bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma cell-free circulating tumor DNA (ctDNA) detection in longitudinally followed glioblastoma patients using TERT promoter mutation-specific droplet digital PCR assays.
Authors: Cordova Christine , Syeda Mahrukh M. , Corless Broderick , Wiggins Jennifer M. , Patel Amie , Kurz Sylvia Christine , Delara Malcolm , Sawaged Zacharia , Utate Minerva , Placantonakis Dimitris , Golfinos John , Schafrick Jessica , Silverman Joshua Seth , Jain Rajan , Snuderl Matija , Zagzag David , Shao Yongzhao , Karlin-Neumann George Alan , Polsky David , Chi Andrew S. 
Published: May 2019

2026 Background: There is a critical need for more specific and less invasive diagnostic and pharmacodynamic biomarkers in glioblastoma (GBM) patients (pts). Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in the ctDNA of IDH wildtype ( IDHwt) TERT promoter mutant GBM pts with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we explored the dynamics and clinical associations of mutant TERT ctDNA levels in GBM pts undergoing therapy. Methods: We examined 14 pts with suspected IDHwt GBM based on preoperative MRI. Plasma was isolated and frozen from ~15 mL whole blood samples collected pre- and post-op, at end of radiation (RT), and 1, 3, and 6 m after end of RT. TERT promoter mutations were identified in FFPE tumor samples using ddPCR assays for C228T/C250T. Plasma samples were analyzed using ddPCR assays specific for the corresponding tumor mutation. The validated thresholds for positive detection were 1.5 (C228T) and 1.7 copies/mL (C250T). Results: 13/14 (92.9%) IDHwt tumors had TERT mutations (7 C228T and 6 C250T). Six of these 13 (46%) pts had positive plasma TERT ctDNA preop (4 C228T, 2 C250T). The mean cross sectional area of enhancing disease at presentation for positive or negative preop mutant ctDNA was similar. All 4 pts with multiple contrast enhancing lesions had positive preop mutant ctDNA. 2 pts who were negative initially developed detectable mutant ctDNA preceding progression. 3/4 pts with equivocal radiographic pseudoprogression had ctDNA dynamics that correlated with eventual clinical outcome. One patient with unresectable GBM had declining mutant ctDNA in later collections during clinical stability. Conclusions: We detected plasma TERT ctDNA in 46% of TERT mutant GBM pts before surgery, and in 100% of pts with multiple contrast enhancing lesions. TERT mutant ctDNA levels correlated with pseudoprogression or true disease progression and predicted progression before MRI. These data suggest that larger studies to test circulating cell-free TERT mutation as a diagnostic and pharmacodynamic biomarker in GBM are warranted.
Clinical characteristics, treatment (Tx) patterns, and overall survival (OS) in advanced (Adv) NSCLC patients (Pts) with and without brain metastases (BM).
Authors: Nash Smyth Emily Nash , Tiu Ramon Velasquez , Willard Melinda D , Beyrer Julie , Zhu Yajun Emily , Bowman Lee , Sheffield Kristin M , Han Yimei , Brastianos Priscilla 
Published: May 2019

2035 Background: BM in NSCLC pts are associated with significant morbidity and mortality. This analysis describes the frequency and timing of BM development, pt characteristics, systemic txs, and OS in NSCLC pts with and without BM. Methods: This retrospective observational study identified pts from the Flatiron-Foundation Medicine NSCLC Clinico-Genomic Database diagnosed from 1 Jan 2011 to 31 Oct 2017 with adv NSCLC and a tumor sample analyzed via FoundationOne. Tx pattern data were summarized by period (1 Jan 2011-1 Mar 2015; 2 Mar 2015-31 Dec 2017), therapy class (eg, anti-VEGF and EGFR, platinum-based), and BM occurrence. Descriptive statistics were used to summarize data; Chi-square and t-tests assessed statistically significant differences. OS was measured by site of met (BM only vs no-BM only vs BM and no-BM) via K-M methods from adv diagnosis until death or last activity date (censored). Results: Of 3257 pts, 1018/3257 (31.3%) had BM during follow-up; 726/1018 (71.3%) presented with BM within 30 days of adv diagnosis. The median age at adv diagnosis was 66.2 yrs. Relative to pts without BM, BM pts were younger, more likely to be female, of Asian descent, have stage IV disease, ≥2 met sites (including BM) at initial presentation, ≥3 met sites (including BM) during follow-up, and non-squamous histology (all p < 0.01). Approximately 78% (n = 2534) were treated with ≥1 systemic tx; platinum-based chemo-combinations were the most common 1st line tx, regardless of BM status. Increased use of PD-1/L1 tx was seen in 1st, 2nd, and 3rdline during the latter vs earlier period. No statistically significant difference in OS was observed in pts with BM only (17.1 mos; 95% CI 12.5-29.9), no-BM only (21 mos; 95% CI 19.4-22.8), or BM and no-BM (20.4 mos; 95% CI 18.9-23.3) (log rank p = 0.3027). Conclusions: In met NSCLC pts with a tumor sample that was molecularly profiled, OS was comparable, regardless of site(s) of disease; additional multivariate analyses including molecular profiles are needed. BM screening at initial diagnosis is important given the frequency in NSCLC. Future studies should assess whether the shift in systemic tx patterns impact the development and clinical outcomes.
Phase II trial of palbociclib in recurrent RB-positive anaplastic oligodendroglioma: A Spanish group for research in neurooncology (GEINO) trial.
Authors: Sepulveda-Sanchez Juan Manuel , Gil Gil Miguel J. , Alonso Miriam , Vaz Salgado María Ángeles , Vicente Elena , Mesia Barroso Carlos , Rodriguez Sanchez Angel , Durán Gema , De Las Penas Ramon , Muñoz-Langa José , de Velasco Guillermo , Hernandez-Lain Aurelio , Hilario Amaya , Navarro L Miguel , Benavides Manuel , Oleaga Laura , Cantero Diana , Ruano Yolanda , Sanchez-Gomez Pilar , Pineda Estela 
Published: May 2019

