tbuckley/cabot-search huggingface dataset:
Allometric scaling of preclinical pharmacokinetic and toxicokinetic parameters to predict clinical pharmacokinetics of BXQ-350 saposin C protein-phosphatidylserine nanovesicles.
Authors: Charles A Cruze, Olivier Rixe, John Charles Morris, Vinay K. Puduvalli, John L. Villano, Trisha Michel Wise-Draper, Angela N. Johnson, Robert Wesolowski, Gary A. Thompson
Journal: Journal of Clinical Oncology (2018)

e14537 Background: Interspecies allometric scaling is used to extrapolate pharmacokinetics (PK) from preclinical data to human PK and dosing. Efficacy of BXQ-350, a novel Saposin C phosphatidylserine lipid nanovesicle therapy that targets tumor cell phospholipids, has been demonstrated in murine tumors, and pharmacokinetic and toxicokinetic (PK/TK) parameters have been derived in animal models. This study compares predictions based on allometric scaling of animal PK/TK data with FIH data for BXQ-350. Methods: PK was assessed over 24 hr after IV BXQ-350 doses in mice (30 mg/m2) and rats/monkeys (60 mg/m2). TK was assessed at day 1 and 24 in rats/monkeys (24, 72 and 240 mg/m2 5 days/wk). Saposin C was analyzed by ELISA, and noncompartmental PK methods were used. Preclinical PK/TK was allometrically scaled to predict human PK and exposure (AUC) at 0.7-2.4 mg/kg therapeutic doses. Values were compared to actual FIH Phase 1 data (NCT02859857). Results: Human clearance, terminal volume of distribution (Vz), half-life, and AUC (at 0.7 and 2.4 mg/kg doses) were within predicted ranges, though human ranges were somewhat narrower for clearance (63-114 vs 81-102 mL/kg/hr), Vz (135-650 vs 285-380 mL/kg), and half-life (0.8-4.5 vs 2.0-3.4 hr). Notably, actual vs predicted AUC hr*ng/mL at 0.7 and 2.4 mg/kg were not significantly different (7,100 vs 6,100 and 38,000 vs 36,000, respectively). Efficacy occurred in murine models at 4-16 mg/kg (AUC 7,400-29,600), aligned with human exposure at 0.7-2.4 mg/kg doses. Conclusions: Allometric scaling of animal PK/TK data provided reasonable estimates of human PK and exposure (AUC) for BXQ-350 and can thus be expected to have good predictive utility for extrapolating drug dose and pharmacokinetic parameters. Table. Predicted vs Actual PK/TK Predicted1 Actual2 Clearance, mL/kg/hr 63-114 81-102 Volume of distribution (Vz), mL/kg 135-650 285-380 Half-life, hrs 0.8-4.5 2-3.4 AUC at 0.7 mg/kg, hr*ng/mL 6100 7100 AUC at 2.4 mg/kg, hr*ng/mL 36000 38000 Murine Efficacy-associated AUC (~4-16 mg/kg), hr*ng/mL 7,400-29,600 - 13-animal composite PK/TK models2High/low geometric mean for 0.7-2.4 mg/kg Phase 1 cohorts
Utilization of bioimpedance spectroscopy (BIS) to reduce rates of breast cancer related lymphedema (BCRL) in extremely high-risk patients.
