tbuckley/cabot-search huggingface dataset:
Three dimensional organotypic ex vivo culture of tissues from post-operated tumor samples: Strengths and limitations.
Authors: Nandini Dey, Yuliang Sun, Amy K. Krie, Luis Rojas, David Starks, Xiaoqian Lin, Kirstin Anne Williams, Megan Megan Quast, Jennifer Carlson, Shelby Hintze Jepperson, Vladimir Lazar, Pradip De, Casey B. Williams, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2017)

e23151 Background: Evolution of tumor occurs in two phases, pretreatment phase, and posttreatment phase.Tumorigenic history and path of tumorigenic evolution determine the response of tumor cells to antitumor drug and thus the outcome of treatment. Carcinomas from the same organ-site with similar genomic alterations in different patients may vary in their tumorigenic history and their diverse paths of tumorigenic evolution which cause them respond differently to the same antitumor drugs. Uniqueness of tumorigenic history and paths of tumorigenic evolution in individual patient makes it ideal to test drugs, N-of-1. Here we present our experience with 3D organotypic ex vivo culture of tumor tissue from post-operated tumor samples. Methods: Informed consent was obtained from patients ( NCT02470715). The investigation was approved by IRB of the Avera Cancer Institute and the Western IRB. Surgically resected tissue was obtained from patients with different tumors of different organ sites including ovarian, breast, lung, endometrium, and cervix at the Avera Cancer Institute, SF, SD. Tissues from patients were collected in two formats, paired samples (tumor and tumor-adjacent normal) and unpaired samples. Results: As extracellular matrix lost in cell cultures, provide important signals for cell survival, differentiation and drug resistance we have established a protocol to culture slices in the 3D format. We have established 3D slice cultures (3x3 mm) of tumor-derived tissues which can be maintained ex vivo for at least three days. Tumor cells / normal cells from different tumors/tumor-adjacent normal tissues from day zero (non-cultured) were used to compare day1, day2, and day3 cultures. At the end of the culture period, slices were embedded in paraffin for histological analysis following H&amp;E staining as well as IHC-staining for proliferation index (Ki-67), cellular proliferation signals (pS6RP), apoptosis (activated caspase 3), or tumor angiogenesis (CD31). Ki67 staining was characteristically different in cultured normal and cultured tumor tissues. Conclusions: Here, we show that tumor-derived tissues survive in 3D Matrigel culture for a minimum of 6 hours and maximum up to 3 days. Clinical trial information: NCT02470715.
A sensitive and accurate test for simultaneous detection of 36 BRAF and NRAS mutations.
Authors: Nancy Patten, Victoria H. Brophy, Winnie Hui, Rachel Anne Langland
Journal: Journal of Clinical Oncology (2018)

e24153 Background: Activating mutations in the mitogen-activated protein kinase pathway are among the most common mutations found in cancer cells. Because of the interaction between BRAF and NRAS, there is interest in simultaneous testing for mutation status of these genes. We have developed a multiplexed, allele-specific PCR kit for broad and sensitive detection of 36 BRAF and NRAS mutations. The BRAF/NRAS Mutation Test kit has been verified for use with FFPE tissue and plasma (Research Use Only).The sample to result can be performed in eight hours or less. A web-based analysis tool enables automated and rapid interpretation of results. We describe the studies done to verify the test performance and to evaluate its correlation with an Illumina MiSeq method. Methods: We tested contrived specimens as well as FFPE tissue and plasma specimens from melanoma, non-small cell lung, and colorectal cancer patients. Results for analytical sensitivity, exclusivity, repeatability, and correlation with the MiSeq method are reported. Results: The BRAF/NRAS Mutation Test demonstrated high sensitivity, specificity and broad mutation coverage. Repeatability was 100% across all samples, operators, and instruments. Analytical sensitivity was high for tissue and plasma samples. 1% sensitivity was achieved for 34 mutations using mutant plasmid DNA in 50ng genomic DNA. 2.5% mutant allele frequency in 50ng FFPE DNA and as low as 0.03% from 2mL plasma were detected. Plasmids containing highly similar HRAS, KRAS, and KRAS pseudogene plus A-RAF, C-RAF, and BRAF pseudogene sequences were not detected, showing specificity for NRAS and BRAF. The test showed high concordance for 164 tumor FFPE tissue from melanoma, CRC, and NSCLC (98.2%) and 186 plasma specimens from melanoma and CRC (98.9%) when compared to MiSeq sequencing. Conclusions: The BRAF/NRAS Mutation Test is a sensitive and reproducible kit for the detection of 11 BRAF mutations in exons 11 and 15 and 25 NRAS mutations in exons 2, 3, and 4. The simplified lab workflow and assay reliability make it suitable for the accurate detection of mutations from tissue and plasma biopsies.
Access to specialist care and treatment in patients with advanced non-small cell lung cancer.
Authors: Apar Kishor Ganti, Hossein Borghaei, Fred R. Hirsch, Murry Wynes, Arliene Ravelo, Raluca Ionescu-Ittu, Irina Pivneva, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2016)

