tbuckley/cabot-search huggingface dataset:
Phase 2 trial of chemotherapy followed by consolidative radiation therapy for initial treatment of oligometastatic NSCLC.
Authors: Tamjeed Ahmed, James John Urbanic, Ryan Hughes, Ralph D'Agostino, Brian Lally, Jimmy Ruiz, Michael D Chan, Payal Gandhi, Andy Dothard, Kyle Rusthoven, Marcelo Raul Bonomi, A. William Blackstock, William J. Petty
Journal: Journal of Clinical Oncology (2017)

9047 Background: Unselected patients with stage 4 lung cancer who receive front line platinum based chemotherapy and maintenance chemotherapy have demonstrated a PFS less than 6 months with very few patients alive at 5 years. Patients with a small number of metastatic lesions may have a different biology, and aggressive local treatment of oligometastases is an active area of investigation. Methods: Patients were required to have stable disease or response after 3-6 cycles of platinum based chemotherapy and PS 0-2. Oligometastatic disease was defined as a maximum number of 5 metastatic lesions for all disease sites including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Results: 29 patients were enrolled between 10/2010 and 10/2015. 3 patients were excluded from analysis due to concerns regarding eligibility/treatment response. Despite closing early due to slow accrual, the study met its primary endpoint for success which was PFS greater than 6 months. The median PFS (95% CI) was 11.0 months (7.4-15.9 months) and the median OS was 22.2 months (13.3-45.7 months). The 1-year, 3-year, and 5-year OS were 73%, 35%, and 29%. Conclusions: Patients with oligometastatic NSCLC who received platinum based chemotherapy followed by oligometastatic consolidative radiation without maintenance chemotherapy demonstrated prolonged disease control and overall survival. Clinical trial information: nct01185639.
Bevacizumab and its impact on survival for patients receiving subsequent anti-EGFR therapy: Updated results from the SA metastatic CRC registry.
Authors: Timothy Jay Price, Christos Stelios Karapetis, Robert Padbury, Matthew E. Burge, Amitesh Chandra Roy, Guy Maddern, David Roder, Cynthia Piantadosi, Amanda Rose Townsend
Journal: Journal of Clinical Oncology (2017)

3569 Background: Debate exists as to whether first line bevacizumab effects subsequent sensitivity to anti-EGFR therapy. Authors hypothesize that initial anti-VEGF therapy may induce biological changes that then increase the risk of acquired resistance to subsequent EGFR inhibitors. Methods: A retrospective cohort study was performed to compare the characteristics and survival of patients who were treated with an anti-EGFR therapy 2nd line and beyond by two groups defined by the first line therapy; 1. chemotherapy (chemo) plus bevacizumab (bev) and 2. chemo alone. Survival for this analysis is from the time of commencing first line chemotherapy and secondly from anti-EGFR therapy. Pearson chi test analysis was performed to determine whether receiving first line bev was associated with worse overall survival (OS). Results: 348 mCRC patients who received chemo with or without bev and then an anti-EGFR therapy were studied. Patient characteristics are summarised in the table below. The significant differences between group 1. Vs. 2. were as follows; median age 63.8 years v 67.9 years (p = 0.005), lower use of single agent FU 6.4% v 19.2%, KRAS status not tested (reflecting the practice changes over time) 19.3% v 39.2%, KRAS MT 2% v 4%, and where BRAF MT status was known (11%); BRAF MT rate 23% v 0. Median OS for the 2 groups was 34.2 months, and 28.2 months respectively (p = 0.12) from first line therapy. Median OS for patients who underwent single agent anti-EGFR as subsequent therapy was also not significantly different, 31.1 months group 1 (n = 60) versus 27.7 months group 2 (n = 85), p = 0.52. Results based on commencement of anti-EGFR therapy are under way. Conclusions: Survival was not significantly different between the two groups, and the trend was towards higher OS with chemo plus bev suggesting that in our registry population, bev administration in first line therapy with chemo did not lead to a worse outcome overall for those patients subsequently receiving anti-EGFR therapy, either with chemotherapy or as a single agent. Updated results from commencement of anti-EGFR therapy will give further insights and will be presented at the meeting.
Fear of progression in patients with low-risk malignant melanoma.
Authors: Katharina C. Kaehler, Tobias Wagner, Christine Blome, Andrea Forschner, Claus Garbe, Ralf Gutzmer, Axel Hauschild, Lucie Heinzerling, Elisabeth Livingstone, Berenice M. Lang, Carmen Loquai, Dirk Schadendorf, Patrick Terheyden, Matthias Augustin
Journal: Journal of Clinical Oncology (2017)

e21615 Fear of progression in patients with low-risk malignant melanoma Fear of cancer progression (FoP) is one of the problems most commonly reported by cancer patients and is among the most prevalent cancer-related worries in cancer survivors. FCR is highly variable in different cancer entities. Background: This study aimed to elicit the prevalence and significance of FCR in melanoma patients with low risk tumors and further to assess psychosocial and demographic factors predicting severity of FoP as well as to determine the impact of FoP on quality of life (QoL). Methods: In total, 133 patients with low-risk melanoma (pT1a) completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS), and the EQ-5D questionnaire, as well as self-constructed questions on the socio-demographic background. Results: MeanFoP-Q-SF sum score was 30.1 points (± 8.4 points SD) and the median 29 points. Two thirds of patients deviated not more than 1 SD from the mean. Risk factors for elevated FoP were female gender (p &lt; 0.01), young age (p = 0.04) and working (p = 0.02) patients and patients with severe comorbidities (p = 0.03). Cancer in closely related persons predicted higher FoP (p &lt; 0.01). HADS anxiety scale (r = 0.49, p &lt; 0.01) and depression scale (r = 0.26, p &lt; 0.01) correlated with FoP. A negative correlation with the EQ-5D index was found (r = -0.34, p &lt; 0.01). Conclusions: As in many other malignancies,FoP is prevalent in low-risk melanoma patients and is associated with reduced QoL. Severe comorbidities, cancer in related persons, gender and income could be identified as predictors of FoP. Considerable high levels of FoP even in patients with low-risk malignancies underline the need of psychosocial support and intervention for special subgroups of melanoma patients to enable the patient to manage FoP more successfully.
Ovarian cancer pathway map development as an approach to identifying priority areas for quality improvement in Ontario.
Authors: Helen Mackay, Jasmin Soobrian, Sarah E. Ferguson, Wylam Faught, Jillian Ross, Claire Holloway
Journal: Journal of Clinical Oncology (2016)

e18190 Background: Disease Pathway Management (DPM) is the unifying approach to the way in which Cancer Care Ontario (CCO) sets priorities for cancer control, plans cancer services and improves the quality of care in Ontario. In January 2015, DPM began developing an ovarian cancer pathway map (OCPM) to map the patient journey along the ovarian cancer care continuum. Objective: to report on the OCPM development process as a tool to identify key priorities for ovarian cancer management. Methods: DPM convened a multidisciplinary/multi-stakeholder ovarian cancer working group with regional and specialty representation from across Ontario. Over 12 months, 30 individuals participated in an in-person meeting and monthly teleconferences. The OCPM was drafted using guidelines developed by CCO’s Program in Evidence Based Care (PEBC) and considered multiple sources of evidence-based practice from several jurisdictions. Throughout the development process the working group was asked to discuss and reach consensus on key priorities for improving care. Results: Twenty-five priority areas were identified across the continuum in: prevention, diagnosis, treatment, and follow-up. Opportunities were identified for: development/endorsement of evidence-based guidelines, quality improvement, horizon scanning, and an OCPM knowledge translation strategy. Potentially actionable items were aligned with relevant internal and external stakeholders including the PEBC, provincial drug reimbursement programs and other quality improvement teams within CCO. Conclusions: The process of bringing multidisciplinary experts together in order to develop the OCPM successfully identified key priorities across the spectrum of care in Ontario and allowed identification of potential opportunities for quality improvement, development of practice guidelines and new models of care. In turn, the OCPM provides a patient-centred disease focused framework from which stakeholders can approach and evaluate new initiatives in the context of the ovarian cancer care continuum.
Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).
Authors: Mark M. Awad, Magda Bahcall, Lynette M. Sholl, Frederick Hugh Wilson, Cloud Paweletz, Marzia Capelletti, Giulia Costanza Leonardi, Masayuki Watanabe, Hideo Baba, Emily S. Chambers, Amanda J. Redig, Mizuki Nishino, Paul A VanderLaan, Daniel Botelho Costa, Yu Imamura, Pasi A. Janne
Journal: Journal of Clinical Oncology (2018)

9069 Background: Non-small cell lung cancers (NSCLC) harboring METex14 activating mutations can respond dramatically to treatment with MET TKIs, but the mechanisms of acquired resistance to these therapies are not well understood. Methods: We performed next generation sequencing on serial plasma samples and/or tumor biopsies and one autopsy case from patients with METex14 mutant NSCLC to identify mechanisms of resistance to the type 1 MET TKI crizotinib and the type 2 MET TKI glesatinib. Results: Samples from 12 patients with METex14 mutant NSCLC were included in this analysis. In 4 cases (33%), acquired MET alterations were identified including one case with amplification of the mutated METex14 allele and three cases with MET tyrosine kinase domain secondary site mutations; in two of these cases, more than one MET resistance mutation was present in the same patient. Secondary mutations in MET included H1094Y, G1163R, L1195F, L1195V, D1228N, Y1230H, and Y1230S. In 4 cases (33%), bypass track activation was identified, including massive genomic amplification of wild-type KRAS, BRAF, and/or EGFR. In 4 cases (33%), the resistance mechanism was not identifiable. A case of acquired resistance to glesatinib with acquired amplification of the mutated METex14 allele had a confirmed partial response after switching to crizotinib. Data from resistant preclinical models and patient-derived cell lines and mouse xenografts will be presented. Conclusions: Novel therapeutic strategies will be needed to delay or overcome multiple complex mechanisms of acquired MET TKI resistance in METex14 mutant NSCLC.
Fluoropyrimidine-associated myocardial toxicity as a global metabolic effect compared to vascular spasm and visibility on FDG PET scanning.
Authors: Andrew Peter Dean, Domenic Higgs, Peter Robins, Paul Stobie, Philip Craven, Ciara Daly, Samantha Carija
Journal: Journal of Clinical Oncology (2017)

e14013 Background: Myocardial toxicity from fluoropyrimidines is a rare but potentially serious side effect, estimated by some as occurring in up to 9%. Coronary spasm has been suggested as the underlying mechanism, despite a lack of supporting evidence and other toxicity mechanisms have been proposed. Matsubara described Krebs cycle dysfunction in the presence of 5FU with depletion of high energy phosphate compounds in rodent myocardial tissue with ECG changes. Following a chance discovery of abnormal myocardial FDG uptake on a PET scan shortly after presenting with presumed 5FU cardiac toxicity (angina, ST elevation, troponin rise; normal coronary vessels on imaging), we prospectively evaluated all instances of angina occurring during 5FU infusion with coronary artery imaging and FDG PET scan. Methods: We identified 5 patients who experienced angina during 5FU therapy. They were investigated for coronary ischaemia and also underwent PET scanning to assess myocardial FDG uptake. Data was collected from patient records, and subsequent cardiac investigations. Results: In all 5 cases, PET scan demonstrated markedly abnormal FDG uptake throughout the myocardium, with the ventricular blood pool demonstrating more FDG activity than myocardium. No significant underlying coronary artery disease was identified. All 5 patients had previous PET scans with normal myocardial FDG uptake. Conclusions: We identified a consistent pattern of abnormal FDG uptake throughout the myocardium for all scanned patients with chest pain following administration of 5FU. This was not restricted to a single arterial territory. There were no typical ECG changes of spasm. Obstructive coronary disease was excluded with angiographic imaging or myocardial perfusion scanning. The FDG PET scans suggest global myocardial metabolic change, supporting the notion of 5FU being a direct myocardial toxin inhibiting myocardial glucose utilization. The myocardium may then be dependent on fatty acid metabolism, posing additional risk to patients on low fat diets. Our data provides new insight into the mechanism of 5-FU myocardial toxicity and further prospective assessment using PET is warranted.
Abstract 15171: Development of Targeted Drug Delivery Agents for Cardiac Regeneration
Authors: Siva Sai Krishna Dasa, Yaqin Xu, Marc E Seaman, Brent A French, Kimberly A Kelly
Journal: Circulation (2013)

