tbuckley/cabot-search huggingface dataset:
P03.05 Supporting function of nurses to facilitate TTFields therapy for primary and recurrent Glioblastoma in clinical routine
Authors: M Kilias, C Pellet, A F Hottinger
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields, Optune®) are an approved novel GBM treatment modality with antimitotic efficacy. Optune delivers alternating low-intensity (1–3 V/cm) and intermediate-frequency (200 kHz) electric fields to the brain through transducer arrays applied to the shaved skull. Treatment efficacy is correlated to patient compliance. Patients with a monthly compliance of 90% achieved a median 5-year survival of 29%. Raising awareness for Optune therapy duration requires extensive counselling to achieve optimal compliance. The present study aimed to identify the beneficial value of oncology nurses during the process of patient education and presents a guideline for successful patient communication. Materials and Methods: For successful implementation of TTFields into GBM therapy, the current treatment education process was analyzed critically to detect how nurses can improve the communication to patients regarding Optune. To increase therapy acceptance and compliance a specific nurse training program was established to improve the education of patients on the integration of TTFields therapy into daily life routine. Additionally, a communication algorithm was developed to improve communication with the patient, based on patient-adapted phrasing and by optimizing time of explanation, motivation and consistency. Assessment of the role of nurses in the education strategy on TTFields revealed that nurses can improve patient education during the treatment pathway. Nurses participated in the explanation of all treatment options using patient-adapted terminology starting at diagnosis. Guidelines for successful patient communication were established. This education strategy allowed patients to familiarize themselves with available treatment options to make conscious treatment decisions that improve acceptance and awareness for compliance. As a positive side effect of continuous integration of nurses into the patient education process is reduction of physicians’ workload. Educational training by nurses promotes basic scientific understanding.The development of guidelines for successful patient communication established a consistent education in a patient-adapted manner, which subsequently, improved patient education, acceptance, and compliance. Based on the benefits experienced, we recommend that trained nurses should be an integral part in the GBM patient education process.
Multi-center phase Ib study of intermittent dosing of the MEK inhibitor, selumetinib, in patients with advanced uveal melanoma not previously treated with a MEK inhibitor.
Authors: Kimberly Mayumi Komatsubara, Alexander Noor Shoushtari, Sapna Pradyuman Patel, Parisa Momtaz, Shahnaz Singh-Kandah, Amanda Carter, Suzanne Cain, Lauren Taiclet, Sarah DeNoble, Tiffany Negri, Danielle Lacey, Grazia Ambrosini, Shing Mirn Lee, Gary K. Schwartz, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2017)

TPS9597 Background: Uveal melanoma (UM) is a rare subtype of melanoma with no effective therapy for advanced disease. UM is characterized by mutations in GNAQ and GNA11 leading to constitutive activation of the mitogen activated protein kinase (MAPK) pathway. We have previously shown that targeting the MAPK pathway though MEK inhibition with Selumetinib (AZD6244, ARRY-142886) using a continuous dosing schedule improved progression free survival (PFS) in a randomized Phase II study of Selumetininb versus chemotherapy in patients with metastatic UM; however, no PFS or overall survival (OS) benefit was observed in a subsequent randomized Phase III study of Selumetinib and chemotherapy versus chemotherapy alone. We hypothesize that an intermittent dosing schedule of Selumetinib may be more effective than continuous dosing by achieving higher dose levels, better drug tolerability, and more complete target inhibition. We propose a Phase Ib study of Selumetinib in UM using an intermittent dosing schedule. Methods: A total of 28 subjects will be enrolled using the time to event continual reassessment method (TITE-CRM). Key inclusion criteria include a diagnosis of advanced UM, measurable disease by RECIST v1.1, and no prior MEK inhibitor therapy. Eligible subjects will be treated with Selumetinib starting at a dose level of 125 mg orally twice a day, using a 3-days-on and 4-days-off per week schedule. The primary goal of this study is to estimate the maximum tolerated dose (MTD) of intermittently dosed Selumetinib. Secondary endpoints are response rate, PFS and OS. Responses will be evaluated every 8 weeks by a CT scan of the chest and CT or MRI of the abdomen/ pelvis using RECIST v1.1 criteria. Mandatory tumor biopsies will be obtained at baseline, cycle 1 day 3 (Selumetinib-on day), and between cycle 1 day 11-14 (Selumetinib-off day) in 20 subjects, and optionally at progression. Tumor tissue will be assessed for MAPK pathway inhibition and reactivation at each time point, as well as mechanisms of resistance. Recruitment is currently ongoing. Clinical trial information: NCT02768766.
Genomic diversity between Asian and United States intrahepatic cholangiocarcinoma patients.
Authors: Reham Abdel-Wahab, Siqin Liu, Jeffrey S. Ross, Alexa Betzig Schrock, Siraj Mahamed Ali, Jingyu Cao, Li Zhuang, Jianzhen Lin, Rachna T. Shroff, Milind M. Javle, Kai Wang, Haitao Zhao
Journal: Journal of Clinical Oncology (2018)

e16137 Background: Genetic heterogeneity in intrahepatic cholangiocarcinoma (IHCCA) has been hypothesized based on differing disease etiologies between Eastern and Western population. Our study aim was to explore genetic variations between Chinese and the United States (U.S.) IHCCA pts. Methods: Comprehensive genetic profiling of formalin-fixed, paraffin-embedded tumor tissue for 272 U.S. IHCCA pts and 69 Chinese IHCCA pts was performed using next-generation sequencing. We measured tumor mutational burden (TMB) in U.S. and Asian patients and classified pts into three groups; low ( < 6 mut/Mb), intermediate (6 – 19 mut/Mb), and high (≥20 mut/Mb). Univariate analysis was done using the x2 for categorical variables and independent samples t-test was performed to compare the means of TMB in the two cohorts. Results: In the U.S. cohort, 57% of pts were females as compared with 23% in Chinese pts (P < .0001). A total of 997 genetic aberrations (GAs) were identified in U.S. pts with an average of 3.7 GA per tumor. In Chinese pts, a total of 207 GAs were identified in 69 pts with an average of 3 GA per tumor. The most frequent GAs present in > 5% of pts were TP53, ARID1A, KRAS, BAP1, CDKN2A/B, IDH1, PIK3CA, FGFR2, MCL1, BRAF, PBRM1, and ATM. TP53 was more frequently noted in Chinese pts (P = .001) while, CDKN2A/B was higher in U.S. pts (P = .0001). Out of 9 commonly dysregulated pathways in cancer, GAs in DNA repair gene pathway occurred more frequently in Chinese pts (P = .03) with predominant GAs in BRCA2, ATR, and TP53 (P = .07, .04, and .001, respectively). TMB was evaluated in 144 pts from U.S. cohort and 64 pts from Chinese cohort. The mean TMB among U.S. and Chinese pts was 5.5 mut/Mb and 10.4 mut/Mb, respectively. Moreover, in U.S. cohort 4.9% of pts had TMB-H, 19.4% had TMB-I and 75.7% had TMB-L as compared with 10.9% with TMB-H, 48.4% TMB-I and 40.6% TMB-L (P < .001) in Chinese pts. Conclusions: The frequency of TMB-H and DNA repair mutations is higher in Asian pts as compared with U.S. pts. These data will potentially support further immune biomarker analysis and immunotherapy trials for IHCCA.
Variations in the use of definitive chemoradiotherapy and immunoradiotherapy for patients with locally advanced head and neck cancer.