Authors: Sharon Wing Wai Chan, H May Lee, Frank Vicini, Polly Suk-yee Cheung
Journal: Journal of Clinical Oncology (2018)

e22112 Background: We evaluated the use of bioimpedance spectroscopy (BIS) as part of a structured surveillance program for the development of breast cancer-related lymphedema (BCRL) in very high risk patients undergoing axillary lymph node dissection (ALND). Methods: Between Jan 20, 2011 and June 30, 2017, 114 patients undergoing ALND were prospectively followed with BIS, which included a pre-operative baseline assessment. An L-Dex increase of > 10, triggered intervention with an over-the-counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complex decongestive physiotherapy (CDP) to treat chronic BCRL was monitored. Results: The median follow-up was 26 months (range: 5-67). Of the 114 patients, 84% received taxane-based chemotherapy, 90% axillary radiation therapy (RT) and 55% had an elevated body mass index (BMI). Overall, 98% of patients had at least one additional high-risk feature, 86% had at least two, and 45% had all 3 (either taxane chemotherapy, axillary RT, elevated BMI). 32 patients (28%) developed an elevated L-Dex score triggering intervention with an OTC sleeve. 14 of these patients (12.8% overall) required CDP. At last follow-up, only 6 total patients (5.3%) had unresolved BCRL requiring additional CDP treatment. Conclusions: Prospective surveillance utilizing BIS resulted in low rates of chronic BCRL (5.3%) in this uniquely large and extremely high-risk cohort of breast cancer patients undergoing ALND. These results, combined with additional emerging data, support the utilization of BIS to monitor patients for BCRL and to reduce the development of its chronic, irreversible stage.
The role for resection of post-chemotherapy residual liver masses in the management of non-seminomatous germ cell tumor.
Authors: Eugene J Pietzak, Melissa Assel, Daniel M. Tennenbaum, Maria Becerra, Darren R. Feldman, Dean F. Bajorin, Robert J. Motzer, George J. Bosl, Brett Stewart Carver, Daniel Sjoberg, Joel Sheinfeld
Journal: Journal of Clinical Oncology (2016)

e16047 Background: To evaluate the oncologic outcomes and histologic concordance of post-chemotherapy residual liver mass resection with post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND). Methods: After obtaining IRB approval, we reviewed our prospectively maintained database for patients with NSGCT who underwent post-chemotherapy residual liver mass resection and concurrent PC-RPLND between 1990 and 2015. Results: A total of 36 patients were identified, of which, 29 (81%) presented with a liver mass at initial diagnosis and 17 (47%) received salvage chemotherapy prior to surgery. Teratoma was found in 14 (39%) and 6 (17%) of PC-RPLND and liver resection specimens, respectively. Viable GCT was found in 7 (19%) and 3 (8%) of PC-RPLND and liver resection specimens, respectively. Among patients who had either teratoma or viable GCT on PC-RPLND, 29% (95% CI 10%, 56%) had teratoma or viable GCT on liver resection as well. The rate of benign versus malignant histologic discordance was 21% (95% CI 6%, 46%), with 4 of 19 patients having either teratoma or viable GCT on liver resection when only fibrosis/necrosis was found in their PC-RPLND (Table 1). At 3 years after surgery, the Kaplan-Meier estimated probability of cancer-specific survival was 73% (95% CI 55%, 85%) and progression-free survival was 75% (95% CI 56%, 87%). Conclusions: Clinically significant histologic discordance was observed between post-chemotherapy residual liver mass resection and PC-RPLND. In addition to histologic discordance, post-chemotherapy liver mass resection is further supported by the favorable survival outcomes these advanced NSGCT patients experienced. Until more reliable predictors of post-chemotherapy histology exist, complete surgical resection of all sites of residual disease should be performed, whenever feasible. RPLND Histology Liver Resection Histology (95% CI) Fibrosis/ Necrosis (n = 27) Teratoma or Viable GCT (n = 9) Teratoma (n = 6) Fibrosis/Necrosis (n = 19) 79% (54%, 94%) 21% (6%, 46%) 16% (3%, 40%) Viable GCT (n = 3) 67% (9%, 99%) 33% (1%, 91%) 0% (0%, 71%) Teratoma (n = 10) 60% (26%, 88%) 40% (12%, 74%) 30% (7%, 65%) Teratoma or Viable GCT (n = 17) 71% (44%, 90%) 29% (10%, 56%) 18% (4%, 43%)
Transfusion support and post-transplant complications in autologous transplant patients receiving hyperbaric oxygen.