IIntroduction: Coronary heart disease is a leading cause of death in developed nations and currently available drugs only slow the progression of heart faliure. Given that regenerative agents will likely need to be precisely delivered to the infarct/border zone to fully realize cardiac regeneration, we hypothesized that suitable targeting ligands could be identified by biopanning a phage display library in a mouse model of myocardial infarction (MI). Methods: A phage display library was biopanned in vivo to identify peptides specific for the infarct/border zone of the heart 4 days post-MI. After three rounds of biopanning, 50 phage clones were selected from the infarct and 50 from the border zone and their DNAs were amplified and sequenced. Peptide sequences were deduced from DNA sequences and phage clones were grouped (4 clones/group) based on their phylogeny and sequence similarity. Each group was then labeled with a near IR fluorescent dye (VT 680) and mixed with negative control phage clone (Panc-27) ...
Phase I/II trial of anti-PD-1 checkpoint inhibitor nivolumab and <sup>177</sup>Lu-DOTA<sup>0</sup>-Tyr<sup>3</sup>-Octreotate for patients with extensive-stage small cell lung cancer.
Authors: Chul Kim, Deepa Suresh Subramaniam, Stephen V. Liu, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2018)

TPS8589 Background: Small cell lung cancer (SCLC) accounts up to 15% of all new cases of lung cancer. 60% of patients with SCLC present with extensive-stage SCLC (ES-SCLC). Despite initial sensitivity to chemotherapy, patients with ES-SCLC relapse quickly. Studies have shown that somatostatin receptors are expressed in SCLC. 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) is a 177Lutetium-labeled somatostatin analog that can target somatostatin receptor positive cancer cells. Mounting evidence suggests that radiation therapy can augment the immunogenic response. Based on these findings, we hypothesize that Lutathera and nivolumab, an anti-PD-1 therapy, may have synergistic effects on the generation of anticancer immunity and this combination given as maintenance treatment may delay progression in patients with ES-SCLC. Methods: This is a multicenter phase I/II trial of Lutathera and nivolumab in patients with ES-SCLC (NCT03325816). Patients with tracer uptake on gallium-68 dotatate PET scan (NETSPOT) will be eligible. In the phase I part, we aim to determine the recommended phase II dose of Lutathera and nivolumab in patients with relapsed or refractory ES-SCLC, non-progressing ES-SCLC after first-line chemotherapy, or advanced grade I-II pulmonary neuroendocrine tumors. In the phase II part, patients with ES-SCLC are randomly assigned to either maintenance treatment with Lutathera and nivolumab or observation, after completion of front-line chemotherapy. The primary endpoint for the phase II part is progression-free survival (PFS). Crossover is allowed at progression for those in the observation group. Assuming a median PFS of 2 months following first-line platinum-based chemotherapy for ES-SCLC in the observation group, and an expected median PFS of 5 months for the maintenance therapy group (hazard ratio 0.4), a total of 52 patients are required to have 80% power at a two-tailed alpha of 0.05. Seven cancer centers will participate in the trial: Georgetown University, Hackensack University Medical Center, Walter Reed National Military Medical Center, Memorial Sloan Kettering Cancer Center, Vanderbilt University, UCLA, and UCSF. Clinical trial information: NCT03325816.
A novel biomarker combination and its association with resistance to chemotherapy combinations with bevacizumab: First results of the PERMAD trial.
Authors: Thomas Seufferlein, Ludwig Lausser, Alexander Stein, Gerald W. Prager, Stefan Kasper, Michael Niedermeier, Lothar Müller, Stefan Kubicka, Alexander Koenig, Petra Buechner-Steudel, Kai Wille, Lukas Perkhofer, Alexander Hann, Andreas Wolfgang Berger, Dirk Arnold, Hans Kestler, Thomas Jens Ettrich
Journal: Journal of Clinical Oncology (2018)

