bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes in patients with melanoma brain metastases at a tertiary cancer center.
Authors: Phillips William J , Lo Bryan , Ong Michael , Smith Tyler , Song Xinni 
Published: May 2019

e13586 Background: Brain metastases are observed in more than 40% of all patients with stage IV melanoma. In recent years, more extensive use of stereotactic radiation (STRT) and the advent of immune checkpoint inhibitors and BRAF targeted therapies have positively impacted outcomes in patients with metastatic melanoma (MBM) In this study, we examined real-world clinical outcomes of patients presented with melanoma brain metastases (MBM). Methods: This retrospective review evaluated MBM patients treated at the Ottawa Hospital. Clinical, radiologic, and pathologic variables were collected from the electronic medical records from January 2000 to June 2018. Results: A total of 277 patients fulfilled the inclusion criteria. Median overall survival was 4 months. LDH was the only significant prognostic factor in this study. Over 65% of brain metastases were detected due to the presence of neurological symptoms, while surveillance and restaging identified asymptomatic brain metastases in the remaining patients. Detection by neurological symptoms was related to larger (p < 0.001) and haemorrhagic (p = 0.032) intra-cranial lesions as well as decreased overall survival (HR = 1.2, p = 0.018). With regards to locoregional treatment STRT radiation outperformed WBRT alone in patients with single and oligo (2-6 lesions) brain lesions (HR = 0.149, p = 0.001 for oligo; HR = 0.149, p = 0.003 for single) and was associated with approximately a 3-fold increase in median survival. STRT was used 2-fold less frequently in patients with more than one lesion (54.8% in single; 31.7% in oligo). In patients receiving systemic therapy, immunotherapy is the only modality demonstrated overall survival benefit compared to no systemic treatment (HR = 0.511, p = 0.014). Furthermore, patients receiving STRT in combination with immunotherapy outperformed patients receiving STRT with WBRT (HR = 0.389, p = 0.009). Conclusions: Results from this study support the consideration of routine screening of high-risk asymptomatic patients, the increased use of STRT in patients with multiple intra-cranial lesions. The efficacy of immunotherapy in patients with MBM is consistent with current clinical trial data.
Cytopenia following axicabtagene ciloleucel (axi-cel) for refractory large B-cell lymphoma (LBCL).
Authors: Logue Jennifer Marilyn , Krivenko Gabriel S , Larson Victoria , Bachmeier Christina A , Chavez Julio C. , Davila Marco L. , Khimani Farhad , Lazaryan Aleksandr , Liu Hien D , Pinilla-Ibarz Javier , Shah Bijal D. , Dholaria Bhagirathbhai R. , Jain Michael D. , Locke Frederick Lundry 
Published: May 2019

e14019 Background: Axi-cel is an anti-CD19 CAR T-cell therapy that can lead to long term disease control for patients with refractory LBCL including DLBCL, PMBCL, HGBL, and tFL. Beyond day 30, grade 3 or higher cytopenias were reported in 17% of patients (Locke 2019). We sought to further characterize cytopenias after axi-cel. Methods: We evaluated patients with LBCL treated with axi-cel at Moffitt from May 2015 to May 2018. Counts at apheresis and days 30, 90 and 180 after axi-cel infusion were recorded. Data was censored at date of progression, death or last follow-up. AEs were per CTCAE v4.03. Results: 52 patients were identified. Count data at each time is presented in the table. In total, 37.8% (17/45), 17.8% (8/45), and 28.9% (13/45) of patients experienced any grade 3-4 neutropenia, anemia or thrombocytopenia beyond day 30. Beyond day 30: 24.4% (11/45) received G-CSF; one (2.2%) received a TPO-agonist; none received an EPO-agonist; 15.6% (7/45) IVIG; 11.1% (5/45) PRBC; and 8.9% (4/45) platelet transfusion. 11 patients had bone marrow biopsies to evaluate cytopenias, at a median of 50 days (range 29-434) following axi-cel infusion. Median cellularity was 16.3% (range 5-45%), and 3/11 had reticulin staining indicating fibrosis. One patient, previously reported (Locke, Mol. Ther, 2017), had therapy related MDS and evidence of prior CHIP mutation. Conclusions: Prolonged neutropenia, lymphopenia, anemia, and thrombocytopenia occurred at least 180 days following axi-cel therapy in LBCL patients, in the absence of disease progression. Transfusion burden was low, and most patients recovered without an intervention.[Table: see text]
Correlation between circulating cell-free RNA biomarkers and response during combination immunotherapy in previously refractory metastatic TNBC patients.
Authors: Garner Chad , Seery Tara Elisabeth , Nangia Chaitali Singh , Lee John H. , Huang Liyang , Sender Leonard S. , Rabizadeh Shahrooz , Soon-Shiong Patrick 
Published: May 2019

