bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of next-generation sequencing (NGS) in patients with high grade glioma.
Authors: Kewan Tariq Zuheir , Covut Fahrettin , Thapa Bicky , Spiro Timothy Peter , Haddad Abdo S. , Daw Hamed 
Published: May 2019

e13541 Background: Clinical utility of NGS in high grade glioma patients remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 7/2013 and 10/2018 after high-grade glioma diagnosis at Cleveland Clinic. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by log-rank test. Cox regression analysis was performed to identify predictors of OS. Results: We identified 153 patients, 130 (85%) had glioblastoma multiforme (GBM) and 23 (15%) had grade III glioma, 51 (33%) were female, and median age at diagnosis was 58 (range: 18 – 92). Sixteen (10%) patients had secondary glioma and 34 (22%) had multilobar involvement. ECOG performance score at diagnosis was 0 or 1, 2, and ≥ 3 for 79 (52%), 54 (35%), and 13 (9%) patients, respectively. Glioma was surgically resected for 112 (73%) patients, 85 (56%) had total and 27 (18%) had subtotal resection, whereas other 41 (27%) patients underwent biopsy only. Radiotherapy, temozolomide, and bevacizumab were given to 132 (86%), 129 (84%), and 67 (44%) patients, respectively. NGS revealed median of 5 mutated genes (range: 0 – 19), commonly mutated genes were TERT (63%), CDKN2AB (60%), EGFR (42%), TP53 (42%), PTEN (38%), and IDH1/2 (20%). Two patients received bevacizumab for KDR amplification, 1 received off-label lapatinib for EGFR amplification, and 3 received off-label everolimus for multiple mutations. Median follow-up was 18 months. Three-year OS and PFS for patients with GBM vs grade III glioma were 29% (95% CI: 22 – 39) vs 78% (95% CI: 63 – 97) and 17% (95% CI: 11 – 25) vs 74% (95% CI: 58 – 94), respectively (p < 0.0001 for both). On univariable analysis, each 10 increase in age, ECOG ≥3 vs < 3, grade IV vs III glioma, surgical resection vs biopsy, radiotherapy, temozolomide, bevacizumab, and IDH / TP53 / EGFR / TERT / PTEN / CDKN2AB / ATRX mutations predicted OS (p < 0.01 for all). On multivariable analysis, ECOG ≥3 vs < 3, grade IV vs III glioma, surgical resection vs biopsy, temozolomide, bevacizumab, PTEN and CDKN2AB mutations have remained to predict OS (p < 0.01 for all). Conclusions: In our cohort, NGS results provided additional prognostic value, however led to change in the management for only 4% of patients with high-grade glioma.
Multi-parametric MRI as supplement to mRANO criteria for response assessment to MDNA55 in adults with recurrent or progressive glioblastoma.
Authors: Roettger Diana , Shaikh Faiq , Bisdas Sotirios , Bexon Martin , Coello Melissa , Merchant Fahar , Merchant Nina 
Published: May 2019

