tbuckley/cabot-search huggingface dataset:
Randomized, open-label, phase Ⅱ trial of everolimus versus thalidomide in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma.
Authors: He Huang, Xue Ying Li, Huang Ming Hong, Zhao Wang, Xiaojie Fang, Fangfang Li, Chen Peng, Quanguang Ren, Fushen Sha, Limei Zhang, Suxia Lin, Qing Liu, Tongyu Lin
Journal: Journal of Clinical Oncology (2018)

7560 Background: Patients with diffuse large B-cell lymphoma (DLBCL) with a high International Prognostic Index (IPI) are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy. This study aimed to compare the efficacy and safety of everolimus (EVE) v thalidomide (THA) as maintenance therapy in patients with DLBCL in complete remission and with a high risk of relapse after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Methods: This was a single-center, phase Ⅱ, randomized, open-label trial. Patients with stage II bulky or stage III to IV DLBCL, IPI ≥2, and a positron emission tomography/computed tomography-confirmed CR to first-line R-CHOP were randomized to receive EVE 5 mg/day for 1 year or THA 100 to 300 mg/day for 2 years or until disease relapse, unacceptable toxicity, or death. Eligible patients who refused any maintenance therapy were included as control group. Primary end point was disease-free survival (DFS). Results: A total of 102 patients were randomized to EVE (n = 50) or THA (n = 52). After a median follow-up of 34.2 months, 2-year DFS were 84.9% with EVE v 84.2% with THA (HR, 0.958; 95% CI, 0.370 to 2.484). 2-year overall survival (OS) were 93.4% with EVE v 91.4% with THA (HR, 0.711; 95% CI, 0.169 to 2.998). The control group included 137 patients, for whom 2-year DFS and OS was 62.4% and 81.6%, respectively. Both EVE and THA arms had a superior DFS (EVE v control, HR, 0.345; 95% CI, 0.165 to 0.722; THA v control, HR, 0.350; 95% CI, 0.174 to 0.706) and OS (EVE v control, HR, 0.216; 95% CI, 0.067 to 0.701; THA v control, HR, 0.335; 95% CI, 0.132 to 0.852) compared to control group. Grade 3 or 4 adverse events with EVE v THA were mucositis (8%), leukopenia (8%), thrombocytopenia (4%), infection (2%), and leukopenia (6%), thrombocytopenia (4%), infection (2%), respectively. Conclusions: The efficacy of everolimus and thalidomide as maintenance therapy was similar, both of which significantly improved DFS and OS in patients with high-risk DLBCL after achieving CR to R-CHOP. Everolimus administered 5 mg/day and thalidomide administered 100 to 300 mg/day were tolerated well.
Pelvic exenteration for gynecologic malignancy: A NSQIP analysis of post-operative morbidity and mortality.
Authors: Sarah Sears, Kimberly Erin Resnick, Sareena Singh
Journal: Journal of Clinical Oncology (2018)

e17574 Background: Pelvic Exenteration (PE) has been utilized for many years for the radical resection of various gynecologic malignancies. Much data exists describing the morbidity and mortality of PE, however this information is based largely on single-institution experiences. Our objectives were to estimate the complication and mortality rate of PE and to determine predictors of post-operative complications using a national patient sample. Methods: All patients who underwent PE for gynecologic malignancy from 2005-2014 were identified from the ACS-NSQIP database. Demographic and clinical characteristics were collected. Rate of complications (medical and surgical) was determined. Patients were divided into 2 groups: those who experienced a complication and those who did not. Standard statistical methods were used. Statistical analysis was performed using SPSS v. 22.0 (IBM). An α-level of 0.05 was considered statistically significant. Results: We identified 321 patients who underwent PE. Seventy-four percent (n = 237) patients experienced at least one complication. Patients who experienced a complication were more likely to have dyspnea at rest (8.9% vs. 2.4%, p = 0.048), ASA Class ≥ 3 (75.1% vs. 57.1%, p = 0.002), longer operative time (436.7 min vs. 298.1 min, p < 0.001), anemia (Hct < 36%) (53.6% vs. 40.5%, p = 0.039), and hypoalbuminemia (albumin < 3.5 g/dL) (54.9% vs. 41.7%, p = 0.038). Multivariate logistic regression identified the following predictors for developing a complication: ASA Class ≥ 3 (O.R. 4.162, 95% CI 1.023 – 3.18, p = 0.041), longer operative time (O.R. 25.6, 95% CI 1.003 – 1.006, p < 0.001), and hypoalbuminemia (O.R. 4.6, 95% CI 0.319 – 0.985, p = 0.044). Incidence of post-operative fatality was 1.2%. Conclusions: The results of our review of this national multi-institutional population reinforces that PE is a procedure associated with high morbidity. The rates of post-operative morbidity and mortality are consistent with what is in the current literature. We identified clear risk factors for post-operative morbidity that can be used in pre-operative counseling for patients undergoing PE that are generalizable to a broad patient population.
Outcomes of lung cancer patients with leptomeningeal metastases in the targeted therapy era.
Authors: Kathryn Sara Nevel, Natalie DiStefano, Xuling Lin, Aimee Cowan, Anna Skakodub, Shahiba Ogilvie, Elena Pentsova, Adrienne Ann Boire
Journal: Journal of Clinical Oncology (2018)