e15545 Background: Antiangiogenic agents are frequently used in the systemic treatment of metastatic colorectal cancer (mCRC). Since these strategies target not the tumor but the tumor associated endothelium establishing positive or negative predictive biomarkers has turned is challenging. Recent research indicated a potentially predictive value of cytokines and angiogenic factors (CAF) for early detection of progression during treatment with chemotherapy and bevacizumab. The PERMAD trial is a two-phase trial with the primary objective to evaluate of the impact of a personalized, marker-driven treatment approach with early detection of progression and modification of treatment. The aim of the first phase is to establish a combination of CAFs that allows early detection/prediction of disease progression (PD) under a treatment with FOLFOX plus bevacizumab (Bev). The second phase is a randomized part with marker-driven switch of anti-angiogenic agent and maintenance of the chemotherapy backbone until definite radiological PD compared to a conventional treatment approach of changing chemotherapy and antiangiogenic agent at time of radiologic PD. Here we report the results from the first phase examining samples of thirty patients. Methods: During the run-in phase 102 CAFs were established in blood samples taken prior to treatment and q2w thereafter until PD. Using machine learning we aimed at establishing a combination of 5 out of the 102 CAFs that fulfilled these criteria: cytokines should be affected by PD, but not by treatment itself and should indicate PD at least 2 months prior to the time of PD as determined by MD-CT which was performed every 2 months. Results: Using our machine learning approach we could establish a combination of markers that is associated with > 80% accuracy with PD 2 months prior to radiological PD under a treatment with FOLFOX plus Bev. This combination will be corroborated in another 20 patients and used for the second, randomized part of the trial. Conclusions: Using advanced bioinformatics we have identified a biomarker combination that is associated with subsequent PD with a high accuracy under a treatment with FOLFOX plus Bev. Clinical trial information: NCT02331927.
Outcomes of patients with diffuse large B-cell lymphoma treated with immunochemotherapy based on cell of origin.
Authors: Avyakta Kallam, Jayadev Manikkam Umakanthan, Matthew Alexander Lunning, Julie Vose, Philip Jay Bierman, Kai Fu, Lynette Smith, Gregory Bociek
Journal: Journal of Clinical Oncology (2016)

7568 Background: Advances in gene expression profiling for Diffuse Large B-Cell Lymphoma (DLBCL) help classify cases based on Cell of Origin (COO). This identifies distinct molecular subtypes including germinal center B cell-like (GCB) and nongerminal center B-cell-like (non-GCB) groups. These subtypes respond differently to different therapeutic agents, thus making them a potential biomarker to predict response to treatment and clinical management. The aim of this study is to compare outcomes between GCB and non-GCB groups after treatment with Rituximab containing regimens. Methods: 241 cases of DLBCL for which COO data was available were analyzed retrospectively. Chi-square tests were used to compare patient characteristics between the groups. The Kaplan-Meier method was used to estimate survival distributions. Overall survival was defined as time from diagnosis to the date of death from any cause. For event-free survival, events included death, progression, or recurrence after a complete remission. Log-rank test was used to compare survival distributions by group. All tests were 2 sided and p values of less than 0.05 were considered significant. Results: Median age was 65.2 years. Median follow up of surviving patients was 6.3 yrs. 113 pts were classified as non-GCB and 128 were GCB. 77% of the non-GCB group achieved complete remission compared with 67% of the GCB group (p = 0.0043). In multivariate analysis, only IPI and COO retained significance for EFS with a HR (Hazard ratio) of 2.22 [95% CI 1.53-3.22, P < 0.0001] for IPI 3-5 and 1.79 [95% CI 1.23-2.58, p = 0.0021] for non-GCB. Statistical significance was noted among IPI and COO for OS with HR of 2.31 [95% CI 1.52-3.51, P < 0.0001] for IPI 3-5 and 1.76 [95% CI 1.16-2.67, p = 0.0081] for non-GCB. Conclusions: Although patients belonging to the non-GCB group had a higher probability of achieving CR, higher IPI and non-GCB subtype were associated with a lower probability of EFS and OS. Both groups show a plateau on cumulative incidence of relapse curves suggesting that both subgroups have potential for cure with rituximab containing regimens.