Authors: Haitham Abdelhakim, Amy Cantilena, Tara L. Lin, Siddhartha Ganguly, Anurag Kumar Singh, Leyla Osman Shune, Sunil H. Abhyankar, Brea Lipe, Joseph McGuirk, Dennis Allin, Omar Salah Aljitawi
Journal: Journal of Clinical Oncology (2016)

e19004 Background: High-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) is associated with neutropenia, anemia and thrombocytopenia in the post-transplant period. The recovery time of blood cell counts post-transplant affects the duration of transfusion dependency. It has been demonstrated that hyperbaric oxygen (HBO) therapy improves engraftment of umbilical cord blood (UCB) CD34+ cells in an animal model. Its use in a pilot clinical trial in UCB transplant was well-tolerated with signs of improved engraftment. Accordingly, we have investigated the use of HBO to improve engraftment following auto-HCT. Herein, we evaluate post-transplant complications and transfusion needs in our HBO treated patients. Methods: The charts of patients who received HBO and auto-HCT on our pilot trial were reviewed for patient characteristics, infused cell dose, blood and platelet transfusions, infections and mucositis. Results: Of the twenty patients who were treated on study, 19 completed HBO therapy and were included in this analysis. Patients had a median age of 63 year (25-67). Ten patients were females (53%), 9 (47%) had underlying Multiple Myeloma, 8 (42%) had Non-Hodgkin’s Lymphoma, and 2 (6%) had Hodgkin’s disease with a mean cell dose used of 3.5x106 cells/kg. All patients (100%) achieved engraftment and survived the first 100 days. Ten patients (52.6%) required red blood transfusion with an average unit use of 1.1. All patients required platelet transfusion with an average unit use of 2.52. The average number of days of granulocyte cell stimulating factor used was 6.21. Nine patients (47%) developed neutropenic fever, 2 of them were found to have bacteremia. Four patients (23.5%) developed mucositis, only one with grade 3 or higher. Six patients (31.5%) of the patients who were initially treated as outpatient were admitted to the hospital for diarrhea (n = 3, 15.7%), neutropenic fever (n = 2, 10.5%) & a fall (n = 1). For those who were admitted, their average hospital stay was 6 days, with 2 patients (10.5%) needing ICU admission. Conclusions: HBO incorporation into auto-HCT is feasible with favorable effects on post-transplant complications that warrant further investigation.
Validation of a prognostic 53-immune-gene panel in stage II/III melanoma.
Authors: Margaret Borgardus, Robyn Denise Gartrell, Douglas Kanter Marks, Camden L Esancy, Sarabjot Pabla, Marc S. Ernstoff, John M. Kirkwood, Rui R. Chang, Bret Taback, Sandra J. Lee, John Krolewski, Carl Morrison, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2018)

9576 Background: Patients with resected stage II/III melanoma are at high risk of systemic metastasis and prognostic indices to stratify these patients for adjuvant immunotherapy. We previously defined and validated a 53-immune-gene panel predictive of non-progression (AUC = 0.787), recurrence free survival (RFS, p < 0.001) and disease specific survival (p = 0.024). Here, we present a second validation of the prognostic ability of this immune-gene panel in an independent cohort of 81 patients with stage II/III primary melanoma. Methods: Dermatopathology reports for 1349 melanoma patients seen at Columbia University Medical Center between 2001 and 2014 were queried to identify 81 patients with stage II-III primary melanoma with FFPE tissue and at least 24 months of clinical follow-up available. Presence of tumor was confirmed by a dermatopathologist, RNA was extracted from tissue, and expression of the 53-immune-gene panel was assessed using NanoString. Data was processed using nSolver software and prediction score calculated. Results: 81 patients with stage II-III primary melanoma were analyzed, of whom 61 were alive or had no evidence of disease at death and 20 died from melanoma. Of the 81 patients, 69 had progression data available, 22 patients had progression of disease, while 47 had non-progression. Prediction scores correlated with non-progression (AUC = 0.722). In the complete 81 patient cohort, the signature correlated with disease specific survival (p= 0.008) and overall survival (p = 0.0007). Over the course of follow up 36 patients died. Using median score as a cutoff, hazard ratio for death in the high risk group was 2.8 (95% CI 1.3-6.0). Conclusions: We validate in a second retrospective population the prognostic ability of our previously-identified 53-immune-gene panel in patients with stage II/III primary melanoma. The 53-gene panel may constitute a powerful clinical tool to aid in predicting disease course in melanoma and may allow for stratification of patients for adjuvant immunotherapy, facilitating rapid acquisition of significant survival statistics in clinical trials. Prospective retrospective (PRA) validation of the signature in samples collected as part of the E1697 trial of adjuvant interferon is planned.
A comparative outcome analysis comparing systemic therapies in Mycosis Fungoides and Sezary Syndrome.
Authors: Walter Hanel, Robert Briski, Charles W Ross, Thomas F Anderson, Mark S Kaminski, Alexandra C Hristov, Ryan A. Wilcox
Journal: Journal of Clinical Oncology (2016)

7571 Background: Cutaneous T-cell lymphomas (CTCL), with few exceptions, remain incurable and treatment is largely palliative. We performed a retrospective analysis of systemic treatment outcomes of patients diagnosed with MF/SS at the University of Michigan. Methods: We identified 223 patients with MF/SS evaluated at the University of Michigan from 1997-2013. Disease characteristics and treatments received were retrospectively analyzed using our CTCL database. The primary endpoint was time to next treatment (TTNT). Treatment outcomes were analyzed using Kaplan-Meier method. Results: Among 223 patients, with a median follow-up of 4.2 years, 89 (39.9%) required systemic therapy, including 46 (20.6%) with limited stage disease (stageI-IIa) and 43 (19.2%) with extensive stage disease (stage IIB-IV). A total of 227 treatment episodes were analyzed. Among all patients, retinoids (27.2 months) and interferon (7.9 months) had the longest TTNT compared to chemotherapy (4.0 months) and HDACi (4.2 months). Among all patients receiving first line treatment, retinoids was associated with a superior TTNT. (retinoid vs chemotherapy; median TTNT 29.7 months vs 2.2 months, p < 0.001; retinoid vs HDACi; median 29.7 months vs 6.8 months, p < 0.001; retinoid vs INF, 29.7 months vs 7.7 months, p = 0.049). Interferon had a superior TTNT among patients with limited-stage disease with progression after one line of therapy (IFN vs chemotherapy; median TTNT 9.1 months vs 2.0 months, p = 0.02; INF vs HDACi; median 9.1 months vs 3.7 months, p = 0.01). In patients with extensive stage disease, retinoids (7.3 months), INF (7.3 months) and ECP (12.4 months) had a significantly improved TTNT as compared to chemotherapy (2.2 months). In extensive stage disease after first line therapy, INF had the highest TTNT (7.9 months), although it did not reach statistical significance compared to chemotherapy (5.2 months), HDACi (4.3 months) or denileukin diftitox (2.8 months). Conclusions: With the exception of interferon, retinoids, or ECP, durableresponses are rarely achieved with systemic therapies in MF/SS patients, particularly those with advanced-stage disease. Therefore, clinical trial participation with novel agents should be encouraged.