e14027 Background: A commercial liquid biopsy test was included as an exploratory component of an integrated immunotherapy clinical trial in previously refractory metastatic TNBC patients, combining innate, high-affinity natural killer cell (haNK) therapy with adenoviral and yeast-based vaccines and an IL-15 superagonist (NCT 03387085). The purpose of the study was to assess the utility of cell-free circulating RNA (cfRNA) as a predictor of treatment response. Methods: Blood was drawn from trial participants at baseline and at 2-6 week intervals throughout the treatment protocol. cfRNA and cfDNA were extracted from plasma and tested for analytes by quantitative PCR (qPCR) in a CLIA and CAP certified laboratory. This study is based on the analysis of 18 the cfRNA analytes (AR, PD-L1, CTLA-4, LAG-3, EGFR, HER2, ERCC1, TIM-3, MGMT, RRM1, SLC29A1, TOP1, TOP2A, TOP2B, TUBB3, TYMP, TYMS, XRCC1) in six patients that had at least three testing time points; new patient recruitment and serial testing are ongoing. The relative expression of each RNA analyte was normalized by beta-actin. Tumor size was evaluated by imaging using the RECIST criteria. Results: The amount and variability of cfRNA was positively correlated with the tumor size. As cfRNA quantity and variability increased or decreased, a corresponding increase or decrease in tumor size was observed, respectively. Not all 18 genes showed consistent patterns of change across the six patients, however the average expression and variability of the 18 genes showed evidence of a correlation with tumor size change from baseline (p-values = 0.08 and 0.03, respectively). Only trace levels of PD-L1 expression were observed in all 6 patients at baseline, prior to the initiation of the combination immunotherapy. Among the 5 patients that showed a reduction in tumor size of at least 10%, 4 also showed an associated increase in cfRNA PD-L1 expression from nearly 0 to normalized values between 2.1 and 6.8. Conclusions: Exploratory analysis in an ongoing combination immunotherapy clinical trial for TNBC showed that increasing and decreasing cfRNA levels are correlated with increasing and decreasing tumor size, respectively. Increased PD-L1 cfRNA levels are correlated with beneficial treatment response. Liquid biopsy of cfRNA could provide an effective biomarker of treatment response. Clinical trial information: NCT03387085.
Circulating tumor cell (CTC) PD-L1 and interferon regulatory factor-1 (IRF-1) expression as biomarkers of anti-PD-(L)1 response.
Authors: Kennedy Laura , Ramirez Arturo B. , U'Ren Lance , Sun Yao , Durenberger Grace , Chow Laura Quan Man , Grivas Petros , Gadi Vijayakrishna K. 
Published: May 2019

e14032 Background: Anti-PD-(L)1 checkpoint inhibitors (CPI) are remarkable due to durable responses, tolerability, and improvements in survival across multiple solid tumors. Unfortunately, CPI produce objective responses in only a small subset of solid tumors patients (pts). We hypothesized that PD-L1 and IRF-1 expression on CTC may correlate with CPI response, and evaluate their expression in this pilot study. Methods: Pts with metastatic solid tumors initiating anti-PD(L)-1 mono- or combination therapy were eligible. Pts had 7.5 cc of blood drawn for CTC evaluation at 3 timepoints: baseline, after 1 CPI dose, and 3-6 months after starting CPI or at time of CPI discontinuation. Peripheral blood CTC were isolated with the AccuCyte kit and stained for CK/EpCAM, anti-CD45, nuclear dye, PD-L1, and IRF-1. CTCs were then identified with CyteFinder software. Results: 16 pts have enrolled to date with median age 71 years (range 28-83) and median ECOG = 1 (range 0-3). 50% were female. Diagnoses include NSCLC (50%), head and neck cancer (13%), breast cancer (13%), and others (24%). CTC were identified at baseline in 13/16 pts (# CTCs range 0-101). 12 pts with baseline CTC have had restaging scans since starting CPI. By RECIST 1.1, 3 pts had partial response (PR), 1 had stable disease (SD), and 8 had progressive disease (PD). The pts with PR more frequently had IRF-1 staining on baseline CTC (Table), and 1/3 had PD-L1 staining. 6 pts had tumor PD-L1 staining available for correlation, and 3/6 of those pts were PD-L1+ (tissue PD-L1 ≥ 1%). 1/3 pts with PD-L1+ tumor staining had CTCs that were PD-L1+. In the 3 pts with negative PD-L1 tumor staining, 1 pt had a mixed PD-L1+/PD-L1- CTC population and the others had no PD-L1 staining. Conclusions: CTC isolation and enumeration seem feasible across tumor types. Pts with PR to anti-PD-(L)1/ might have higher prevalence of IRF-1+ CTC; however, results are preliminary and more pts and samples are being evaluated. [Table: see text]
Expression of soluble DC-HIL/gpnmb receptor in the blood of metastatic non-small cell lung carcinoma treated with anti-PD1/PDL1 monoclonal antibodies.
Authors: Chung Jin-Sung , Ramani Vijay , Kobayashi Masato , Popat Vinita , Cruz Ponciano D , Gerber David E. , Ariizumi Kiyoshi 
Published: May 2019

e14038 Background: Anti-PD1/PDL1 therapy benefits only a minority (10-20%) of treated NSCLC. Identifying markers distinguishing responders vs. non-responders will improve management of NSCLC. DC-HIL receptor is a new checkpoint whose inhibitory mechanisms are divergent from the PD1 pathway. Tumor cells express DC-HIL receptor and its soluble form (sDC-HIL). We tested whether sDC-HIL expression regulates NSCLC response to anti-PD1/PDL1 Ab using animal models and human clinical samples. Methods: Tet-Off controlled sDC-HIL-transfected LL2 lung cancer cells were i.v. injected into mice (lung mets) and treated with doxycycline (Dox). Day 6, mice were sorted into 2 groups with/without Dox and treated with i.p. 200 μg Ab, every 2 d /6 shots. Day 18, # of lung-LL2 cells were counted by FACS and IFN-γ+ T cells in tumors analyzed. Advanced NSCLC patients (n = 51) treated with immune checkpoint inhibitors were every 6 weeks evaluated for partial response (PR), stable (SD) and progressive disease (PD) by RECIST. Serum were collected on weeks 0, 2, and 6 and assayed for sDC-HIL amounts by ELISA. Results: In mice treated with Dox (halt sDC-HIL expression), anti-PDL1 Ab treatment markedly reduced lung mets and increased IFN-γ+ T cells (p < 0.001), whereas this excellent outcome was not noted in Dox-untreated mice (induce sDC-HIL). For NSCLC, PD1/PDL1 therapy produced PR (n = 3), SD (n = 25) and PD (n = 23) at week 6. sDC-HIL blood levels at week 0 did not correlate with tumor size, but the levels at week 6 of PD patients were significantly higher than PR/SD patients (8.4 ± 5.6 vs. 4.0 ± 1.6 ng/ml, p = 0.001, Mann-Whitney test) and healthy donors (2.6 ± 0.9 ng/ml). Most patients (26 out of 30 cases) showed fluctuation in sDC-HIL levels during treatment. PD-patients (14/15 cases) showed increasing or persistently elevated levels ( > 4 ng/ml), with one case at low levels ( < 4 ng/ml). SD/PR-patients (13/15) had decreasing or persistently low levels, with 2 exceptions with high levels in all time points. Conclusions: sDC-HIL blood level may serve as a biomarker to indicate tumor-resistance of advanced NSCLC patients to PD1/PDL1 therapy. The degree and direction of sDC-HIL fluctuation may be useful to predict prognosis for NSCLC.
Correlation of response to stereotactic radiotherapy and immunotherapy with toxicity and predictions by differences in Treg population.
Authors: Reinwald Simone , Ratnayake Gishan , Yu Di , Ward Rachel , Smith Robin , Haydon Andrew , Van Zelm Menno , Senthi Sashendra 
Published: May 2019

