tbuckley/cabot-search huggingface dataset:
Association of efficacy and adverse events of special interest of avelumab in the JAVELIN solid tumor and JAVELIN Merkel 200 trials.
Authors: Karen Kelly, Juliane Manitz, Manish R. Patel, Anja H. Loos, Arthur Allignol, Vikram K. Chand, Vijay Kasturi, Kevin M. Chin, John Warth, Hao Zhang, Anja von Heydebreck, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

3057 Background: Immune checkpoint inhibitors (ICIs) are associated with unique adverse events of special interest (AESI), including infusion-related reactions (IRRs) and immune-related AEs (irAEs). It has been observed that patients (pts) responding to treatment might have a higher likelihood of AEs, potentially due to longer treatment duration. Understanding the association between AESIs and efficacy outcomes may improve the assessment of benefit/risk and thus aid in informed treatment decisions. Methods: We pooled and analyzed efficacy/safety data from NCT01772004 and NCT02155647. We performed an association analysis between response and IRRs. The association of efficacy and irAEs was analyzed using approaches that accounted for time dependency: Cox models analyzed overall survival under consideration of time-varying indicators for irAEs; multistate models were used to gain insight into underlying mechanisms. Results: 1783 pts were included in this analysis. 25.5% of pts had ≥ 1 IRR; 0.7% of pts had a grade 3-4 IRR. 97.3% of pts with IRRs had first onset during the first 3 infusions. No association between response and IRRs was observed. irAEs were observed in 16.8% of pts, most commonly hypothyroidism (6.7%) and rash (6.6%); grade 3-4 irAEs occurred in 2.7% of pts. 2.2% of pts discontinued avelumab treatment due to an irAE. An improved probability of survival was observed for pts who experienced irAEs (HR, 0.74 [95% CI, 0.61-0.88]). The multistate model did not suggest that occurrence of irAEs predicted response; however, responders were more likely to develop irAEs than others who remained on treatment. The discontinuation rate did not increase upon occurrence of irAEs. Conclusions: The overall incidence of AESI was low, and most were grade ≤ 2. The occurrence of IRRs did not impair the rate of response. The data suggest a survival benefit for pts who experienced an irAE; however, not having an AE did not preclude a response to avelumab. Continued awareness of irAEs may improve clinical outcomes in all pts, with particular vigilance needed if a pt is responding and remains on treatment. Clinical trial information: NCT01772004, NCT02155647.
Abstract B065: Genomic analysis of localized prostate cancer identifies AZIN1 as driver of metastatic progression
Authors: Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Elien Smeets, Stefan Prekovic, Christine Helsen, Hendrik van Poppel, Wouter Everaerts, Christine Buerki, Elai Davicioni, Steven Joniau, Frank Claessens
Journal: Cancer Research (2018)

Abstract High-risk PCa (HRPCa) remains very heterogeneous with an unacceptable variation in patient outcome after radical prostatectomy, with cancer-specific mortality rates ranging from 4.6% to 20.3% at 10 years’ follow-up. Clearly, we need a better understanding of the tumor biology to enhance the subclassification, enable the identification of lethal PCa, and eventually allow a more precise decision-making regarding treatment. We created a matched case-control study of two clinically identical HRPCa patient groups, both treated with radical prostatectomy but where one developed metastatic recurrence (n=19) and the other did not (n=25), despite very-long-term follow-up. The integrated analysis of copy number aberrations and transcriptome analysis highlighted a focal amplification of 8q22.3 in the metastatic group, associated with a higher expression of antizyme inhibitor 1 (AZIN1) in our cohort. This association of high AZIN1 levels with the metastatic HRPCa phenotype suggests a role for AZIN1 as possible predictor and/or target for metastatic HRPCa. AZIN1 is one of the regulators of the polyamine synthesis, which play a central role in many cellular processes. Our in vitro analyses confirmed that modulation of AZIN1 expression determines both growth and migratory potential of prostate cancer cells. Future experiments are planned to confirm these data in the in vivo setting. RNA sequencing after knockdown of AZIN1 in PCa cells revealed several transcriptional programs that are activated/deactivated upon AZIN1 knockdown. This showed among others a significant upregulation of genes involved in extracellular matrix composition, including genes encoding for subunits of the collagen IV, which is an integral part of the basement membrane. Ongoing experiments focus on identifying the mechanism by which AZIN1 regulates collagen IV expression. Citation Format: Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Elien Smeets, Stefan Prekovic, Christine Helsen, Hendrik van Poppel, Wouter Everaerts, Christine Buerki, Elai Davicioni, Steven Joniau, Frank Claessens. Genomic analysis of localized prostate cancer identifies AZIN1 as driver of metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B065.
Role of melanoma cell-intrinsic RIG-I and STING signaling for checkpoint inhibitor-mediated anticancer immunity.
Authors: Simon Heidegger, Alexander Wintges, Sarah Bek, Martina Schmickl, Julius Fischer, Paul-Albert Koenig, Tobias Haas, Hendrik Poeck
Journal: Journal of Clinical Oncology (2018)

3081 Background: Strong inter-individual variation in clinical response to immune checkpoint inhibitors (ICB) including anti-CTLA-4 remains a major challenge, but the molecular pathways that modulate ICB efficacy remain ill defined. Methods: Using CRISPR/Cas9 technology to generate melanoma cells lines that lack nucleic acid receptors or downstream signaling molecules together with available genetically deficient mouse models, we addressed the importance of nucleic acid receptor signaling in both tumor and host cells for the efficacy of anti-CTLA-4 immunotherapy. Results: We demonstrate that anti-CTLA-4 immunotherapy relies on melanoma cell-intrinsic activation of the cytosolic RNA receptor RIG-I (DDx58) but not the DNA sensing adaptor protein STING. Mechanistically, RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103+ dendritic cells, subsequent expansion of tumor antigen-specific CD8+ T cells and the accumulation of CD8+ T cells within the tumor tissue. These processes were independent of tumor-cell derived type I IFN (IFN-I), but additionally required host STING, MAVS and IFN-I signaling. Consistently, therapeutic targeting of RIG-I with 5’-phosphorylated-RNA in both tumor and non-malignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade. Conclusions: Our data are consistent with the finding that expression of RIG-I in human melanomas has been associated with clinical benefit to CTLA-4 blockade and identify activation of RIG-I/MAVS signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer. These findings not only nominate tumor intrinsic RIG-I activity as potential biomarker for treatment response to checkpoint inhibitors, but predict that targeting this pathway may serve as a basis for the development of new combined modality approaches to increase the response rate of checkpoint inhibitor-based immunotherapy, particularly in individuals that do not have a sufficient spontaneous antitumor T-cell immune response.
Predictive value of neutrophil subtypes in response to neoadjuvant therapy in breast cancer patients.
Authors: Linxiaoxi Ma, Liang Guo, Zhimin Shao, Xiaoming Zhang, Jiong Wu
Journal: Journal of Clinical Oncology (2018)

e12642 Background: Several studies reported on effective predictive markers of neoadjuvant therapies in breast cancer. However, the predictive value of polymorphonuclear neutrophil (PMN) subtypes remains unclear so far. Methods: Blood samples of 180 breast cancer patients before treated with neoadjuvant therapy and 118 healthy donators from Fudan University Shanghai Cancer Center were collected in this prospective study during July 2015 to October 2016. PMN subtypes were analyzed with multiparameter flow cytometry. Neoadjuvant therapeutic regimen mainly included taxanes with sequential anthracyclines. In Her-2 positive diseases, paclitaxel-carboplatin-trastuzumab regimen was the main choice. In this series of patients, at least 4-6 cycles would be delivered pre-operatively. Pathologic evaluation after surgery showed 35 pathologic complete response (PCR) and 145 non-PCR. The association in PMN subtypes is examined with t test, and others with Χ2 test. Results: PMN was divided into 4 subtypes based on CD16 and CD62L: CD16-CD62L-(Early), CD16-CD62L+(Immature), CD16+CD62L+(Mature), and CD16+CD62L-(Activated). In addition, HLADR+ PMN was defined as “DR+ PMN”. Compared with healthy donators, breast cancer patients had lower CD16+CD62L+ PMN (P < 0.001), higher CD16+CD62L- PMN (P = 0.001) and DR+PMN (P < 0.001). We further investigated patients treated with neoadjuvant therapy and found that PCR patients had higher CD16+CD62L+PMN (P = 0.019). Univariable regression analysis demonstrates markers associated with PCR were ER negative (O.R. = 2.125, 95% CI 1.308-3.452, P = 0.002), Her-2 positive (O.R. = 2.217, 95% CI 1.355-3.628, P = 0.002), CD16+CD62L+ PMN(%) > 97.4 (O.R. = 3.276, 95% CI 2.161-4.965, P < 0.001). Multivariate regression analysis indicates CD16+CD62L+ PMN(%) > 97.4 (O.R. = 6.493, 95% CI 368-12.521, P < 0.001) was the independent predictors of PCR. Conclusions: PMN status was different between healthy people and breast cancer patients. It was indicated that peripheral blood PMN subtype could have predictive value after neoadjuvant systemic treatment in breast cancer patients. Further validation study should be warranted to test its significance in clinical practice.
A Randomized Study of Geriatric Assessment with Management (GAM) in Older Adults with Cancer.
Authors: Allison Magnuson, Chintan Pandya, Tatyana Lemelman, Molly Goodman, William Dale, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2016)