2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.
The timing of chemoradiotherapy after surgical resection and its impact on overall survival in glioblastoma.
Authors: Press Robert H. , Shafer Sarah L. , Jiang Renjian , Buchwald Zachary S. , Abugideiri Mustafa , Tian Sibo , Morgan Tiffany , Behera Madhusmita , Sengupta Soma , Voloschin Alfredo Daniel , Olson Jeffrey J. , Curran Walter John , Eaton Bree Ruppert , Shu Hui-Kuo George , Zhong Jim 
Published: May 2019

2051 Background: Prior studies examining time to initiate chemoradiotherapy (CRT) after surgical resection (S) in glioblastoma (GBM) have not provided clear consensus on its clinical impact. We sought to evaluate the effect that differential timing of adjuvant therapy may have on overall survival (OS). Methods: With the National Cancer Database (NCDB), patients (pts) with GBM who underwent S and adjuvant CRT from 2004-2013 were analyzed. Analysis was performed for the entire cohort as well as by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classes (i.e. I, II, and III). Time from S to CRT was grouped weekly (i.e. 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, and > 8 weeks). Pts were excluded if they died within the first 8 weeks to account for immortal time bias. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed with OS as the primary outcome. Results: A total of 30,414 pts were included for analysis. RPA class I, II, and III contained 903, 4,347, and 25,164 pts, respectively. The most common time to initiate CRT was week 4-5 (n = 7389), and this group served as reference for survival analysis. On MVA, weeks 0-1 (hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.02-1.35), 1-2 (HR 1.24, CI 1.17-1.32), and 2-3 (HR 1.11, CI 1.07-1.15) demonstrated worse OS (all p < 0.03). For RPA class I pts, week 1-2 (HR 2.07, CI 1.08-3.95) was associated with worse OS (p = 0.028). For RPA class II pts, weeks 1-2 (HR 1.34, CI 1.14-1.57), 2-3 (HR 1.18, CI 1.07-1.31), and 3-4 (HR 1.10, CI 1.0-1.21) were associated with worse OS (all p < 0.05). For RPA class III pts, weeks 0-1 (HR 1.18, CI 1.02-1.38), 1-2 (HR 1.22, CI 1.14-1.3), and 2-3 (HR 1.09, CI 1.05-1.14) were associated with worse OS (all p < 0.03). No time point after week 5 was associated with change in OS for the overall cohort or any RPA class subgroup. Conclusions: These data provide insight into the optimal timing of CRT in GBM and describe RPA-class specific outcomes. In general, OS was negatively impacted if CRT started less than 3 weeks from S. Waiting up to 8 weeks, however, was not detrimental to OS and suggests delaying CRT beyond week 4-5 should be considered if clinically indicated without undue concern.
Efficacy of re-irradiation with carbon ions (RiCi) in patients with recurrent high-grade glioma (rHGG) compared to the standard re-irradiation with photons (RiP): The reference multicenter cohort of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Knoll Maximilian , Waltenberger Maria , Bougatf Nina , Bernhardt Denise , Adeberg Sebastian , Budach Volker , Baumann Michael , Stuschke Martin , Fokas Emmanouil , Grosu Anca , Zips Daniel , Belka Claus , Combs Stephanie E , von Deimling Andreas , Bendszus Martin , Wick Wolfgang , Unterberg Andreas , Rieken Stefan , Debus Juergen , Abdollahi Amir 
Published: May 2019

