tbuckley/cabot-search huggingface dataset:
Dynamic predictions of patient survival using longitudinal tumor size in non-small cell lung cancer: Approach towards personalized medicine.
Authors: Nidal Al-Huniti, Dmitry Onishchenko, James Dunyak, Eric Masson, Gabriel Helmlinger, Diansong Zhou, Hongmei Xu, Helen Tomkinson, Kald Abdallah, Donald Stanski
Journal: Journal of Clinical Oncology (2017)

e20606 Background: Tumor burden has long been used for the clinical diagnosis, staging, prognosis and treatment of non-small cell lung cancer (NSCLC), as described, for example, in the 7th edition of the AJCC/UICC NSCLC staging guidelines. Previous longitudinal tumor size approaches have used fixed tumor kinetic parameters or tumor shrinkage at a given timepoint, to correlate PFS and OS in a stepwise fashion. Here we describe a joint modeling approach which allows for individual, patient-level predictions of survival during NSCLC treatment. Joint modeling simultaneously fits OS and tumor size dynamics, converting full information from individual tumor assessments into a personalized prediction of survival - thereby avoiding dichotomization of response measure in a patient. Methods: Clinical data from IPASS Phase 3 study of Iressa (gefitinib) in NSCLC were used to fit a joint model of OS and tumor size. The data from a follow-up study (IFUM, Phase 4) for the same drug in a narrower population were used to validate the model on an independent set of subjects. This part included simulating clinical trials from the model and comparing the simulated survival with the observed data. The survival estimation method for individual patients followed from a Bayesian formulation and was implemented in R packages JM and JMbayes. Results: A joint model for overall survival and tumor size was developed and validated using clinical trial simulations. Individual survival estimates were obtained for subjects in a subsequent study based on early data cut-off for tumor assessments. Patient-level predictions were shown to be accurate as well as study-level survival estimates. The model was able to update individual survival predictions in real time. Conclusions: Joint tumor size / survival modeling provides a promising area of investigation for prediction of survival in individual patients. It can be used as a quantitative tool for estimating time-evolving risk of death based on early tumor size measurements. A clinically validated version of such a tool may allow physicians to better choose between treatment continuation and change, following tumor size measurements from standard clinical care.
P02.04 Tumor treating fields induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy
Authors: T Voloshin, S David, Y Porat, A Shteingauz, M Munster, N Kaynan, M Giladi, E Kirson, U Weinberg, Y Palti
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are a clinical anti-neoplastic treatment delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. The anti-mitotic effects of TTFields include disruption of the mitotic spindle and abnormal chromosome segregation, which trigger different forms of cell death. We evaluated if TTFields-induced cell death is perceived as immunogenic by the immune system. Murine Lewis lung carcinoma (LLC), CT-26 colon carcinoma, and ovarian surface epithelial (MOSE) cells were treated with TTFields using the inovitroTM system. Calreticulin (CRT) levels on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured by ELISA assay. ER stress was detected by phosphorylation of the translation initiation factor eIF2α using immunoblot analysis. TTFields-induced upregulation of autophagy was evaluated by immunoblot and immunofluorescence of LC3. Bone marrow derived dendritic cells (DCs) were co-incubated with TTFields treated LLC-1 cells and phagocytosis by DCs and DCs maturation were evaluated by flow cytometry. Mice orthotopically implanted with LLC cells were treated with TTFields, immune checkpoint inhibitor anti-PD-1, or a combination of the two. Tumor volume was monitored and flow cytometry analysis performed to phenotypically characterize infiltrating immune cells. Cancer cells died during TTFields application exhibiting ER stress leading to CRT translocation to the cell surface, and released damage-associated molecular patterns including the chromatin-binding protein HMGB1 and ATP. TTFields promote upregulation of autophagy which may explain ATP depletion following treatment. TTFields-treated cells promote phagocytosis by DCs and DCs maturation under co-culture conditions. In vivo, the combined treatment of lung tumor-bearing mice with TTFields with anti-PD-1, significantly improved therapeutic efficacy compared to TTFields or anti-PD-1 alone. Significant increase in the number of tumor infiltrating immune cells was observed in the TTFields plus anti-PD-1 group. These infiltrating cells, specifically macrophages and DCs, demonstrated upregulation of surface PD-L1 expression. Cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production relative to untreated mice. The results suggest that TTFields application induces both ER stress and autophagy, resulting in immunogenic cell death. Combining TTFields with anti-PD-1 may achieve tumor control by further enhancing antitumor immunity.
The impact of pathologic differentiation (well/ poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs.
Authors: Seung Tae Kim, Su Jin Lee, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Journal: Journal of Clinical Oncology (2017)