Correlation of AR-V7 expression in whole blood with efficacy of abiraterone acetate (ABI) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Arun Azad, Tilman Todenhöfer, Craig Stewart, Jian Gao, Bernhard J. Eigl, Peter C. Black, Anthony M. Joshua, Kim N. Chi
Journal: Journal of Clinical Oncology (2016)

e23075 Background: Detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has been linked to primary resistance to ABI and enzalutamide (ENZ) (Antonarakis et al. N Engl J Med 2014). We have recently developed a RT-PCR assay for detecting prostate cancer (PCa)-associated transcripts in whole blood. Using this assay, which is not time sensitive and does not require CTC capture and enrichment, we correlated whole blood AR-V7 expression with outcomes on ABI. Methods: 2.5 ml whole blood was collected into PAXgene RNA tubes. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG. For each gene, the highest CT value among 20 normal controls was set as the threshold for a positive (+) test. Gene expression was correlated with the following clinical endpoints: PSA50 response rate (RR) (PSA decline ≥ 50% confirmed ≥ 3 weeks later), PSA30 RR, time to PSA (PCWG2 criteria) or clinical progression (change in anti-cancer therapy or decline in ECOG performance status (PS) ≥ 2 levels due to PCa), and overall survival (OS). Results: 37 mCRPC patients commencing ABI were recruited from 2 Canadian academic centres. Median age was 70. 59% received prior docetaxel. All pts were ABI and ENZ naïve. PSA50 RR was 37% and PSA30 RR was 48%. Median progression-free survival (PFS) was 3.8 months (mos) and median OS was 21.0 mos. 11% (4/37) of pts were AR-V7+. AR-V7+ pts had higher ALP (P= 0.04; Χ2), higher LDH (P= 0.07) and were more likely to be ECOG PS ≥ 2 (P= 0.052). AR-V7+ disease was associated with lower PSA50 RR (0% vs. 42%, P= 0.10; Χ2) and PSA30 RR (0% vs. 52%, P= 0.051) plus shorter median PFS (0.7 mos vs. 4.0 mos, P< 0.001; log-rank) and median OS (5.5 mos vs. 22.1 mos, P< 0.001). Other factors associated with worse OS were high ALP (P= 0.02), liver metastases (P= 0.03), ≤ 36 mos on primary hormone therapy (P= 0.04), HOXB13+ (P= 0.03) and KLK2+ (P< 0.001). Conclusions: AR-V7 expression in whole blood was associated with very poor outcomes on ABI. Our data serve to reinforce the potential utility of AR-V7 as a prognostic and predictive biomarker for mCRPC. Validation of these findings in larger datasets is ongoing.
Abstract MP16: Relations of Physical Activity to Gait Speed in Older Adults From the Framingham Offspring Study: Effect Modification by Age
Authors: Nicole L Spartano, Asya Lyass, Martin G Larson, Ramachandran S Vasan, Joanne M Murabito
Journal: Circulation (2016)

Background: Older adults (≥ 65 years [y]) may have difficulty meeting the Physical Activity (PA) Guidelines for Americans. Recent literature suggests that light activity is an important determinant of physical function in older adults. We hypothesized that PA (especially light activity) is associated with gait speed in older adults. Methods: Framingham Offspring Study examination 9 participants, free of mobility limitations with accelerometry and physical performance data (timed 4 meter walk), were included in this investigation (n=1449, age ≥ 50y). Sedentary time (1486 counts/min) and steps/day were also assessed. We used linear regression to relate gait speed (dependent variable) to PA levels (independent), adjusting for sex and wear time. For interactions observed between PA and age at the p≤0.1 level, regression models were stratified by age group: age 50-64 y (n=422, 55% women), age 65-44 y (n=704, 54% women), and age ≥75 y (n=323, 52% women). Results: Only 38% of adults aged 50-64 y achieved the PA Guidelines, i.e., 150 min MVPA per week. Guideline achievement dropped to 15% in participants ≥75 y. Average gait speed decreased from 1.23 to 1.08 m/s across age groups. Each 10 min increment in MVPA was associated with a 0.01 m/s higher gait speed in the full sample (p&lt;0.001); no interaction by age group was detected. The association of light activity with gait speed increased in the older age groups; 10% more time spent in light activity was associated with 0.03 m/s higher gait speed in adults 65-64 y (p=0.04, Table 1) or 0.09 m/s higher gait speed in adults ≥75 y (p&lt;0.001). More steps and lower sedentary time were also associated with higher gait speed. Discussion: Our cross-sectional study demonstrated an association of light-intensity PA with gait speed in adults ≥65 y. These data warrant future research on the impact of light activity on physical function and health outcomes in the elderly.