9094 Background: Access to appropriate care is critical in the management of patients with advanced (stage IIIB or IV) non-small cell lung cancer (aNSCLC). This study assessed treatment patterns among patients with aNSCLC who were seen or not by a cancer specialist (CS). Methods: Patients aged ≥ 65 years diagnosed with aNSCLC between 2007 and 2011 were identified in the SEER-Medicare database (n = 9,651) and were followed for ≥ 4 months post-diagnosis. Patient’s first biopsy within ± 8 weeks of diagnosis was defined as the index date. Two cohorts were defined based on visits to CS (oncologist or hematologist / surgical / radiation oncologist) from 6 weeks pre-index date until end of follow-up (end of data availability [12/31/2013] or end of Medicare Parts A, B and D eligibility). Results: 9,284 patients seen by a CS (96%) and 367 patients not seen by a CS (4%) were observed for a median of 11 months post-diagnosis. Compared to patients seen by a CS, those not seen by a CS were older (median age 78 vs. 74 years), more likely to be widowed (38 vs. 28%), and resided in areas with higher poverty (35 vs. 24%) and lower education levels (35 vs. 21%, p < .01 for all). Cancer-directed therapy was received by 90% of patients: 92% of patients seen and 36% of those not seen by a CS (p < .01, Table). Surgical resection (54%) was the most common treatment in patients not seen by a CS. Conclusions: Approximately 4% of patients with aNSCLC were not seen by a CS and 10% were untreated. Significant demographic differences exist between patients seen by a CS and those who were not. Addressing disparities in access to specialist care and treatment is imperative for the equitable lung cancer care of all Americans. Patients seen by CS N = 9,284 Patients not seen by CS N = 367 P-value Treated patients, N (%) 8,508 (92) 133 (36) < 0.01 Therapy types,* N (% of treated) Systemic EGFR-inhibitor 1,876 (22) 21 (16) 0.08 ALK-inhibitor < 11 (0)† < 11 (<3)† > 0.99 Targeted therapy 235 (3) < 11 (<3)† > 0.99 Chemotherapy 6,443 (76) 47 (35) < 0.01 Radiation 6,118 (72) 13 (10) < 0.01 Stereotactic radiosurgery 901 (11) < 11 (<3)† 0.01 Radiofrequency ablation 131 (2) < 11 (<3)† 0.46 Surgery Cryoablation 103 (1) < 11 (<3)† 0.68 Brachytherapy 66 (1) < 11 (<3)† > 0.99 Surgical resection 1,125 (13) 72 (54) < 0.01 * Used alone, in combination or sequentially. † Per SEER-Medicare data agreement cell sizes with < 11 patients must be suppressed.
TCT-616 Impact of general cardiology follow-up on optimal cardiovascular risk factor management post-revascularization: outcomes in a nationalized healthcare system
Authors: Richard Jung, Trevor Simard, Alisha Labinaz, Francisco Ramirez, Pietro Di Santo, Ian Pitcher, Pouya Motazedian, Rebecca Rochman, Robert Moreland, Jeffrey Marbach, Paul Boland, Kiran Sarathy, Saleh Alghofaili, Juan Russo, Etienne Couture, Michael Froeschl, Alexander Dick, Benjamin Hibbert
Journal: Journal of the American College of Cardiology (2018)
A randomized, controlled trial to assess a multi-level intervention to improve adherence to oral cancer medications.
Authors: Rashmika Potdar, Sneha Karki, Claudia M. Dourado, Kamran Mohiuddin, Djeneba Audrey Djibo, John Charles Leighton, Jean G Ford
Journal: Journal of Clinical Oncology (2018)

TPS6621 Background: Cancer treatment with oral cancer medication is complex. Cancer patients require substantial skills to adhere to- and achieve the goals of therapy. Medication adherence among cancer patients is increasingly important, as treatment with oral medications is increasingly prevalent. The rates of adherence to oral therapy vary widely by population, cancer type, and level of education. To date, however, there is no clear evidence on the effect of improvements in health literacy on patients’ adherence to oral cancer medications. We hypothesize that compared to usual care, the addition of a multilevel intervention will result in greater adherence to oral cancer medications. Methods: In a single-center, patients are randomized 1:1 to receive usual care, including clinical care plus education by a registered nurse (Arm 1), or the addition of a multilevel intervention (Arm 2). The multilevel intervention includes a brief web-based educational video on cancer and oral cancer drugs, periodic reinforcement of educational messages with videos, brief phone calls 24 hours and 2 weeks after each encounter, and offer of facilitative services, if needed. Health literacy is recorded at baseline, using REALM R. Adult cancer patients on any oral cancer medication are eligible to participate in the study. Exclusion criteria include ECOG ≥3, concurrent chemo-radiation, hormonal therapy, non-adherence (defined as history of missing 2 or more Oncology clinic appointments), pregnancy, residence in a nursing home, dementia, or lacking decisional capacity. The primary outcome of interest is medication adherence, indicated by the proportion of expected refills completed for oral cancer medications during the follow up period. Secondary outcomes include adherence to follow up visits, adherence to other prescribed medications, healthcare utilization, and other healthcare outcomes. With a one-sided alpha = 0.05, the target sample size of 110 patients, would yield 90% power to test the primary hypothesis. To date, we have randomized 19 participants, and enrollment proceeds as planned. Clinical trial information: NCT03245411.
Abstract 15066: Porphyromonas ginigivalis-Induced Atherosclerosis is Transferred by Bone Marrow Transplant
Authors: Mohamed Omar, Maria Alexiou, Maria Febbraio
Journal: Circulation (2016)

Periodontal disease (PD) is a destructive inflammatory disease of the periodontium and Porphyromonas gingivalis (Pg) is a keystone pathogen in its early onset. Mounting evidence supports a role for...
The use of exosome and immune profiling to analyze a phase 2 study on the addition of patritumab or placebo to cetuximab and a platinum agent for recurrent / metastatic head and neck cancer (R/M HNSCC) patients.
Authors: Tony Ng, Fabian Flores-Borja, Giovanna Alfano, Paul Barber, Gregory Weitsman, Felix Wong, Jose Vicencio, Myria Galazi, Jana Doyle, Jonathan Greenberg, Martin David Forster, Anthonius Coolen
Journal: Journal of Clinical Oncology (2018)

6043 Background: The use of patritumab (Daiichi Sankyo), an internalizing anti-HER3 monoclonal antibody, in combination with cetuximab and cisplatin was investigated in a cohort of patients with R/M HNSCC in a Phase II trial (NCT02633800). We investigated the EGFR-HER3 dimer (an established marker of cetuximab resistance within a previous study) in the circulating exosomes from patients enrolled in this trial. The objective was to identify non-invasive treatment stratification and longitudinal monitoring markers. Since antibody-directed cytotoxicity is involved as a mechanism of action for these therapies, exosomal microRNAs (miR21 and miR142), which promote the expansion of functional myeloid-derived suppressor cells (MDSC), as well as other suppressive adaptive and innate immune cell components are postulated as potential immune monitoring parameters. Methods: We extracted exosomes from patient serum at 2 timepoints: pretreatment (c1) and pre-cycle 2 (c2, day 1). Exosomes were stained with fluorescently labelled antibodies for fluorescence lifetime imaging microscopy (FLIM) to assess EGFR-HER3 dimerization by FRET. Serum exosomal miRs were analyzed using ddPCR. PBMCs were analyzed by flow cytometry with antibodies against CD3, CD4, CD8, CD25, CD127, CD45RO, CCR6, CCR7, and HLA-DR (T cells panel), or CD3, CD11b, CD14, CD16, CD19, CD24, CD27, CD33, CD38, and IgD (B cells/MDSC panel). We used Bayesian multivariate survival analysis, blinded, with overfitting prevention, to prospectively determine parameter contributions to risk. Results: Multivariate risk scores/signatures were derived that predicted either: progression free survival (PFS), with parameters including c1 MDSC, and c2 CD27-IgD-double-negative exhausted memory B cells; or RECIST response, with parameters including suppressive transitional B cells (c1 - c2 difference predicting response), and exosomal EGFR-HER3 dimer (c1 - c2 difference negatively predicting response). Conclusion: This study prospectively establishes an effect of exosomal and immunological factors on the efficacy of anti-HER/chemo combination therapies, paving the way for future stratification strategies that combine with immunological therapies. Clinical trial information: NCT02633800.
CRLX101 plus olaparib in patients with metastatic castration-resistant prostate cancer.
Authors: Gang Chen, Fatima Karzai, Ravi Amrit Madan, Lisa M. Cordes, Marijo Bilusic, Helen Owens, Amy Hankin, Monique Williams, Anna Couvillon, James L. Gulley, William L. Dahut, Anish Thomas
Journal: Journal of Clinical Oncology (2018)