2057 Background: Local recurrence after surgery and radio(chemo)therapy remains a major obstacle in curative treatment of patients with HGG. Eradication of radioresistant glioma subpopulations (hypoxic- and stem cell like cells) together with formation of an antiangiogenic and immuno-permissive glioma niche are among beneficial radiobiological effects recently attributed to carbon ion irradiation in preclinical models. The impact of this novel therapy in management of rHGG patients remains elusive. Methods: 197 patients with rHGG (grade III: 71, IV: 126) received RiCi between Nov 2009 and Feb 2018 at HIT with a median dose of 42GyRBE in 14 fractions. In DKTK-ROG multicenter cohort n:565 rHGG patients (grade III: 63, IV: 479) underwent RiP between 1997-2016 with a median dose of 36 Gy in 14 fractions. Median follow up was 34.2 months (M) for RiCi and 7.1 M for RiP (DKTK) cohort. All three prognostic scores validated in DKTK-ROG cohort were evaluated and re-irradiation risk score (RRRS) considering initial grade, Karnofsky Performance Score and age at re-irradiation was utilized for stratification and matched comparisons. Results: Median PFS was 5.08 [4.26-5.87] M (grade III: 6.79, grade IV: 3.64) after RiCi, data was not available for RiP. Median OS was 10.52 [9.28-12.66] M (grade III: 28.2, grade IV: 8.53) after RiCi compared to 7.93 [7.15-8.79] M (grade III: 10.89, grade IV: 7.93) after RiP. Among the three prognostic scores evaluated, RRRS most robustly correlated with OS. RiCi was associated with HR of 0.52 ([0.49-0.72], p = 0.0000002), and HR 0.66 ([0.51-0.85], p = 0.001) for RRRS matched analysis. Conclusions: Carbon ions demonstrated activity in rHGG. This effect is most prominent in grade III while grade IV patients may further benefit from innovative multimodal strategies. Based on these encouraging results prospective randomized trials utilizing RRRS for stratification are recommended.
Functional profile and clinical significance of major tumor infiltrating lymphocyte subsets in lung cancer-associated brain metastases.
Authors: Lu Benjamin Y. , Gupta Richa , Stewart Tyler , Kluger Harriet M. , Jilaveanu Lucia , Schalper Kurt A. , Goldberg Sarah B. 
Published: May 2019

2066 Background: Despite the biological and clinical implications, the immune composition and functional characteristics of adaptive immune cells in brain metastases (BrM) are poorly understood. Using multiplexed quantitative immunofluorescence (QIF), this study evaluates the level and functional profile of major T-cell subsets in primary lung tumors, BrM, and extracranial metastases (ECM) from lung cancers. Methods: A tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor samples of 94 lung cancer patients treated at Yale Cancer Center between 2002-2013. Multiplexed QIF was used to evaluate the cases with a panel containing phenotype markers for major T-cell subsets (CD3, CD4, CD8 and FOXP3), and cell-localized activation and proliferation (granzyme-B and Ki-67). Signal for each marker was measured in marker-selected tissue compartments using the Automated Quantitative Analysis (AQUA) platform. Associations between markers and major clinicopathologic variables were studied. Results: In total, 40 primary lung tumors, 63 BrM, and 15 ECM were analyzed, including paired samples from 22 patients. Lung cancer histology included adenocarcinoma 62.5%, squamous cell carcinoma 11.5%, small cell 9.4%, and other non-small cell 16.7%. BrM had both significantly lower levels of CD3+ T-cells ( p< 0.0001) and T-cell granzyme B ( p= 0.0188) compared with primary lung tumors. No significant differences were observed in T-cell Ki-67 levels across tissues. FOXP3 measured in CD4+ T-cells were significantly lower in BrM compared with primary malignancies ( p= 0.0002) and ECM ( p= 0.0404). Among patients with BrM, higher levels of CD3+ T-cells in BrM were associated with longer overall survival. Conclusions: Lung cancer-associated BrM have lower T-cell infiltration, cytolytic function, and regulatory T-cells than primary lesions. These results indicate lower adaptive anti-tumor responses in BrM and suggest the presence of a tolerogenic microenvironment in the brain. Overcoming this could be used to design optimal treatment strategies.
Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers.
Authors: Luke Jason J. , Powderly John D. , Merchan Jaime R. , Barve Minal A. , Hotson Andrew N. , Mobasher Mehrdad , Kwei Long , Luciano Gabriel , Buggy Joseph J. , Piccione Emily , Miller Richard A. 
Published: May 2019

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.
Targeting MHC-linked wild type p53 with TCR mimic single chain diabody for cancer immunotherapy.
Authors: Paul Suman , Douglass Jacqueline , Schaefer Annika , Hsiue Emily Han-Chung , Pearlman Alexander , Mog Brian , Hwang Michael , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Zhou Shibin 
Published: May 2019