10055 Background: In older adults without cancer, GAM reduces adverse outcomes. This study‘s aim was to evaluate the feasibility and impact of incorporating GAM into the clinical care of older cancer patients receiving systemic therapy. Methods: Patients aged 70+ with advanced solid tumor cancers initiating first- or second-line treatment were consecutively recruited from a single institution (n = 80). Geriatric assessment (GA) with validated tools was performed at baseline and 3 months. Cancer and Aging Research Group (CARG) toxicity score was calculated at baseline. Patients were randomized to control vs. intervention (standardized algorithm providing GAM recommendations to treating oncologist based on GA impairments). Primary outcome was prevalence of grade 3-5 toxicity within 3 months (CTCAE v4). Secondary outcomes included feasibility and impact on hospitalizations, dose reductions and delays. Results: Average age was 76 (70-89). GI (48%) and lung (39%) cancers were most common. The majority were stage IV (67%) receiving first-line therapy (92%). Treatment included chemotherapy (68%), chemoradiotherapy (22%), and targeted therapy (10%). At baseline, the intervention group had more patients with high-risk CARG scores (score ≥ 10) (15 vs 35%, p = 0.04) and higher rates of IADL impairment (33 vs 67%, p = 0.02). Other baseline measures were similar. In the intervention arm, 35.4% (145/409) of GAM recommendations were implemented by the treating oncologist. 59% of patients experienced grade 3-5 toxicity within 3 months, with no significant difference between control and intervention (61 vs 57%, p = 0.74). At 3 months, there was resolution of baseline differences in IADL dependence (44 vs 42%; p = 0.9). There were no differences in rates of hospitalization (36 vs 21%, p = 0.17), dose reduction (42 vs 32%; p = 0.39) or dose delay (33 vs 37%; p = 0.69). Conclusions: Although the intervention group had higher CARG scores at baseline, there was no difference in toxicity rates, suggesting possible benefit from GAM. Resolution of IADL differences suggests progressive functional loss in the control group. Future research should strive to increase GAM recommendation uptake and investigate if increased uptake further improves outcomes. Clinical trial information: NCT01915056.
Neuroblastoma metastatic to the central nervous system: Survival analyses from the German Childhood Cancer Registry and the literature.
Authors: Frank Berthold, Marc Hömberg, Ole Baadsgaard
Journal: Journal of Clinical Oncology (2017)

10555 Background: Therapeutic innovation has resulted in an overall decline in childhood neuroblastoma (NB) mortality; however, metastatic NB to the central nervous system (CNS NB), which has emerged as a sanctuary site for NB metastases, remains difficult to treat and is typically fatal. The objective of this study was to describe the natural course of CNS NB. Methods: Data were sourced from a custom query of the German Childhood Cancer Registry (GCCR) and from the literature. Survival statistics were prepared from a diverse, thus generalizable, pool of CNS NB patients. Data are presented as secondary event-free and overall survival (EFS and OS) after diagnosis of first CNS recurrence from initial high-risk NB. Results: The GCCR query identified 85 patients with CNS NB diagnosed from 1990–2010, including 57 with isolated CNS disease. The median (95% confidence) EFS and OS times were 2.6 (1.5–3.8) and 4.7 (2.1–7.2) months, respectively, for all CNS NB patients, and 2.8 (1.4–4.1) and 6.8 (2.1–11.5) months, respectively, for isolated CNS NB patients. Secondary OS at 12, 18, and 36 months was 29.4%, 18.8%, and 8.2%, respectively, for all CNS NB patients, and 35.1%, 22.8%, and 12.3%, respectively, for isolated CNS NB patients. Thirteen publications were selected with 83 patients treated from 1979–2013. In addition to an inclusive analysis, a restricted analysis was performed, excluding patients who did not receive therapy with curative intent, to assess survival after therapeutic intervention. Median OS (95% confidence) was 5.6 (3.0–8.0) and 8.7 (5.8–11.0) months in the inclusive and restricted analyses, respectively. The proportion of patients surviving 12, 18, and 36 months at reporting were 24%, 12%, and 3.6%, respectively, for the inclusive population, and 33%, 17%, and 5%, respectively, for the restricted population. Conclusions: An assessment of the natural course of CNS NB from two sources arrived at similar conclusions with respect to overall and long-term survival. In general, median secondary OS is &lt; 6 months and &lt; 10% of patients survive 36 months. The findings were consistent across geographic regions and have not changed appreciably in 4 decades.
Customized electronic alerts to boost pneumococcal vaccinations in high risk cancer patients.
Authors: Ananta Bhatt, Shoshana Hort, Daniel J Gelb, Todd MacKenzie, Frederick Lansigan
Journal: Journal of Clinical Oncology (2017)