e13559 Background: Modified response assessment in neuro-oncology (mRANO) criteria are widely used in GBM but seem insufficient to capture Pseudoprogression (PsP), which occurs due to extensive inflammatory infiltration, increased vascular permeability, tumor necrosis and edema. mRANO criteria recommend volumetric response evaluation using contrast-enhanced T1 subtraction maps for identifying PsP. Our approach incorporates multi-parametric MRI biomarkers to unravel the true PsP from recurrence or distinguish Pseudo Response (PsR) - following anti-VEGF agents - from delayed (immuno)response. Methods: Multiple time-points MRI (18-24h after convection-enhance delivery of the anti-IL4-R agent MDNA55, then at 30-day intervals) was utilized to determine response. Multi-parametric MRI biomarkers analyzed included (1) 3D-FLAIR-T2-based tumor volume assessment reflecting edema, necrosis and tumor infiltration; (2) 3D-gadolinium-enhanced-based tumor volume estimation reflecting active tumor infiltration, neo-angiogenesis and disrupted blood brain barrier; (3) Dynamic susceptibility contrast-based relative cerebral blood volume (rCBV) measurements for estimation of the vascular tumour properties; and (4) Diffusion weighted imaging – Apparent diffusion coefficient measurements that assess interstitial edema, tumor cellularity and ischemic injury. Results: We demonstrate similar imaging phenotypes on conventional FLAIR-T2- and enhanced T1- MR images among different disease states (PsP vs true progression, PsR vs and immuno-response) and describe the perfusion and diffusion MRI biomarkers that improve response staging including PsP masking true progression, PsP masking clinical response, early progression with delayed response, and differentiation between true and PsR. The results are compared with the mRANO-based assessments for concurrence. Conclusions: Incorporating multi-parametric MRI measurements to determine the complex underlying tissue processes enables a better assessment of PsP, PsR and delayed tumour response, and can supplement mRANO-based response assessments in GBM patients undergoing novel immunotherapies.
Lobectomy confers a survival benefit over gross-total resection without lobectomy in cases of primary glioblastoma in non-eloquent area: A retrospective study.
Authors: Kim Euihyun 
Published: May 2019

e13561 Background: Following resection, the microscopic remnants of glioblastomas in nearby tissue cause tumor recurrence more often than other tumors. Although surgical oncologists traditionally resect some of the surrounding normal tissue, whether further removal of nearby tissue may improve survival in cases of primary glioblastomas (pGBM) is unknown. In this single-center retrospective study, we assessed whether lobectomy confers a survival benefit over gross-total resection without lobectomy when treating pGBM in the non-eloquent area. Methods: We selected 28 patients who had complete resection of a histopathologically-diagnosed pGBM in the right frontal or temporal lobe, and divided them into two groups according to whether gross-total resection of the tumor involved lobectomy (SupTR group, n = 15) or did not (GTR group, n = 13). Progression-free survival (PFS), overall survival (OS), and Karnofsky Performance Status (KPS) scores were compared statistically between groups (p≤0.05 for significant differences). Results: Median post-operative PFS times (GTR, 9.7 months [95% CI 2.9-16.5]; SupTR, 35.0 months [95% CI 11.1–58.9]; p = 0.082) and mean KPS scores (GTR, 73.4; SupTR, 71.3; p = 0.586) were not significantly different; however, median post-operative OS times were (GTR, 14.4 months [95% CI 12.1–16.7]; SupTR, 35.0 months [95% CI 17.4–52.6]; p = 0.018). In multivariate analysis, the SupTR group was significantly better than the GTR group in terms of both OS (HR 0.249; 95% CI 0.085–0.730; p = 0.011) and PFS (HR 0.362; 95% CI 0.0134–0.982; p = 0.046). Conclusions: In cases of completely resectable, non-eloquent area pGBMs, including lobectomy improved overall survival without negatively impacting patient performance.
Trametinib for aggressive gliomas in adults with neurofibromatosis type 1.
Authors: Romo Carlos G , Slobogean Bronwyn L , Blair Lindsay Karen , Blakeley Jaishri O'Neill 
Published: May 2019

e13562 Background: Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. NF1 is characterized by multiple benign and malignant tumors. Central nervous system tumors have an overall standardized incidence ratio of 37.5 in population studies with high rates of aggressive gliomas in adults with NF1. The response to standard glioma therapies is mixed. MEK1/2 inhibitors have shown activity in NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about the optimal dose or sequencing of MEK1/2 inhibitors for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and aggressive gliomas. Methods: A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program between 2016-2018. Results: Three patients met selection criteria. Two received trametinib as initial therapy (2 mg daily). All developed an acneiform rash; one had transient transaminitis requiring temporary discontinuation and subsequent dose reductions. Clinical benefit was achieved associated with two partial radiographic responses. Conclusions: Astrocytomas in adults with NF1 often have a more aggressive course than suggested by histology. The cases presented here demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in this patient population. These observations highlight the need for further research in this area. [Table: see text]
Impact of Zika virus infection in human glioblastoma cell lines.
Authors: Fay Andre P. 
Published: May 2019