e15686 Background: Herein, we investigated the impact of pathologic differentiation (well or poorly differentiated) in metastatic grade 3 GEP-NEC patients receiving etoposide and platinum-based therapy. Simultaneously, we evaluated a more exact Ki67 index cut-off point to select patients with grade 3 GEP-NEC who might benefit from etoposide plus platinum (EP)-based therapy. Methods: Among patients pathologically diagnosed with metastatic grade 3 GEP-NECs at Samsung Medical Center between June 2013 and March 2016, 31 GEP-NEC patients receiving etoposide and platinum-based therapy were included in this study. Results: Primary sites included 13 foregut-derived GEP-NECs [stomach (n = 4), duodenum (n = 4), and pancreas (n = 5)] and 2 hindgut-derived GEP-NECs of the rectum. Sixteen unclassified GEP-NECs originated from 7 gall-bladder (GB), 6 liver and 3 unknown primary sites. According to pathologic differentiation, 14 patients had well differentiated and 17 had poorly differentiated grade 3 GEP-NECs. Between well differentiated and poorly differentiated grade 3 GEP-NECs, there was a significant difference in the distribution of Ki67 index. There was no significant difference of treatment efficacy between well and poorly differentiated grade 3 GEP-NECs (RR; 35.7% vs. 41.2%, p = 0.525). Tumor response to EP occurred in 5 of 7 patients with Ki67 &gt; 60% and 7 of 24 with Ki67≤60%, which was significantly different (RR; 71.4% vs. 29.2%, P = 0.043). There was no significant difference in PFS according to pathologic differentiation (well differentiated vs. poorly differentiated) and Ki67 index ( &gt; 60% vs ≤60%). Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( &gt; 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.
Abstract 17599: Medicare Beneficiaries With Indicators of Statin Intolerance Have Increased Coronary Heart Disease Risk
Authors: Paul Muntner, Shia T Kent, Lisandro D Colantonio, Robert S Rosenson, Keri L Monda, Lei Huang, Vera Bittner, Angelika Manthripragada
Journal: Circulation (2015)

Introduction: Statin intolerance has been reported to occur in 5% to 20% of patients initiating therapy. There are few data on coronary heart disease (CHD) and mortality risk among patients with statin intolerance. Hypothesis: Patients with indicators of intolerance to treatment will have higher myocardial infarction (MI), CHD-related hospitalization and all-cause mortality risk compared to those with high adherence to statins. Methods: Using a 5% Medicare sample, we conducted a retrospective cohort study of patients with a history of CHD initiating statins between 2007 and 2011. Statin intolerance was defined as switching from statins to ezetimibe, down-titrating statins with ezetimibe initiation, ezetimibe monotherapy, having a rhabdomyolysis or antihyperlipidemic event claim followed by statin down-titration or discontinuation, statin down-titration or switching between 3 or more types of statins over the first year following statin initiation. High adherence was defined as proportion of days covered with statins ≥80% over the year following initiation using Medicare Part D claims. Patients were followed for MI, CHD-related hospitalization and mortality. Results: Among 51,169 Medicare beneficiaries with CHD initiating statins, 21,818 (42.6%) maintained high adherence to statins and 3,978 (7.8%) met the definition for statin intolerance. Over a median of 2.1 years of follow-up, the incidence of MI for those with statin intolerance and high adherence to statins was 17.9 (95% CI 15.1-20.7) and 15.2 (95% CI 14.1-16.3) per 1,000 person-years and CHD-related hospitalization was 43.1 (95% CI 38.7-47.5) and 35.4 (95% CI 33.6-37.1), respectively. After adjustment for demographics, co-morbid conditions, and the Charlson co-morbidity score, the hazard ratio for MI comparing patients with indicators of statin intolerance to those with high statin adherence was 1.22 (95% CI: 1.02-1.45) and 1.20 (95% CI 1.07-1.35) for CHD-related hospitalization. In contrast, statin intolerance was not associated with increased mortality risk (hazard ratio 0.99; 95% CI 0.91-1.07). Discussion: Patients with indicators of statin intolerance have an increased risk for MI and CHD-related hospitalization. Approaches are needed to reduce CHD risk in these patients.
Novel management of oral chemotherapy adherence using Navigating Cancer's patient-reported outcomes mobile application.
Authors: Ray D. Page, Noshia Conerly, Leigh Ward, Amanda Hodges
Journal: Journal of Clinical Oncology (2016)

e21676 Background: With oral chemotherapy use on the rise, our practice has focused on how to best manage these patients. Specifically, we were concerned about oral drug adherence and the unmanaged side effects that can escalate to unnecessary hospitalizations. From 3/2015 to 1/2016, we piloted a novel mobile application and software solution to routinely capture patient-reported outcomes (PROs) on oral adherence and side effects with real time information to our triage nursing staff. Methods: 104 patients starting oral chemotherapy were contacted to participate. Over half the patients (57) were interested and 28 enrolled. 29 were not able to participate due to no smartphone access. The average age was 62 years (19-87). Patients received daily text messages, prompting them to report oral adherence and side effects. The outcomes reported were made visible to a telephone triage nurse in real-time via a software dashboard.Results: The average response rate of the 26 actively participating patients (12 male/14 female) that received and replied to daily smartphone check-in prompts was 60%. When prompted about oral adherence, 76% of these patients (on average) indicated they took their medication. Out of 2,450 adherence-related daily mobile check-ins, patients indicated that they had not taken their oral medication 2% of the time. Out of 1,380 side-effect-related daily mobile check-ins, patients reported an adverse event 15% of the time. Two patients were hospitalized; which 1 was symptom-related (anemia/dyspnea). All patients who responded to the survey (n = 20) agreed, or strongly agreed, that this program favorably affected their ability to take their prescribed medication and communicate side effects. One patient said, “It’s like a life line for us”. Conclusions: This pilot, using a first-in-market mobile application for PROs with real-time triage reporting, demonstrated the ability to successfully track oral drug adherence and proactively manage adverse events to decrease unnecessary hospitalizations. The study proved that patients of varying ages and both sexes had a high willingness and compliance to report outcomes via this mobile application, with excellent patient satisfaction scores.
Murine pre–B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor
Authors: Haiying Qin, Kazusa Ishii, Sang Nguyen, Paul P. Su, Chad R. Burk, Bong-Hyun Kim, Brynn B. Duncan, Samikasha Tarun, Nirali N. Shah, M. Eric Kohler, Terry J. Fry
Journal: Blood (2018)
Effect of enforced expression of <i>cxcl8</i> by hematopoietic stem and progenitor cells on niche interactions and hematopoietic progenitor cells in adult zebrafish.
Authors: Bradley Wayne Blaser, Serine Avagyan, Leonard Zon
Journal: Journal of Clinical Oncology (2018)

7070 Background: Cxcl8 is an angiogenic chemokine that is highly expressed in a subset of patients with MPN or clonal hematopoiesis of indeterminate potential (CHIP), a finding which is associated with poor outcomes. Our recent work has discovered a novel role for cxcl8 and its receptor, cxcr1, in supporting colonization of hematopoietic stem and progenitor cells (HSPCs) within the sinusoidal endothelial cell niche of the embryonic zebrafish known as the caudal hematopoietic territory (CHT). We hypothesized that enforced expression of cxcl8 by HSPCs would alter HSPC-niche interactions and expand HSPCs in adults. Methods: Expression of cxcl8 was enforced in zebrafish HSPCs by microinjecting DNA constructs containing the HSPC-specific Runx1+23 enhancer/promoter element into HSPC (Runx1+23:mCherry) or endothelial cell (kdrl:mCherry) reporter zebrafish. Time lapse fluorescence video microscopy and single-cell tracking was performed on embryonic zebrafish HSPCs within the CHT niche. Kidney marrow was harvested from adult zebrafish and hematopoietic cell populations were identified by flow cytometry. Results: Enforced expression of cxcl8 by HSPCs nearly doubled the amount of time they resided within the CHT when compared to expression of GFP as a control (3.8 ± 0.5 vs 2.1 ± 0.3 h, p = 0.005, N = 108 tracked cells). Enforced expression of cxcl8 increased the percent of time individual HSPCs spent closely interacting with a single group of CHT endothelial cells by 30% (87% vs 57%, p = 0.001). Flow cytometric analysis of whole kidney marrow in adult zebrafish at 3 months of age showed that cxcl8 expression caused a skewing of the hematopoietic progenitor cell:lymphoid cell ratio in favor of the progenitor compartment (1.96 ± 0.15 vs 1.61 ± 0.10, p = 0.048). Conclusions: Taken together, these data support a model in which pre-malignant HSPC clones aberrantly express cxcl8, acquire a selective advantage over normal clones through enhanced interactions with the endothelial cell niche, and progress over time to a neoplastic state.
Abstract 15632: Left Atrial Stiffness Calculated by Left Atrial Strain is a Feasible Marker for Risk Stratification and Long Term Prognosis in Patients With Heart Failure
Authors: Harutoshi Tamura, Tetsu Watanabe, Gensai Yamaura, Naoto Hashimoto, Masahiro Wanezaki, Satoshi Nishiyama, Takanori Arimoto, Hiroki Takahashi, Tetsuro Shishido, Tamon Yamanaka, Takuya Miyamoto, Isao Kubota
Journal: Circulation (2016)

Introduction: It was reported that left atrial remodeling is occurred in patients with heart failure (HF), and increased left atrial volume index (LAVI) is a powerful predictor for poor prognosis of HF. Recently, it was reported that left atrial stiffness (LAS) reflects pulmonary capillary wedge pressure non-invasively. However, it remains to be determined whether LAS is useful for predicting poor prognosis in patients with HF. Hypothesis: We hypothesized that LAS can predict poor prognosis in patients with HF. Methods: We performed transthoracic echocardiography at discharge in 149 consecutive patients (male 94, 71 ± 13 years old) who hospitalized for HF and were prospectively followed up. There were 46 cardiac events (45%) including cardiac death or rehospitalization for HF during a median follow up period of 381 days (range 37-1438 days). LAS was calculated calculated by the early mitral inflow velocity divided by the early diastolic annular velocity (E/e’) and peak systolic left atrial strain (S-LAs),...
LungMATCH: Rates of molecular testing in the lung cancer community.
Authors: Jennifer C. King, Andrew Ciupek, Tara Perloff, Ashley Blanchard, Kimberly Mason, Edik Blais, R Joseph Bender, David Halverson, Subha Madhavan, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2017)

e20671 Background: For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Yet previous studies indicate that not all patients with NSCLC receive testing, even for actionable mutations in EGFR, ALK, and ROS. We hypothesized low testing rates for patients calling a community HelpLine and that we could increase rates with one-on-one caller education and free precision medicine services. Methods: Caller statistics were collected on the toll-free Lung Cancer Alliance (LCA) HelpLine from Sept 1, 2016 – Jan 31, 2017. Recruitment to the LungMATCH molecular testing program began Nov 10, 2017. Patients are recruited through conversations on the LCA HelpLine, then consented into Perthera Cancer Analysis (PCA) through an IRB-approved registry protocol. PCA includes tissue acquisition, multi-omic molecular profiling, and medical review of testing results and clinical and treatment history. PCA reports are returned to both treating physicians and patients. Data is being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Results: Data from the LCA Helpline identified a gap in molecular testing. 50% (57/115) of patients asked if they received any kind of molecular testing replied "No". Of 32 patients who were tested and knew the results, patients indicated potentially actionable changes in EGFR(15), ALK(8), PD-L1(3), RET, MET, BRAF, and HER2, along with KRAS (4). Since LungMATCH launch, 23 interested patients were referred for PCA. Six patients consented and are undergoing PCA with seven more in the consent process. Reasons for non-consent include: doctor refusal, initiation of testing at the treating institution, concern about financial implications, and one death. Updated results will be presented. Conclusions: Our data indicate that patients with lung cancer are not receiving molecular testing in accordance to guidelines. To address this, we created a program through nonprofit-corporate partnership that navigates patients and their physicians through comprehensive precision therapy. This type of program is feasible and there is patient interest.
P01.123 Matched-pair analysis of long- versus short-term survivors of glioblastoma: molecular markers make the difference
Authors: V N Sommerlath, S Brehmer, M Guiot, S Hetjens, M Seiz-Rosenhagen, D Hänggi, F Wenz, K Petrecca, F A Giordano
Journal: Neuro-Oncology (2018)