TPS5096 Background: Prostate cancer is the most commonly diagnosed cancer among men in the United States. While prostate cancer is initially responsive to androgen deprivation therapy (ADT), most patients will develop castration-resistant disease. In the past several years, despite multiple new therapeutics (docetaxel, abiraterone and enzalutamide) have been approved by FDA, the majority patients will become resistant to treatments in 2-3 years. Therefore, it is necessary to find new treatments in metastatic castration-resistant prostate cancer (mCRPC). Methods: This phase II expansion cohort will evaluate the efficacy and safety of CRLX101 plus Olaparib in patients with mCRPC. CRLX101 is a nanoparticle drug conjugate with a camptothecin (CPT) payload that provides durable inhibition of topoisomerase I (Top1) specifically in the tumor. CPT stabilizes the Top1-DNA cleavage complex during DNA replication and prevents Top1-mediated DNA relegation, ultimately leads to apoptosis. Poly ADP ribose polymerase (PARP) plays a role in the repair of topoisomerase I-induced DNA damage. By inhibiting PARP, Olaparib may increase the potency of CPT and thus olaparib plus CRLX101 offers a potential treatment option in patients with mCRPC. Synergistic activity between camptothecin and olaparib has been shown in preclinical data. The primary endpoint of this study is overall response rate (ORR), the secondary endpoints include safety and progression-free survival (PFS), duration of response and PSA responses. Clinical trial registry number of this study is NCT02769962. Results: N/A. Conclusions: N/A. Clinical trial information: NCT02769962.
TCT-431 Twenty-four Months Healing Patterns After Implantation of the Fantom Bioresorbable Scaffold evaluated by Optical Coherence Tomography
Authors: Emil Holck, Jo Simonsen, Didier Carrié, Darius Dudek, Norbert Frey, Matthias Lutz, Bernard Chevalier, Jeffrey Anderson, Jouke Dijkstra, Evald Christiansen, Alexandre Abizaid, Niels Holm
Journal: Journal of the American College of Cardiology (2018)
ERA 223: A phase 3 trial of radium-223 dichloride in combination with abiraterone acetate and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone-predominant metastatic castration-resistant prostate cancer.
Authors: Matthew R. Smith, Chris C. Parker, Bertrand F. Tombal, Kurt Miller, Fred Saad, JunWu Shen, Amily Zhang, Martin Kornacker, Celestia S. Higano
Journal: Journal of Clinical Oncology (2016)

TPS5088 Background: Radium-223 dichloride (Ra-223), a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases (mets), reduced risk of death and delayed time to first symptomatic skeletal event (SSE) v placebo (pbo) in ALSYMPCA (Parker et al. NEJM 2013; Sartor et al. Lancet Oncol 2014). The favorable safety profile of Ra-223 supports combining it with other agents. Abiraterone acetate (Abi) improved radiologic progression-free survival (rPFS) and overall survival (OS) (Ryan et al. NEJM 2012) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC); it has no overlapping toxicity with Ra-223. This study investigates efficacy and safety of Ra-223 + Abi v Abi alone in chemotherapy-naïve patients (pts) with mCRPC to bone. Methods: This phase 3, double-blind, pbo-controlled, multinational trial (NCT02043678) randomizes ~800 pts with asymptomatic or mildly symptomatic chemotherapy-naïve, bone-predominant mCRPC 1:1 to Abi (1000 mg daily, PO) and prednisone (5 mg bid, PO) + Ra-223 (50 kBq/kg IV) q 4 wk × 6 or matching pbo until SSE or death. Sample size is calculated based on the primary end point, SSE-free survival (SSE-FS). 389 events are required to detect a 39% increase in SSE-FS with ~90% power using a stratified log-rank test, at a 2-sided 0.05 level, assuming median SSE-FS is 29.2 mo for Ra-223 v 21.0 mo for pbo. Pts are stratified by geographic region, concurrent use of denosumab or bisphosphonate or none, and total alkaline phosphatase (tALP) < 90 U/L v tALP ≥ 90 U/L. Secondary end points are OS, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, rPFS, and acute and long-term safety. Pts are assessed at each treatment visit for efficacy, safety, and health-related quality of life. Pts who complete all study treatment and have no SSE enter active follow-up. Long-term follow-up begins after pts have an SSE and ends up to 7 years after last Ra-223 dose or at death, loss to follow-up, or withdrawal. As of January 19, 2016, 415 pts were randomized. Clinical trial information: NCT02043678.
A phase Ia/Ib trial of the DNA-dependent protein kinase inhibitor (DNA-PKi) M3814 in combination with radiotherapy in patients with advanced solid tumors.
Authors: Baukelien Van Triest, Lars Damstrup, Johan Falkenius, Volker Budach, Esther Troost, Michael Samuels, Thomas Goddemeier, Poul F. Geertsen
Journal: Journal of Clinical Oncology (2017)