e14039 Background: Combining stereotactic ablative radiotherapy (SABR) and anti-PD1 therapy may result in synergism but the response and toxicity rates has not been established. Biomarkers to predict clinical outcomes in this setting could improve patient selection, informed consent and cost-effectiveness. Here, we report exploratory analyses from Phase I clinical trial. Methods: Metastatic melanoma patients with at least two metastases received SABR to a single metastatic site and standard dose immunotherapy with anti-PD1 and/or anti-CTLA4 therapy. Peripheral blood mononuclear cells (PBMC) were collected prior to each immunotherapy cycle and analysed with 17-color flow cytometry to quantify CD4+ and CD8+ T cell subsets as potential biomarkers for response and toxicity. RECIST v1.1 at six months dichotomized responders (stable disease or any response) from non-responders (progressive disease). The presence of CTCAE v4 defined grade 3 or higher toxicity within six months dichotomized those with and without significant toxicity. Mann-Whitney tests were used to assess differences in biomarkers between response and toxicity groups. The Phi Coefficient (pr) was used to correlate these groups. Results: Sixteen of 25 patients had bloods available for testing. There were 11 responders (5 non-responders) and three with significant toxicity (13 without). At 12 months all responders were still alive, while all non-responders had died. Response significantly correlated with developing toxicity (pr = 0.869, p = 0.027). Prior to treatment, responders had a significantly higher percentage of total regulatory T cells (Tregs; CD4+CD25+CD127-) compared to non-responders (p = 0.011). After SABR and four cycles of immunotherapy, Treg frequencies had significantly changed (p = 0.046), with decreases in most responders and increase in all non-responders. Other CD4+ and CD8+ did not correlate with response or toxicity. Conclusions: Patients developing significant toxicities appear more likely to respond, reinforcing the importance of aggressively managing toxicities rather than ceasing treatment. Patients with higher pre-treatment Treg population and decreasing levels with treatment were significantly more likely to respond to SABR and immunotherapy. Clinical trial information: ACTRN12616001064493.
TCR repertoire analysis from peripheral blood for prognostic assessment of patients during treatment.
Authors: Vodala Sadanand , Nguyen Andrew , Rodriguez Noe , Sieling Peter , Vaske Charles Joseph , Lew Jon Van , Niazi Kayvan , Lee John H. , Soon-Shiong Patrick , Rabizadeh Shahrooz 
Published: May 2019

e14040 Background: Immune checkpoint inhibitors offer substantial clinical advantage to a subset of patients but predictive/novel prognostic indicators are still scarce. T cell receptors (TCRs) play a crucial role in adaptive immunity and anti-tumor immune responses. Net diversity of TCR repertoires are altered in patients receiving immune checkpoint inhibitors. To study the prognostic significance of T cell repertoires as a biomarker of immune responses in cancer patients, we characterized TCR repertoires from peripheral blood using high throughput sequencing. Methods: Total RNA from peripheral blood mononuclear cells (PBMCs) was extracted and used to generate sequencing libraries from five pancreatic cancer patients, four triple negative breast cancer (TNBC) patients and two squamous cell carcinoma (SCC+) patients. Blood draws were collected pre- and post-treatment and target lesion analysis was performed using immune-related response criteria (irRC) and Recist1.1. TCR alpha and beta CDR3s were clonotyped for each sample, and profiles of clonotype proportions were tracked through time/serial biopsies. Additionally the Shannon-Wiener diversity metric was calculated for each time point. Results: Patient samples showing consistent positive responses as measured by irRC and Recist1.1 showed TCR clones persisting throughout all time points. A TNBC super responder showed dramatic increases in mean Shannon-Wiener index from 74 prior treatment to 1177 at first biopsy post treatment (34% decrease by irRC and 26% by Recist1.1 analysis) and achieved an index as high as 3516 in a subsequent biopsy (83% and 64% decrease by irRC and Recist 1.1 respectively). Patients that showed poor response by irRC and Recist1.1 showed TCR clones that were in constant flux. Loss of clonality and/or decrease in absolute numbers was observed in previous and later time points. Conclusions: Patients that show positive response had TCR clones that were stable, which may indicate an existing immune related response towards their tumor. Therapy would allow these existing T-cells to overcome blockade by tumor cells. Patients showing poor response show a TCR repertoire that is constantly changing potentially indicating that the tumor cells are not eliciting a strong T cell specific response. Further functional studies of T cell populations would expand our understanding of T cell based immune therapies.
Plasma biomarkers to predict pembrolizumab response in HCC patients.
Authors: Feun Lynn G. , Li Ying-Ying , Wu Chunjing , Wangpaichitr Medhi , Jones Patricia Denise , Kwon Deukwoo , Hosein Peter Joel , Savaraj Niramol 
Published: May 2019