A small population of patients diagnosed with glioblastoma (GB) survives long-term. We performed a matched-pair analysis of patients that survived three years or longer and patients that survived less than three years. We performed a cross-institutional review of 269 patient records and matched a group of 93 patients surviving 3 years or longer with 176 patients that survived less than 3 years (STS), whereas 83 of all LTS had 2 matches (LTS-2m), and 10 had 1 match (LTS-1m). Matching was performed according to age, Karnofsky Performance Status (KPS), initial therapy (surgery/biopsy) and adjuvant therapy (chemo-radiotherapy/maintenance chemotherapy). Factors of interest were tumor location, extent of resection (GTR/STR), radiation dose, GFAP (expressed/partially expressed/not expressed), MGMT promoter hypermethylation status as well as IDH-1 mutation status and ki67 index. There were no statistically relevant differences in tumor location, extent of resection, radiation dose or ki67 index between STS and LTS. In turn, the incidences of MGMT promoter hypermethylation (STS vs. LTS-2m:p=0.008; STS vs. LTS-1m: p=0.013) and IDH-1 mutations (STS vs. LTS-2m: p=0.008; STS vs. LTS-1m: p=0.046) were significantly higher in LTS. GFAP expression, which is frequently lost with increasing grade of de-differentiation, was also seen significantly more often in LTS than in STS (STS vs. LTS-2m: p=0.002; STS vs. LTS-1m: p=0.019). This cross-institutional analysis corroborates the prognostic roles of molecular markers such as MGMT and IDH-1 over all other factors that may partially depend on caregivers.
Different patterns of non immediate allergic reaction to BRAF inhibitor in two patients with metastatic melanoma.
Authors: Miguel-Angel Berciano-Guerrero, Rocío Lavado, Álvaro Montesa, Martina Alvarez, Angela Santonja, Vanessa de Luque, Cynthia Robles, Marta Gómez, Lorenzo Alonso-Carrión, María Salas
Journal: Journal of Clinical Oncology (2017)

e21052 Background: Non immediate allergic reactions (niAR) related with oncology drugs are a rare entity. Usually, it is called Drug Reaction with eosinophilia and sistemic symptoms (“DRESS”), occurring at first ten days of treatment.Recently, the treatment of metastatic melanoma (MM) has included new drugs in patients wtih BRAF V600E mutation. Despite skin reactions are usual, niAR to these drugs have not been reported. We present 2 clinical cases with mm treated with BRAFi, developing such niAR. Methods: Patient 1: 47yo female with lymph node relapse and multiple subcutaneous skin metastases (previously pT1N0M0 melanoma) that received nivolumab in adjuvant setting. BRAF-mutated. She starts with Vemurafenib-Cobimetinib (V-C). At 8 days, niAR (maculo-papular exantema G4, fever G2). After discontinuation of this treatment (3 weeks), it is changed to Dabrafenib(50%)-Trametinib (D-T). With only 1 dose, skin niAR (G3) is newly developed. Biopsy are taken at the beginning (T0), during (T1) and after desentizitation (T2). Patient 2: 60 yo female, lung and lymph node relapse of melanoma (previously pT2bN0M0) after IFN-alpha adjuvant 2 years before. BRAF-mutated. Start with V-C. At 9 days, skin niAR (G4), with fever (G1). Discontinuation of treatment. Biopsys and blood test are taken (T0, T1 and T2). Gene expression was performed with PanCancer Immune Profiling Panel Nanostring™ in this points. Results: Different lymphocytic subpopulations in blood and biopsy at acute phase are showed in table 1. Immune gene expression profiling found decreased expression of 5 genes: UBC, IL8, IL32, NFKB1A and FOS, increasing IFNGR1 (pt 1). In both of pts, desensitizitation protocol by Allergologists was made succesfully, with incremental oncology drugs and steroid reduction protocol. Both of pts had a maior partial response (RECIST), even the scarce of the drug received. Conclusions: D and V develop important “of class” skin niAR. Different immunologic patterns are related with this niAR. Previous exposition to IFN or anti-PD1 therapy might modulate such response. Immune gene expression profiling could be used as a method to identify biomarkers. Desensitization with BRAFi has enough efficacy and tolerance.