e14048 Background: DNA-PK, with its protein subunits, Ku70 and Ku80, regulates one of the major pathways responsible for repair of double-strand breaks in DNA that are induced by radiotherapy (RT) and some chemotherapeutic agents (CT). Therefore, the combined strategy of RT with a DNA-PKi is promising. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT and chemo-RT (CRT). Methods: Patients (pts) with tumors or metastasis in the head and neck region or thorax in need of palliative RT (10 x 3 Gy) are eligible for the dose escalation part Ia, with a starting dose of 100 mg once daily. Dose escalation decisions are aided by the Bayesian logistic regression model with overdose control. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: As of January 2017, 7 pts had been enrolled into the part Ia dose escalation arm and treated with 100 mg daily. The most frequent adverse events (AEs) were fatigue, constipation, decreased appetite, dry mouth, dysphagia, headache, oral pain, radiation skin injury, and mucositis in more than 1 pt (20%). No pts discontinued due to AE. Two episodes of grade 3 mucositis lasting &gt; 7 days were reported; one of these was classified as a DLT, and both pts recovered without sequelae. Two of 7 pts enrolled had local tumor control at +300 days. PK analysis demonstrated high exposure variability. Conclusions: M3814 at the 100 mg daily dose was tolerable as palliative treatment and dose escalation is currently at 200 mg. In part Ib of the study, two separate dose escalation arms will enroll pts with either head and neck squamous cell carcinoma (SCCHN; US only) or non-small cell lung cancer (EU and US) to receive CRT 2 Gy x 30-35 over 6-7 weeks with curative intent; the SCCHN cohort is now open for enrollment. For these two cohorts, the DLT window will be 12 weeks. Clinical trial information: NCT02516813.
Correlation of measurements of tumor heterogeneity based on next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) with clinical outcomes in STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).
Authors: Stephanie Yaung, Nalin Tikoo, Alan Nicholas, Nicolas Sommer, Johanna C. Bendell, Herbert Hurwitz, Richard Price, John F. Palma, John J. Lee, Fergal Casey
Journal: Journal of Clinical Oncology (2018)

3545 Background: STEAM (clinical trial NCT01765582) assessed efficacy and safety of concurrent and sequential FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. The AVENIO ctDNA Expanded and Surveillance Kits (Research Use Only) were used to detect somatic mutations by NGS in tissue, and pre- and post-induction plasma samples. Methods: Plasma-based molecular measures of tumor heterogeneity were defined as: 1) Plasma Recovery Rate (PRR), a ratio of shared plasma and matched tissue variants to total plasma variants; 2) Mutant-Allele Tumor Heterogeneity (MATH), a measure of variant allelic frequency dispersion, applied here to plasma; and 3) Multi-Variant Gene Count (MVGC), a count of genes harboring > 1 somatic mutations in plasma. Results: Overall, greater pre-induction tissue-plasma discordance correlated with shorter OS, and subjects with complete tissue-plasma concordance (defined as PRR = 1, suggesting monoclonality) had longer PFS (18.3 vs 9.5 mo, HR 0.43, 95% CI 0.2 - 0.91, logrank p = 0.023). High plasma allele frequency dispersion, assessed as MATH in the top quartile, correlated with shorter PFS in pre-induction plasma (8.1 vs 11.7 mo, HR 1.8, 95% CI 1.1 - 3.1, logrank p = 0.026) and in post-induction plasma (7.4 vs 12.2 mo, HR 2.9, 95% CI 1.7 - 5.2, logrank p = 0.00012). Similar trends were seen for OS. Subjects with > 1 somatic mutation in a gene, classified as MVGC > 0, in post-induction plasma had shorter OS. An increase in MVGC from pre- to post-induction correlated with shorter OS (14.8 vs 26.4 mo, HR 4.6, 95% CI 1.9 - 10.9, logrank p = 0.00029). Conclusions: Analyses with AVENIO ctDNA Kits on STEAM reveal the potential prognostic value of measuring plasma-based tumor heterogeneity, with higher heterogeneity correlating strongly with poor outcomes. Pre-induction, a lower rate of recovery of plasma variants in tissue and high plasma dispersion correlated with shorter survival. Post-induction, high plasma dispersion and intragenic heterogeneity correlated with shorter survival. These hypothesis-generating results require further validation.