e13563 Background: Glioblastoma (GBM) is the most common central nervous system (CNS) tumor. Despite available therapies survival remains poor, and new treatment strategies are needed. Oncolytic viral therapy is under investigation in GBM. Zika virus (ZV) infection has demonstrated inhibition of neuronal precursor cells proliferation in preclinical studies. This study aims to evaluate the effects of ZV infection on human glioblastoma cell lines survival. Methods: Two GBM cell lines (U138 and U 251) were infected by 2 hours with ZV using the titer of PFU/ml diluted in 1:100, 1:1000, 1: 10000. Cell. We performed tests to evaluate cell viability by MTT and protease active assay, cell migration trough a wound healing assay and cell infiltration using insert culture method. Also the cell lines were tested by cell adhesion capacity, apoptosis (Caspase 3/7), interleukins levels and cell surface markers for CD 14 and CD73.These results were compared to controls. Results: Our study has demonstrated a reduction in cell viability in U138 lineage trough MTT assay. In the U251 lineage and in the others tests for cytotoxicity/viability, ZK did not altered cell viability neither cell migration compared to controls. We showed that ZV caused reduction in cell invasion and resulted in increased rates of apoptosis in both cell lines. We observed that infection of ZV caused increased rates of cell adhesion and CD73 marker. Conclusions: These findings suggest that ZV infection may be associated with increased CD 73 Expression thus increasing cell adhesion and cell infiltration. The ZV may be cause an increase rates of apoptosis and influencing cell cytotoxicity and viability. Further investigations to explore the role of ZV in GBM treatment are warranted.
The impact of a dedicated multidisciplinary tumor board on care for patients with brain metastases.
Authors: Wang Nancy , Cohen Justine Vanessa , Goss Nathaniel C. , Bertalan Mia , Keeley Maura C. , Cahill Daniel P. , Oh Kevin S. , Brastianos Priscilla Kaliopi 
Published: May 2019

e13585 Background: Brain metastases are the most common tumors to affect the central nervous system. Treatment options have recently evolved with the use of targeted therapies, immunotherapy, and increased clinical trials availability. We describe our institutional experience with a novel, weekly tumor board dedicated to brain metastases and its impact on treatment decisions and survival. Methods: We conducted a single institution cohort study at a large academic hospital with a dedicated center for CNS metastases. Attendance at tumor board included representatives from neuro-oncology, medical oncology, radiation oncology, neurosurgery, and neuroradiology. We prospectively gathered data on patient demographics, clinical history, and tumor board recommendations. Patients were followed to assess treatment course and survival. The Kaplan Meier method was used to calculate time to progression. Results: A total of 49 patients were presented over 2 months, with 4 patients presented twice. The median age at presentation was 63 yrs with a median ECOG of 1. The primary malignancy was 35% melanoma, 49% lung, 22% breast, the remainder other. Most patients had advanced, heavily pretreated disease: 69% had Stage IV disease at time of tumor board presentation with a median of 2 prior lines of systemic therapy, 73% had multiple brain metastases, 39% had prior surgical resection of brain metastases, and 57% had prior CNS radiation. The tumor board recommended a change in management in 26/53 case presentations: 5 surgery, 8 radiation, 9 medical therapy, 3 clinical trial, and 1 surveillance. Recommendations were followed in all except 4 cases due to patient preference and loss to follow-up. When active therapy was recommended, the median time to start was 7 days. Only 3 patients have died at a median follow-up of 62 days. 9 patients have progressed, with a median time to progression of 57 days. Conclusions: A multidisciplinary brain metastasis tumor board provides unique opportunities in the management of complex brain metastasis patients in an era of rapidly evolving therapeutic options. Additional follow-up is needed to assess long-term outcomes, and comparison to non-tumor board presented patients will be necessary.
A phase I dose escalation and dose expansion study of the anti-programmed cell death-1 (PD-1) antibody AK105.
Authors: Kotasek Dusan , Coward Jermaine , de Souza Paul L. , Underhill Craig , Jin Xiaoping , Li Baiyong , