs of systemic therapy in OC from 1980-2014. Surrogacy between IEP and OS was explored. Details of design and outcomes were compared over time. Results: Of 3247 abstracts, 166 met inclusion criteria. Median (med) sample size rose from 123 (1980s) to 815 (2010+ p < 0.0001). Med OS showed incremental gains (17mths 1980s; 39mths 2010+ p = 0.001). Only 1 RCT limited histology type and 6 defined correlative tests. The primary endpoint (PEP) was stated in 53% of RCTs, increasing from 7.4% (1980s) to 100% (2010+ p < 0.0001). Type of PEP varied with time with IEP more common from 2010 (p = 0.008). PFS was the most common IEP (72%). The expected outcome used in the statistical design was defined in 54%. Accurate prediction of the expected med PFS was more common in 2000-2009 than 2010+, with this trend reversed for the predicted med OS. Quality of life was assessed in 35 RCTs (PEP in only 1), increasing from 2% (1980s) to 62% (2010+ p < 0.0001). Targets were defined in 17% with results in the abstract in 37% and article in 86%. Toxicity was recorded in 95%. While 31% of RCTs were statistically significant, 53% were reported as positive. A significant correlation between the HR for PFS and OS (r+0.73) was seen but this did not persist for OS and PFS p values. Conclusions: Incremental gains in OS in OC have been achieved over the last 35 years. The quality of RCT reporting has improved but ongoing vigilance with documentation of statistical justification of endpoints is needed. Though med PFS correlated with med OS, clear surrogacy was not seen.
A pyrolytic compound of curcumin, a dietary deketene curcumin to inhibit gastric carcinogenesis in a mouse model.
Authors: Taichi Yoshida, Masahiro Inoue, Koji Fukuda, Kazuhiro Shimizu, Daiki Taguchi, Hiroyuki Shibata
Journal: Journal of Clinical Oncology (2017)

e15518 Background: Gastric cancer is the second cause of cancer death in the world, killing more than 700,000 people in 2012. The risk factors are Helicobacter pyloriinfection, obesity, smoking, consumption of red meat or alcohol. However, an effective preventive measure of this disease has bot been established. Curcumin, a dietary pigment, that has been used for more than three thousand years, has an anti-tumor potential. However, bioavailability of curcumin is very poor, and it is not used in clinics. Researchers are trying to overcome this short point. To synthesize a new analog bearing higher anti-tumor potential is our solution, and we have successfully developed a series of new diarylpentanoid analogs. Our diarylpentanoid analogs are structurally different from curcumin, a diarylheptanoid. Recently, a breakthrough finding that a deketene curcumin is formed as a result of pyrolysis of curcumin during cooking of curry, was published. This deketene curcumin is identical to one of our analogs, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one, named GO-Y022. For this reason, we investigate the efficacy and safety issues of GO-Y022 in a mouse gastric cancer model. Methods: We assessed anti-tumor potential of GO-Y022 on gastric cancer cell lines, KATO Ⅲ, H-111-TC, GCIY and SH-10-TC. We also examined the potential to inhibit β-Catenin and pSTAT3 levels. We conducted mouse experiment using transgenic mouse model overexpressing Wnt signaling, COX2 and Prostaglandin E2. This mouse is highly seceptible to gastric carcinogenesis. We orally administrated GO-Y022 mixed with food. We checked the safety issues of the treated mouse, and measured the tissue concentration of GO-Y022 by HPLC method. Results: GO-Y022 can inhibit the growth of gastric cancer cell lines significantly. The average IC 50 value of GO-Y022 was 5.05 ± 0.93 μm. That is about five times lower than curcumin. This potential was confirmed in mice. Blood concentration and the tissue distribution of GO-Y022 were negligible except gastrointestinal epithelia. GO-Y022 was safe for mouse models. Conclusions: GO-Y022 can inhibit the growth of gastric carcer in vivo. Oral administration of GO-Y022 can suppress gastic cancer topically.
Intact APM and PD-1:PD-L1 pathway upregulation in HIV-infected head and neck cancer patients.
Authors: Sara I. Pai, J. Jack Lee, Thomas E. Carey, William H. Westra, Soldano Ferrone, Charles Moore, Dong Moon Shin, Robert L. Ferris
Journal: Journal of Clinical Oncology (2017)

6058 Background: HIV-infected individuals have a higher incidence of oral infection with human papillomavirus (HPV) and possibly a higher incidence of head and neck cancer (HNC). Whether this observation reflects defects in the ability of this Òimmune-compromisedÓ patient population to mount sufficient tumor specific immune responses and/or reflects activation of immune escape mechanisms is not known. To address this question, we investigated the expression of HLA class I antigen processing machinery (APM) components and PD-1:PD-L1 pathway activation in HIV(+) HNC patients. Methods: 62 HIV(+) HNC patients diagnosed between 1991-2011 from five tertiary care referral centers in the United States and matched HIV(-) HNC controls were identified. HLA class I APM component, PD-1, and PD-Ll expression were analyzed by immunohistochemical staining. Clinical data was abstracted from the medical records. Results: 44 of 62 (71%) HIV(+) HNC cases were matched based on gender, age ( &lt; 10 years), and anatomic sub-site to HIV(-) HNC patients. There was no significant difference between the cases and controls in HLA-A, HLA-B/C, LMP2, and TAP1, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1. HLA-A, HLA-B/C, and LMP2 expression was significantly correlated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = 0.004, p = 0.026, and p = 0.006, respectively) but not in the HIV(-) controls. Similarly, HLA-A expression was also significantly associated with PD-L1 expression only in the HIV(+) HNC cases (p = 0.029). Conclusions: No defects were detected in the expression of the HLA class I APM components tested. PD-1:PD-L1 pathway was found to be upregulated in both HIV(+) and HIV(-) HNC patients. Our data suggest that recently approved anti-PD-1 immunotherapy should not exclude HIV(+) patients.