2064 Background: Recent improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have substantially altered the management of this disease. In this new era, outcomes of patients harboring LC-LM are not well defined. This study identifies molecular and clinical characteristics of LC-LM and correlates these with clinical outcome. Methods: We retrospectively reviewed charts of 171 patients diagnosed with LC-LM between June 2009 and June 2017 at Memorial Sloan Kettering Cancer Center. Presence of targetable mutations (TM) in the primary tumor and CSF was determined by MSKCC IMPACT. Extent of radiographic involvement was scored by number of gadolinium-enhancing sites in eight locations. CSF studies included cytopathology, quantification of circulating tumor cells (CTCs), and cell free DNA (cfDNA) analysis. Kaplan-Meier survival curves were compared by log-rank analyses. Results: Median overall survival (OS) after LC-LM diagnosis (dx) was 125 days; 80/171 patients harbored a TM. At one year, 29% of patients with a TM were alive versus 12% of those without. Treatment of LC-LM with targeted therapies (TTx) was associated with improved OS (0 TTx = 70 days, 1 TTx = 109 days, 2+ TTx = 507 days; p < 0.0001). A subset of 93/171 patients underwent MRI brain, spine and CSF studies within 30 days of LM dx. Extent of radiographic involvement correlated with OS: 0-2 sites of disease OS = 113 days, 3+ sites OS = 75 days; p = 0.015. CTCs were analyzed in 15/171 patients. Fewer than 50 CTCs/3 mL correlated with OS of 377 days, versus OS 66 days for > 50 CTCs/3mL. cfDNA was extracted from 20/171 patients. cfDNA concentration correlated with outcome; cfDNA < 0.025 ng/µl = OS of 231 days, vs cfDNA > 0.025 ng/µl OS of 60 days p = 0.022. Conclusions: In this largest study of LC-LM, presence of a TM and treatment with TTx were associated with improved OS. Extent of radiographic involvement at dx was also a prognostic indicator. These findings support complete molecular characterization and CNS staging for clinical management, prognostication and clinical trial stratification of LC-LM.
Optimization of trabectedin temporal protocol using mathematical PK/PD modeling.
Authors: Maeva Andriantsoa, Raouf El Cheikh, Diane Charlotte Imbs, Raphael Serre, Florence Duffaud, Joseph Ciccolini, Dominique Barbolosi, Sébastien Salas
Journal: Journal of Clinical Oncology (2018)

e23553 Background: Trabectedin (ET-743, Yondelis) is an antineoplastic agent indicated for the treatment of advanced soft tissue sarcomas (STS). Despite its efficacy, Trabectedin induces severe toxic side effects, especially neutropenia. In clinical settings, this leads to empirical dosing adjustments that disrupt the efficacy-toxicity balance. Developing a quantitative tool that allows for better dosing adjustments using patients-specific data would be of great utility. Methods: Retrospective hematologic, demographic and disease status data from 39 patients with metastatic STS were collected and analyzed. All patients received Trabectedin standard protocol (24-h infusion at the dose of 1.5 mg/m2 every 3 weeks). A mathematical PK/PD model describing the time course of neutrophils under Trabectedin treatment was developed. Model parameters were estimated using nonlinear mixed effects analysis under the software MONOLIX. Further statistical analyses to look for covariates impacting neutropenia incidence were performed. Results: Using the mathematical model and optimization techniques, we propose a new protocol that reduces neutropenia incidence. The optimized protocol consists of three Trabectedin injections: 0.65 mg/m2 D1, 0.3 mg/m2 D8 and 0.55 mg/m2 D15 within a cycle of 28 days. Statistical analysis showed significant correlation (Log-rank p = 0.015) between baseline absolute neutrophil count (ANC) and progression-free survival (PFS). Patients with baseline ANC < 7.5 G/L had a median PFS of 158.5 days, while patients with baseline ANC > 7.5G/L had a median PFS of 71 days. We did not observe significant correlation between demographic covariates, disease status and neutropenia incidence. Conclusions: Mathematical modeling offers a valuable tool to optimize the dosing regimen for Trabectedin treatment. Baseline value of absolute neutrophil count was shown to impact disease evolution; therefore, it should be considered when adjusting Trabectedin protocol to improve dosing personalization.
Evaluation of tumor biomarkers in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer treated with the CXCL12 inhibitor NOX-A12 and preliminary safety in combination with PD-1 checkpoint inhibitor pembrolizumab.
Authors: Niels Halama, Ulrike Pruefer, Anna Frömming, Diana Beyer, Dirk Eulberg, Jarl Ulf Jungnelius, Aram Mangasarian
Journal: Journal of Clinical Oncology (2018)

e15094 Background: NOX-A12 (olaptesed pegol) is a novel inhibitor of the chemokine CXCL12 for treatment of solid tumors. The Opera study (NCT03168139) is a Phase 1/2 open label clinical study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 and safety and efficacy of a combination of NOX-A12 with pembrolizumab in advanced MSS, metastatic colorectal and pancreatic cancer. The study comprises two weeks of NOX-A12 monotherapy followed by repeated 21-day cycles of NOX-A12 plus pembrolizumab. Here we present pharmacodynamic biomarker data from for monotherapy phase with NOX-A12 as well as safety for the combination with pembrolizumab. Methods: Patients received 300 mg NOX-A12 by i.v. infusion on days 1, 4, 8, and 11 of the monotherapy phase. Needle biopsies were taken from suitable liver metastases before treatment and on day 14, peripheral blood was drawn at the same time points. Collected tumor samples were analyzed for immune cell infiltration and cytokine signature. Results: At the time of abstract submission, 15 out of 20 patients have been recruited, thereof 8 with colorectal and 7 with pancreatic cancer. Serial biopsies at baseline and end of monotherapy suitable for IHC analysis were obtained from 7 out of 15 patients. CXCL12 levels were found to be increased in blood, but also in post-treatment tumor biopsies. IHC analysis is ongoing, and results for all patients will be presented. The overall cytokine patterns indicate a specific reaction to NOX-A12 in tumor tissue and in the blood, with distinct patterns in the periphery and in the tumor. Treatment with NOX-A12 monotherapy and in combination with pembrolizumab was generally safe and well tolerated. Conclusions: NOX-A12 penetrates into the tumor where it binds and neutralizes CXCL12. Changes in the tumor-infiltrating leukocyte numbers as well as in the cytokine signature suggest that NOX-A12 modulates the tumor microenvironment. Clinical trial information: NCT03168139.
A phase I study in patients with a human papillomavirus type 16 positive oropharyngeal tumor treated with second generation synthetic long peptide vaccine conjugated to a defined adjuvant.
Authors: Marije Slingerland, Frank Speetjens, Marij Welters, Hans Gelderblom, Inge Roozen, Lilly-Ann van der Velden, Cornelis Joseph Melief, Maarten Zandvliet, Sjoerd van der Burg, Ferry Ossendorp
Journal: Journal of Clinical Oncology (2016)