e18227 Background: Streptococcus pneumoniae remains a leading cause of serious illness, including bacteremia, meningitis, and pneumonia among adults in the United States. Approximately 10% of all patients with invasive pneumococcal disease die of their illness, but case-fatality rates are higher for immunocompromised adults including cancer patients. Current Center for Disease Control (CDC) guidelines recommend routine use of 13-valent (Prevnar 13) and 23-valent (Pneumovax 23) pneumococcal vaccines (PV) for immunocompromised patients. We conducted a quality improvement (QI) project utilizing our electronic medical record (EMR) system to improve PV compliance (PVC) rates in our patients. Methods: We created automatic reminders called best practice alerts (BPA) and linked them to a smart order set within our EMR that appeared upon opening patient charts. The smart set ordered the correct vaccine in sequence based on CDC guidelines. From August 2015- January 2017, we implemented this BPA for one of six hematology providers and the remaining providers were provided with verbal guidelines and reminders to administer PV to their patients. Results: At baseline only 22% of 3000 hematology patients within the practice had received PV. The pilot provider with the BPA linked to a smart order set within the EMR improved PVC within his patients from 23% to 66%. Providers who were just given verbal guidelines improved PVC from an average of 22% to 45%. The difference in the improvement between the pilot provider and the reference group is 21% (p &lt; 0.001). Conclusions: In an EMR era, we took advantage of the tools within our system to improve PVC rates. BPA linked to a smart order set within the EMR provided better means of improving PVC than verbal prompts in high-risk immunocompromised patients. Additionally, the increase in PVC throughout the hematology practice is due to primary care providers using similar reminders within the same EMR. The PV BPA will be conducted as a standard of care in our clinic and will be expanded to oncology patients as well.
Abstract 13470: RV Ejection Efficiency Measured in the Phasic Pulmonary Flow; a CMR Approach in PAH
Authors: Robert W Biederman, Mark Doyle, Geetha Rayarao, Diane Thompson, June Yamrozik, Ronald B Williams, Priscilla Correa-Jaque, Raymond Benza
Journal: Circulation (2015)

Introduction: Measurements of RV function, such as RVEF and RV-measured ventricular-vascular coupling (VVC), maybe important in predicting survival in PAH, but are dependent on load and mathematical assumptions. However, independent measures, such as flow efficiency (FEI) within the main PA may be better predictors. FEI is dependent on the natural ratio between MPA area to pulsatile blood wavelength (λ), where λ is proportional to the product of λ velocity and the pulse time, but is difficult to measure directly. Hypothesis: We hypothesize pulmonary FEI will correlate with the VVC and RVEF. Methods: CMR was performed on 18 pts with PAH to assess RV function. Eight pts additionally underwent RV CMR during physiologic stressors: 1) inhaled NO 2) dobutamine (20μ/kg/min) and 3) volume challenge (500ml NaCl). MPA flow was measured via phase velocity mapping (PVM). The RVEF, VVC ratio and ejection time (ET) were calculated from CMR. The MPA area was measured from the PVM images along with avg velocity (Vel avg . Pulmonary FEI = (average Vel avg x ET) / MPA area. Results: A total of 38 unique measures of RVEF (52±12%), VVC (0.89±.3) and MPA flow conditions were measured: Vel avg (49±15cm/s), MPA area (51±11mm 2 ) and ET (295±61ms). The FEI correlated with RVEF and VVC via log term: RVEF = 11.5 log nat (FEI) + 37.2; and VVC = 0.34 log nat (FEI) + 1.17.Bland-Altman analysis of the measured RVEF vs. the FEI modeled RVEF (Fig 1) has an offset bias of 0, a four SD range of ±14.4; r=0. 0.8, while the measured VVC vs. modeled has a bias of 0 and a 4 SD range of ± 0.45; r = 0.74. Conclusions: The linear combination of average pulmonary blood velocity, ejection time and MPA area combine to form a pulmonary FEI that strongly correlates with RVEF and VVC. Importantly, it is devoid of the afterload/preload assumptions of RVEF and the multitude of assumptions of V 0 and RVEDP in VVC. As such, this index may provide additional clinical value since it reflects the directly measured intrinsic efficiency of integrated RV-PA conditions.
Digoxin plus trametinib therapy of BRAF wild type metastatic melanoma patients.
Authors: Arthur E. Frankel, Ugur Eskiocak, Thomas W. Froehlich, Chul Ahn, Amanda Joy Hoelscher, Sean Morrison
Journal: Journal of Clinical Oncology (2016)