Authors: Shiva Kumar Reddy Mukkamalla, Ritesh Rathore
Journal: Journal of Clinical Oncology (2018)

e18074 Background: Clinical practice guidelines recommend definitive concurrent bi-modality treatment, either with chemoradiotherapy (CRT) or immunoradiotherapy (IRT) using cetuximab, for locally advanced head and neck cancers (HNC). This study analyzes the variations in use of these treatment modalities based on various patient- and disease-specific characteristics along with hospital-level Methods: National Cancer Data Base (NCDB) was queried for patients with locally advanced HNC from 2013-2014. Nasopharyngeal and salivary gland tumors were excluded. Prior to 2013 NCDB classified immunotherapies under chemotherapy. CRT or IRT was defined as start of systemic therapy within 14 days of initiation of radiotherapy (RT). Data analysis was performed using chi-square test, univariate and multivariate logistic regression. Results: An initial cohort of 11,958 patients was identified: 82.6% had received CRT, 7.2% had received IRT and 10.2% received RT alone. Chi-square test demonstrated significantly higher rates of IRT administration among patients treated in the Middle Atlantic, who were ≥75 years, female, insured, diagnosed in 2014, with high Charlson-Deyo comorbidity score (2 or more) and HPV-positive tumors with N0 nodal stage (p < 0.05). Multivariate logistic regression analysis demonstrated that Middle Atlantic treatment centers (odds ratio [OR] 2.08, 95% CI 1.44-3.01), age of ≥75 years (OR 4.58, 95% CI 3.77-5.56), high comorbidity score (OR 1.64, 95% CI 1.22-2.18), diagnosis in 2014 (OR 1.19, 95% CI 1.03-1.38), HPV-positive tumors (OR 1.29, 95% CI 1.05-1.6) and N0 nodal status (OR 1.5, 95% CI 1.11-2.04) were independently associated with patients receiving IRT. Conclusions: Patient- and disease-specific characters as well as hospital-level factors are associated with variations in the receipt of definitive bi-modality treatment (IRT vs CRT) in locally advanced HNC. This difference in practice patterns needs to be evaluated further with correlation to survival outcomes.
TCT-684 Predictors of Target Vessel Failure in Long-term Follow-up with Chronic Total Occlusion Patients after Successful Percutaneous Coronary Intervention
Authors: Kyusup Lee, Sun Hack Lee, Tae oh Kim, Sangwoo Park, Yong-Hoon Yoon, Sang Yong Om, Minsoo Kim, Hanbit Park, Sang-Cheol Cho, Osung Kwon, Pil Hyung Lee, Jung-Min Ahn, Soo-Jin Kang, Duk-Woo Park, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Serum autoantibodies as prognostic biomarkers for stage IV non-small cell lung cancer (NSCLC).
Authors: Melissa R Pergande, Clinton T. Piper, Cristina L. Fhied, Brett Mahon, Mary J. Fidler, Philip Bonomi, Jeffrey Allen Borgia
Journal: Journal of Clinical Oncology (2016)

e23029 Background: Immune escape is a hallmark of cancer and emerging immunotherapies have shown great promise in promoting favorable patient outcomes. In this study, we hypothesized that immunosuppression would modify the humoral response to tumor-associated proteins (autoantigens) and have a profound impact on survival. With this, we aimed to identify and characterize the differences in serum autoantibody composition in stage IV NSCLC patient groups based on clinical outcomes. Methods: Whole cell lysates prepared from stage IV NSCLC tumors (n = 5) were fractionated via reversed-phase HPLC followed by two-dimensional gel electrophoresis. Proteins were immunoblotted in parallel against pooled serum from patient groups (n = 20 each) representing “Good” (progression free survival (PFS) ≥ 6 mo.) and “Poor” (PFS < 6 mo.) treatment outcomes. Proteins found to be differentially immunoreactive in association with these groups were selected using PDQuest v7.3 (BioRad) software package followed by protein identification using an LTQ XL ion trap mass spectrometer. Protein identities were determined using the MassMatrix software v2.0 package, searching both the human genome and a decoy database and employing a threshold sequence coverage of 30% and a Pro-score threshold of 100. Results: A total of12 discrete proteins with outcome-based immunoreactivity were cored and identified based on the findings from the immunoproteomic analysis using a minimum threshold of 2-fold difference in immunoreactivity and p ≤ 0.05. From these findings, autoantibodies against α-enolase, cathepsin D, and triose phosphate isomerase were found to be uniquely present in the cases where PFS was less than 6 months, whereas junction plakoglobulin, macrophage capping protein, and glyceraldehyde phosphate dehydrogenase were found to be uniquely associated with a “good” clinical outcome. Conclusions: We have identified a series of new candidate biomarkers that may have promise as an alternate means to select patients for therapies modulating immune checkpoint inhibition. Studies confirming the prognostic value of these candidate biomarkers in the Luminex platform are currently underway with a cohort of first-line NSCLC patients.
Barriers to tumor mutation burden (TMB) testing in NSCLC patients in the US and EU.
Authors: William H Angel, Ciny Edathanal, Mahaletchumy Krishnam, Pieter De Richter, Ayse Levent
Journal: Journal of Clinical Oncology (2018)

e24192 Background: Biomarker testing is becoming increasingly common across all cancer types, but is particularly prevalent in lung cancer where the most recent guidelines from the College of American Pathologists (CAP) recommend that all labs offer a minimum of EGFR mutation, ALK rearrangement, and ROS-1 mutation testing for lung cancer patients. When the first PD-1 inhibitor was approved, it began the era of immuno-oncology (IO) biomarkers and as research for the next IO-biomarker intensifies, tumor mutation burden (TMB) has surfaced as a possible candidate. Our purpose in this study is to outline the current TMB testing landscape within NSCLC. Methods: An online survey of 254 oncologists, including detailed questionnaires for 786 NSCLC patients, across the US, UK, France, Germany, Italy and Spain was conducted between October and December 2017 by Ipsos Healthcare's syndicated MDx Monitor. Results: Physician awareness of TMB testing in NSCLC varies: 63% in EU5 and 73% in US; however, on average, only 6% of NSCLC patients in the US and 1% of patients in EU5 were tested for TMB. Among those that were not tested for TMB, the most frequently mentioned reasons were lack of data on clinical utility (50% in US, 32% in EU5), testing appropriate only after progression (17% in US, 16% in EU5), lack of targeted therapies (7% in US, 15% in EU5), patient did not meet criteria (16% in US, 12% in EU5), and the patient tested positive for other biomarkers (9% in US, 6% in EU5). Of the few patients in the US that were tested for TMB, 38% (n = 8) were tested at diagnosis, compared to 78% (n = 78) for EGFR, 70% (n = 56) for ALK, 74% (n = 35) for ROS-1 and 81% (n = 89) for PD-L1 expression. Conclusions: There is broad awareness of TMB, however uptake in testing for this biomarker is limited largely due to the lack of physician confidence in its utility in the clinical setting. Additionally, testing for TMB is often bypassed in favor of more established biomarkers such as EGFR, ALK, and ROS-1 – frequently tested as standard procedure for most NSCLC patients – and reserved for later lines of treatment. Therefore, results of ongoing clinical trials will be critical in establishing TMB as a reliable IO-biomarker in NSCLC and this study will serve as a baseline to gauge its uptake and usage moving forward.
A first-in-human phase 1 dose-escalation trial of the oral HIF-2a inhibitor PT2977 in patients with advanced solid tumors.