TPS3113 Background: The synthetic long peptide (SLP) vaccine against the human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 applied to high-grade premalignant HPV16-induced lesions of the vulva was safe and resulted in successful clearance of the lesion in half of the patients correlating with strong and broad T-cell responses against the vaccine peptides. However, in HPV16+ cervical cancer patients the vaccine responses were less vigorous and not sufficient for tumor regression. A second generation SLP vaccine was formulated, in which two E6 long peptides were conjugated to a synthetic Toll-like receptor 2 (TLR2) ligand called Amplivant. The TLR2 ligand-SLP conjugates were shown to enhance antigen presentation by dendritic cells, thereby improving induction of effective anti-tumor T cells in vitro and in preclinical studies. The two selected E6 peptides are immunodominant peptides containing both CD4+ and CD8+ T-cell epitopes in natural HPV16 immunity and upon vaccination with HPV16-SLP in previous clinical trials. Methods: In a recently initiated phase I clinical trial the two with Amplivant conjugated E6 peptides as a mixture (the vaccine is called Hespecta; HPV E Six Peptide Conjugated To Amplivant) were administered to HPV16+ oropharyngeal cancer patients, who first were treated with curative intent. Four dose escalation levels will be tested in six patients per peptide dose, namely 1, 5, 20 or 50 μg of conjugated peptides. The vaccine is administered intradermally three times with a three-week interval. The decision to start enrolment at the next dose level is made by assessing the safety after 4 out of 6 patients have completed the first follow-up visit after the third vaccination with the previous dose level. The dose escalation phase will be discontinued if in two or more patients a grade 3 or 4 vaccine-related toxicity occurs. The primary objective is to determine the ability of the vaccine to induce HPV16 E6-specific T-cell responses. The secondary objective is to study the safety of Hespecta. Currently, 2 patients have been enrolled. Clinical trial information: 2014-000658-12.
Artificial intelligence methods to predict chemotherapy-induced neutropenia in breast cancer patients.
Authors: Peter Abdul DeWan, Orr Inbar, Catherine S. Spina, Karl Rudeen, Charles Lagor, Mark S. Walker, Edward J. Stepanski, Jennifer O. Nwankwo, Brigham Hyde
Journal: Journal of Clinical Oncology (2018)

6555 Background: While chemotherapy improves outcomes in breast cancer patients, it also increases the risk of neutropenia. There is a need for improved risk prediction models of chemotherapy-induced neutropenia. This study developed an artificial intelligence (AI) model to predict neutropenia risk within six months of chemotherapy and compared it to traditional logistic regression models. Methods: We obtained a cohort of 10,288 breast cancer patients from the ASCO CancerLinQ Discovery™ dataset, who were treated with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with or without pre-chemotherapy WBC growth factor prophylaxis. We created a hierarchy of predictors, then trained and evaluated a neural network algorithm. Results: Using only the relevant predictors for this more specific study, we demonstrate an average 27% increase across the scenarios in AUC ROC (p < 0.001) compared to existing studies (Lyman, 2011). We improve prediction by an average of 45%, achieving 0.56 positive predictive value (PPV) and 0.92 negative predictive value (NPV) prior to chemotherapy. Conclusions: These results demonstrate that this larger dataset combined with an AI algorithm enabled substantial improvement in prediction of chemotherapy-induced neutropenia. In the clinical setting, this would improve decisions, and enable early intervention for patients that would benefit most from prophylaxis, thus reducing neutropenic fever and infections requiring hospitalization. Clinical Decision Point Cohort Predictive Models Statistics Logistic Regression (Lyman, 2011) Logistic Regression (Current Study) PH.AI Neural Net (Current Study) N Neutropenia incidence within 6 mo. Stage Distribution (I,II,III,IV) Median time to Neutropenia (days) AUC-ROC # Predictors AUC-ROC # Predictors AUC-ROC # Predictors Prior to Starting AC with Prophylaxis 7097 .017 .14, .50, .31, .04 18 .58 ± .03 7 .73 ± .02 19 .78 ± .04 704 no Prophylaxis 1075 .093 .13, .51, .31, .05 22 .59 ± .03 7 .69 ± .02 15 .74 ± .01 2169 Prior to Starting T with Prophylaxis 6753 .084 .14, .50, .31, .04 31 .59 ± .03 7 .76 ± .02 21 .74 ± .01 2130 no Prophylaxis 1078 .074 .13, .53, .29, .05 15 .57 ± .02 7 .74 ± .02 16 .89 ± .02 873
A bioequivalence study of proposed bevacizumab biosimilar, MYL-1402O (A) vs EU-Avastin (B) and US-Avastin (C).
Authors: Mark A. Socinski, Matthew Hummel, Tjerk Bosje, Andrew Shaw, Mark Shiyao Liu, Mark Baczkowski, Abhijit Barve, Mudgal Kothekar, Eduardo J. Pennella
Journal: Journal of Clinical Oncology (2017)

e14034 Background: MYL-1402O is a proposed bevacizumab biosimilar. The similarity of MYL-1402O to Avastin has been demonstrated in physicochemical analyses, and nonclinical studies. Methods: This single-center, randomized, double blind, three-arm, parallel-group, study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C, and B to C. Subjects were randomized to receive either A, B or C 1 mg/kg over 90 minutes as an intravenous infusion. Dose was selected based on the lower dose in the linear range of PK and acceptable safety in healthy volunteers. Bioequivalence was to be concluded if the 90% CIs of the ratios (A/B, A/C and B/C) of LS means of the natural log transformed AUC 0-inf were within 80% to 125%. AUC 0-t , C max , t max , kel and t½ were assessed as secondary PK parameters. Results: A total of 111 subjects (37/treatment) were enrolled and 110 [37 (A), 36 (B), 37(C)] were included in the analysis. Bioequivalence was demonstrated between A and B, A and C and between B and C. LS mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all of the comparisons. The secondary PK parameters were also comparable with the 90% CIs for ratios of AUC 0-t and C max within 80%-125%. A total of 313 TEAEs were reported, 116 by 33 (89%) subjects who received A, 99 by 29 (78%) subjects who received B and 98 by 28 (76%) subjects who received C. Most TEAEs were consistent with the clinical data of bevacizumab (Avastin). No serious or unexpected TEAEs were reported. TEAEs were grade 1 or grade 2 in severity. The anti-drug antibodies are being evaluated (pending results). Conclusions: These results confirm bioequivalence of Myl-1402O vs. EU-Avastin and US-Avastin. All treatments were well tolerated and no significant safety issues emerged. Clinical trial information: NCT02469987 Clinical trial information: NCT02469987.
Rotavirus Vaccines in China
Authors: Carl D. Kirkwood, A. Duncan Steele
Journal: JAMA Network Open (2018)

Chuanxi Fu, PhD; Zhiqiang Dong, MD; Jichuan Shen, PhD; Zhicong Yang, MD; Ying Liao, MPH; Wensui Hu, MD; Sen Pei, PhD; Jeffrey Shaman, PhD
Screening and Management of High Blood Pressure in Children and Adolescents
Authors: Michael Khoury, Nicolas Madsen
Journal: JAMA Pediatrics (2018)

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Comprehensive genomic characterization of chemotherapy-resistant testicular germ cell tumors (TGCT).
Authors: Andrea Necchi, Gennady Bratslavsky, Robert John Corona, Jon Chung, Sherri Z. Millis, Laurie M. Gay, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti Ramkissoon, Eric Allan Severson, Sugganth Daniel, Jonathan Keith Killian, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Allison W. Welsh, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

4555 Background: Although both seminomatous (Sem) and nonseminomatous (NS) TGCT have a favorable response to platinum-based chemotherapy (CT), a small proportion of them are chemorefractory. Therapeutic options for these patients (pts) are limited, and relevant therapeutic targets are lacking. Methods: The database of Foundation Medicine Inc. was searched, integrated with relevant clinical data. Archival tissues from 108 CT-treated and relapsed TGCT pts (22 Sem and 86 NS) underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) was determined on 114 loci. Results: Sem pts were older than NS (p = 0.007). All pts had failed at least 1 CT regimen for metastatic disease. The mean GA/tumor frequency was 4.1 mut/tumor for NS and 3.1 for Sem (p = 0.08). KRAS alterations (mainly amplifications) were the most frequent GA (47% and 36% in Sem and NS). TP53, CCND2 and FGF6/23 GA frequencies were similar in both Sem and NS. GA in KIT (21% vs 2%), PIK3CA/MTOR (10% vs 0%), PTEN (5% vs 0%) and BRCA2 (5% vs 0%) were more frequent in Sem than NS whereas BRAF (2%) and ERBB2 (1%) GA were found in NS only. Among pts with MTOR alterations, one Sem was treated based on genomic profiling and had an exceptional response to everolimus, after CT and immunotherapy (IT) failure. MSI-High status was not identified in Sem cases and was found only in 2% of NS. The median TMB for the Sem cases was 2.5 mut/Mb and for NS was 2.7 mut/Mb. TMB levels of ≥10 mut/Mb were not encountered in Sem. Higher levels of TMB were more frequent in NS with 5% of NS having ≥10 mut/B and 1% ≥20 mut/Mb. Conclusions: Clinical trials in molecularily-selected pts are warranted for refractory TGCT, particularly the high frequency of KRAS amplification may portend activity of MEK inhibitors. Overall, the GA found in refractory Sem and NS differ significantly. Sem features lower GA frequency with slightly higher potential for targeted therapies in KIT and PI3K/MTOR pathways. Based on rare high TMB and MSI-High status, IT may be of benefit in a small subset of NS.