9527 Background: A 200,000 small molecule library was screened for cytotoxicity with an in vitro 2D and 3D culture of primary human melanoma cells and other normal human cells. Several cardiac glycosides exhibited potent toxicity against melanomas. When combined with the MEK inhibitor trametinib, synergistic effects on the survival of patient-derived melanoma xenograft models were observed. Based on these observations, we conducted a phase 1B study of digoxin plus trametinib in BRAF wild-type metastatic melanoma patients. Methods: Seventeen BRAF wild-type metastatic melanoma patients who were immunotherapy refractory (n = 6) or ineligible for immunotherapy (11) were enrolled. Patients > 18 year old with good performance status and organ function received 8 week cycles of daily digoxin 0.25 mg oral daily adjusted for serum level of 1-2ng/mL and trametinib 2mg oral daily adjusted for side effects. Toxicities were measured by histories, exams and labs using NCI CTCAE v4.1, and responses assessed with exams and CT scans employing RECIST v1.1. Results: Seventeen patients are evaluable for toxicities. 16/17 had grade 1-2 rash, diarrhea, and/or fatigue. Four of the first seven patients discontinued therapy secondary to these side effects. After institution of early patient education and symptomatic interventions, no further patients stopped therapy early. Of sixteen assessable patients for responses, there were 4 partial remissions--PR (25%, 95% CI = 7.3%-52.4%) lasting 2, 2, 4 and 8 months and six stable disease--SD (38%, 95% CI = 15.2%-64.6%) lasting 2, 2, 2+, 8+ and 7 months. The disease control rate—DCR composed of PRs + SDs was 10/16 or 63% (95% CI = 35.4%-84.8%) with median duration of 4+ months. The DCR in NRAS mutant melanoma patients was 4/5 or 80% compared with 5/10 or 50% in NRAS wild-type patients. Conclusions: These results compare favorably with the published activity of trametinib alone in BRAF wild-type melanoma patients where the PR and DCR rates were 10% and 36%, respectively (n = 39, Falchook, Lancet Oncology 13, 782, 2012). Trametinib alone yielded a DCR of 2/7 or 29% in NRAS mutant melanoma patients. Further patient accrual is warranted in an expansion cohort of digoxin + trametinib in BRAF wild-type and NRAS mutant melanoma patients. Clinical trial information: NCT02138292.
Implementation of a screening program for identification of unrecognized inherited marrow failure syndromes.
Authors: Curtis Andrew Lachowiez, Gabrielle Meyers
Journal: Journal of Clinical Oncology (2017)

7055 Background: Inherited marrow failure syndromes (IMFS) are considered diseases of childhood, but testing adults with atypical presentations of diseases associated with IMFS is critical for establishing an optimal treatment protocol. The most common IMFS, Fanconi Anemia and Telomere Biology Diseases, are associated with MDS and aplastic anemia (AA), head and neck cancers, skin, and cervical cancer. Such patients can have profound toxicity with standard chemotherapy regimens. Methods: We implemented a screening protocol in patients at highest risk of an undiagnosed IMFS (MDS under age 60, AA patients under age 65, and head and neck cancers under age 60) with chromosome breakage analysis and telomere length testing. Results: Our protocol diagnosed nine patients (estimated ~10% of patients &lt; age 60 with these diseases) with IMFS. The features of these patients are described in the table. Only three (33%) patients had the classic physical characteristics of IMFS. Three patients were over age 50 when diagnosed with an inherited disorder. Most importantly, in all patients the treatment approach was modified significantly, including minimizing conditioning for BMT, utilizing danazol as first line treatment for AA, as well as aggressive cancer and endocrinopathy screening. Outcomes with modified treatment have been favorable, and occult malignancies were detected through screening in two patients. Conclusions: Inherited marrow failure syndromes are uncommon yet under recognized disorders that significantly impact treatment decisions in addition to implementation of surveillance programs for both the affected individual and their relatives alike. Through this approach of thoughtful screening of patients presenting to our institution with marrow failure we identified an unrecognized IMFS in an estimated 10% of patients. [Table: see text]