Authors: Kyriakos P. Papadopoulos, Eric Jonasch, Naseem J. Zojwalla, Keshi Wang, Todd Michael Bauer
Journal: Journal of Clinical Oncology (2018)

2508 Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that plays a central role in the hypoxic response pathway in tumors. HIF-2α heterodimerizes with HIF-1β and binds to hypoxic response elements in target genes. The first-in-class HIF-2α inhibitor, PT2385, demonstrated clinical activity in patients (pts) with clear cell renal cell carcinoma (ccRCC). PT2977 is a novel, orally administered selective small molecule HIF-2α inhibitor with improved potency compared to PT2385. PT2977 inhibited expression of HIF-2α target genes in tumor cells and induced regression in mouse xenograft models. Methods: Pts with advanced solid tumors who had received at least 1 prior therapy were treated with PT2977 once daily (QD) in a Phase 1 dose-escalation trial to determine the recommended Phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). Plasma PK were measured on days 1 and 15 and PD weekly. Results: 29 pts were treated at doses of 20 - 160 mg QD in the dose-escalation. As of January 15, 2018, no treatment-related dose-limiting toxicities have been observed. The most common all-grade AEs have been anemia (35%), fatigue (24%), edema (17%), headache (17%), and nausea (17%). Anemia (11%) was the most common Grade 3 AE; there have been no Grade 4 events. Exposure increased with dose along with dose-dependent reductions in erythropoietin (PD marker) consistent with the pharmacology of PT2977. At the RP2D of 120 mg, PT2977 was rapidly absorbed (Tmax = 3.1 h) with a Cmax of 1.83 mg/mL, a Cmin of 0.71 mg/mL, and a T1/2 of 20 h. A pt with SDHB mutant paraganglioma has had stable disease (SD) > 25 weeks with sustained decrease in normetanephrine levels. Of 6 pts with ccRCC treated at 120 mg or 160 mg, there was one PR and 4 SD with tumor reductions from 8%-26%. Conclusions: PT2977 is well tolerated and has a favorable safety and PK/PD profile. Early evidence of clinical activity shows promise for HIF2a inhibition in the treatment of ccRCC. PT2977 is currently under evaluation in an expansion cohort of 50 pts with previously treated advanced ccRCC at a dose of 120 mg QD. Clinical trial information: NCT02974738.
PD-L1 status in esophageal carcinoma at the mRNA and protein level.
Authors: Lars Tharun, Andreas H. Scheel, Thomas Zander, Hakan Alakus, Reinhard Buettner, Alexander Quaas
Journal: Journal of Clinical Oncology (2016)

e14555 Background: Immune checkpoint inhibition, particularly of the PD-1/PD-L1 pathway, is a promising new therapeutic approach in solid tumors and has the potential to achieve effective and durable anti-tumor immune responses. Methods: Tissue microarrays of 463 resected esophageal carcinomas (169 squamous cell carcinomas/SCC and 294 adenocarcinomas/AC) were constructed. Tumor cells and accompanying immune cells were assessed for PD-L1 expression by mRNA-in-situ-hybridization (RNAScope) and immunohistochemistry (antibody clone SP142). Results: High level mRNA expression in tumor cells correlated with strong protein expression. Low level mRNA expression in tumor cells was detected in a significantly higher percentage of tumor cells compared to protein expression: 36% of SCC and 41% of AC were mRNA upregulated in tumor cells while only 21% of SCC and 8% of AC were immunohistochemically positive in tumor cells. An additional 15% of SCC and 9% of AC showed immunohistochemical PD-L1 expression solely in the accompanying immune cells with tumor cells being negative. Interestingly, these immune cell positive cases revealed detectable mRNA upregulation much less frequently. Conclusions: The higher fraction of PD-L1 positive tumors at the mRNA level compared to the protein level will in part be attributable to post-transcriptional regulation. This has already been demonstrated in glioma. The upregulation of mRNA might still be a more sensitive determinant of treatment eligibility than protein expression, as in-situ-hybridization is more sensitive compared to immunohistochemistry and might detect PD-L1 expression that is not apparent at the protein level. Past clinical trials revealed that a substantial proportion of tumors showed treatment response despite being assessed as PD-L1 negative by immunohistochemistry; therefore we would like to raise the question if more sensitive methods of PD-L1 detection, such as mRNA-in-situ-hybridization, might have a higher predictive value. Due to the high proportion of PD-L1 positive cases, esophageal cancer seems to be a good candidate for clinical trials with checkpoint inhibitors.
Redox-sensitive prodrug nanoassemblies based on linoleic acid-modified docetaxel to resist breast cancers
Authors: Meng Li, Liwen Zhao, Tao Zhang, Yue Shu, Zhonggui He, Yan Ma, Dan Liu, Yongjun Wang
Journal: Acta Pharmaceutica Sinica B (2018)

Prodrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.