2524 Background: Increased tumor suppressor protein p53 expression is observed in a wide range of human cancers. As a result there is intense interest in targeting p53 for cancer therapy. Intracellular p53 is inaccessible to therapeutic antibodies that bind cell surface proteins. However, intracellular proteins including p53 are degraded into peptides that are presented on cell surface in association with HLA class I molecules. Thus p53 peptide-HLA (p53-HLA) complexes can be antibody targets. Methods: Using phage display we identified a novel anti-p53-HLA single chain variable fragment (scFv) clone-43 that recognizes a wild-type p53 10-mer epitope bound to HLA-A*2402. By coupling our clone-43 scFv with an anti-CD3 scFv, we generated a single chain diabody (scDb) designed to activate T-cells against p53-expressing target cells. Results: In-vitro co-culture of clone-43 scDb with donor human T-cells and p53 expressing SIG-M5 cancer cells results in SIG-M5 cell killing and concomitant T-cell interferon gamma (IFNγ) release. In contrast, similar co-culture with SIG-M5 p53-knock out (KO) cells showed no cell killing and minimal IFNγ release demonstrating specificity of clone-43 to p53 expressing cells. Additionally, in-vivo growth of p53 expressing SW480 cancer cell xenografts in NSG mice was completely terminated by clone-43 scDb injections. A major concern for wild-type p53 epitope targeting is potential on-target off-tumor effect on non-cancerous tissue. We observed significant in-vitro clone-43 scDb mediated killing of human HLA-A*24:02 peripheral blood mononuclear cells. To better evaluate effect of clone-43 scDb on non-neoplastic human cells, we engrafted HLA-A*24:02 human CD34+ hematopoietic stem cells into NSG mice to generate a humanized mouse model with circulating mature human CD45+ cells. Clone-43 scDb treatment resulted in selective depletion of circulating human cells while the same cells persisted in mice treated with unrelated control scDb. Conclusions: Our observation that immune targeting of wild-type p53 epitope results in significant off-tumor hematopoietic cell death is contrary to previously published reports and carries important implications for future anti-p53 antibody and vaccine design for cancer immunotherapy.
Phase 1a/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors.
Authors: Sachdev Jasgit C. , Bauer Todd Michael , Chawla Sant P. , Pant Shubham , Patnaik Amita , Wainberg Zev A. , Inamdar Sandeep P. , Marina Neyssa , Sun Stefanie , Schmidt Maike , Xiang Hong , LoRusso Patricia 
Published: May 2019

2529 Background: B7-H4, a transmembrane protein of the B7 family, is a negative regulator of T cell function, expressed at high levels on several cancers, including approximately 50% of breast, ovarian and endometrial cancers. FPA150 is a fully human antibody against B7-H4 that blocks inhibition of T cell activity and has enhanced antibody-dependent cell-mediated cytotoxicity. It is the first therapeutic molecule targeting B7-H4 to enter the clinic. We report preliminary results from an ongoing phase 1a/1b study of FPA150 in advanced solid tumors. Methods: Phase 1a included dose escalation in which B7-H4-unselected patients with advanced solid tumors were treated with FPA150 at doses between 0.01 to 20 mg/kg every three weeks (Q3W) in an accelerated titration followed by 3+3 design and a separate dose exploration cohort in which B7-H4+ (H-score≥100) patients were treated at doses of 3 or 10 mg/kg Q3W with mandatory pre- and on-treatment biopsies. Results: As of 12/31/2018, 24 patients with a median of 3 prior therapies were treated with FPA150, 6 of whom were in the B7-H4+ dose exploration cohort. Seven patients from dose escalation were also retrospectively identified as B7-H4+. Most patients received FPA150 at 3 mg/kg (n=8) or 10 mg/kg (n=6). Median number of doses was 3 (range 1-11). No dose-limiting toxicities or treatment-related serious adverse events were reported, and there were no treatment-related AEs (TRAEs) leading to discontinuation of FPA150. Most TRAEs were Grade 1-2, with diarrhea and fatigue most common (16.7%). Grade 3 TRAE hypertension occurred in 1 patient. FPA150 displayed approximately dose-proportional exposure at doses ≥0.3 mg/kg with half-life of 1-2 weeks. Conclusions: FPA150 monotherapy demonstrated a favorable safety profile and evaluation of anti-tumor activity is ongoing. 20 mg/kg Q3W was selected as the recommended dose. Phase 1b enrollment of FPA150 monotherapy in patients with B7-H4+ breast, ovarian and endometrial cancer began in February 2019. We will present updated safety, PK, and preliminary biomarker and efficacy data. Clinical trial information: NCT03514121.