e14043 Background: Pembrolizumab (PEM) has been approved as second line therapy for the treatment of hepatocellular carcinoma (HCC). We conducted a single institution investigator-initiated clinical/biomarkers trial to assess potential biomarkers to predict response in unresectable HCC patients (pts) receiving PEM. Methods: PEM was administered at 200mg iv. every 3 weeks for advanced HCC pts who progressed on, were intolerant of, or refused sorafenib. The circulating levels of cytokines/chemokines included IL-1β, IL-6, IL-8, IL-12, IL-18, IFN-γ, TGF-β, IL-10, CXCL9, CCL4, CCL5, as well as PD-1, PD-L1, PD-L2 were measured by ELISA at baselines and at day 60-90. PD-L1 expression in tumor was also assessed by histopathological staining. Results: 29 pts have been treated and 28 were evaluated for response. One pt had complete response, 8 had partial response and 4 had stable disease. Among all the biomarkers tested, only TGF-β at baseline predict response. The mean of plasma TGF-β in responders were 141.9pg/ml vs. 1071.8pg/ml in nonresponders. The cut-off values was determined based on the near medians. The plasma concentration of TGF-β of ≥200pg/ml was an index for nonresponder (P = 0.003). Kaplan-Meier analysis showed that the median overall survival (OS) and progression-free survival (PFS) in pts with TGF-β ≥200pg/ml were 7 months and 2 months, respectively, while in pts with TGF-β < 200 pg/ml, the OS and PFS were over 25 months(P = 0.005 and P = 0.008, respectively). Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1/PD-L-1 (P < 0.05). Since tumor PD-L1 expression is upregulated by IFN-γ, and IL-10, and interacts with PD-1 to suppress T cell, to confirm these relationships, the linear regression was used to analyze the data. Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1 and PD-L1 levels ( P < 0.05). Nine of these 24 patients had tumor available for PD-L1 scoring (PD-L1-positive:3 pts and PD-L1-negative:6pts). Similar to plasma PD-L1 concentration, pts with positive tumor PD-L1 had high levels of plasma IFN-γ or IL-10 ( P < 0.05). Conclusions: Our study confirmed that PEM is active in HCC and TGF-β is a predictive markers for tumor response, PFS, and OS. Support by grant from Merck
Real-time monitoring of circulating stromal cells in the blood to predict responsiveness of new-line therapies in metastatic breast cancer.
Authors: Adams Daniel , Alpaugh R Katherine , Martin Stuart S , Lapidus Rena G. , Chumsri Saranya , Tang Cha-Mei , Williams William , Lacher Markus , Cristofanilli Massimo 
Published: May 2019

e14048 Background: Cancer associated macrophage like cells (CAMLs), a circulating stromal cell subtype, has been shown as an independent prognostic indicator of survival in late stage metastatic breast cancer when cells enlarge to ≥50µm. However, no study has evaluated the clinical relationship between changes in CAML size and their ability to predict treatment response. While CAMLs are prognostic for progression, we hypothesized that monitoring changes in CAMLs after initiation of therapy may be predictive for responsiveness of new treatment regimens. Methods: A prospective 12 months blind multi-institutional pilot study was undertaken to evaluate CAMLs before, and after, induction of a new line of investigational therapy based on CT scans. Patients with progressive metastatic breast cancer (n = 29) who had failed at least 2 prior therapies were recruited. A baseline (BL) blood sample was taken prior to induction of a new therapy and a 2nd sample (T1) taken after initiation (~30 days). Blood was filtered by CellSieve filtration.The quantities and sizes of CAMLs were analyzed based on PFS hazard ratios (HRs) by censored univariate analysis. Results: CAMLs were found in 97% of BL samples and 93% of T1 samples. At first CT scan, after the assigned dose of investigational treatment, 17 of 29 patients had clinical progression with 14/17 (82%) patients having an increased CAML size and 3/17 (18%) having a decreased CAML size. The remaining 12 of 29 patients saw clinically stable, or regression, of disease with 10/12 (83%) having decreased CAML size and 2/12 (17%) having increased CAML size. Overall CAML size change after therapy induction was 83% accurate at predicting response or progression based on CT scans. Further, patients with increasing CAML size at T1 had a 4 month mPFS vs 10 month mPFS for decreasing CAMLs, with a lower 12 month PFS HR = 3.7 (95%CI = 1.5-10.1, p = 0.020). Conclusions: Our data suggests that in metastatic breast cancer, monitoring CAMLs changes over the first 30 days of treatment accurately predicts responsiveness of disease to new treatments. Further, we suggests using blood sampling may increase the clinical value of blood based diagnostics by rapidly predicting the benefit of subsequent therapies.