Design and implementation of a multipurpose BRIDG-harmonized information system at an academic cancer center.
Authors: Thomas R. Klumpp, Joseph Neff, Dania Beadle, Dolores Grosso, Nicholas DeGregorio, Nicholas VanKuren, Christine Bonaccorso, Pierluigi Porcu, Mouneer Odeh
Journal: Journal of Clinical Oncology (2018)

e18602 Background: Informatics infrastructures at most academic cancer centers consist of a largely random amalgamation of poorly documented, inadequately quality-assured, minimally intercommunicating, and often duplicative data repositories, including electronic medical record systems, protocol management systems, laboratory information systems, ad hoc spreadsheets for research projects, etc. The lack of a well-organized infrastructure increases cost and decreases productivity associated with multiple cancer-related activities, and constitutes a significant barrier to collaborative research both within and between institutions, in large part because the various data repositories are nearly always based on different underlying data models. To address these issues, the National Cancer Institute and its collaborators developed a broad-based data model called the Biomedical Research Integrated Domain Group (BRIDG) model. A primary purpose of the BRIDG model is to provide an international standard data model to facilitate collaborative cancer research both within and between institutions. Methods: Over the past four years the Cancer Bioinformatics team at the Thomas Jefferson University Sidney Kimmel Cancer Center has designed and implemented the first iteration of a highly quality-assured, multipurpose, BRIDG-harmonized cancer research information system. Results: Cost reduction and productivity enhancement are beginning to be achieved by consolidating multiple data capturing, data cleaning, and data retrieval efforts for multiple patient care, teaching, research, administrative, and regulatory activities. Conclusions: The NCI-sponsored BRIDG model can be instantiated into a multipurpose academic cancer information system that can reduce costs and increase productivity by combining data capturing, data cleaning, and data retrieval for multiple patient care, teaching, research, and administrative activities simultaneously. To our knowledge, this is the first BRIDG-harmonized multipurpose cancer research information system instantiated at a U.S. academic Cancer Center.
Integrating personalised medicine into the routine cancer diagnostic pathway in Manchester, UK
Authors: J. Henry, J.A. Radford
Journal: Annals of Oncology (2018)

Background: The 100,000 Genomes Project is a central element of NHS England's Personalised Medicine Strategy, which aims to progress the move from a 'one size fits all' approach to patient treatment to more effective personalised therapies. The driver for this lies in the relative inefficacy of generic treatments; leading to at least 40% of patients receiving treatments that have no clinical benefit. This project is an NHS transformation initiative and aims to embed operational processes for Whole Genome Sequencing (WGS) of patient samples into routine clinical practice. Methods: The Manchester Cancer Research Centre (MCRC) Biobank has been coordinating central sample collection in Greater Manchester since 2008. Historically, this activity has fallen outside of routine clinical practice, however integration of Biobanking activity and clinical pathways has enabled Manchester to deliver this national project. Steps taken include: Introducing methods in histopathology for routine frozen sample processing and tumour content assessment Roll-out of a shared patient tracker to facilitate recruitment A two-tier consent model enabling biobank consent at the time of surgery, followed by a more detailed genomic consent once sample eligibility has been confirmed Detailed data capture of sample 'failure' reasons to improve sample conversion rate Routine refrigeration of 'out-of-hours' specimens so that frozen tissue can be collected the following day Development of a 'biopsy pathway' to ensure learning can be main-streamed for real life clinical utility post project. Results: To date, Manchester have submitted ∼900 samples for Whole Genome Sequencing. Key achievements include: Samples submitted from 18 distinct tumour types Reduction of sample failure rates by > 10% Successful introduction of remote consenting model. Conclusions: Delivery of the 100,000 Genomes Project in Manchester is a clear demonstration of holistic working between research infrastructure and clinical service, which will ultimately transform personalised medicine for cancer patients in England. Legal entity responsible for the study: NHS England. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.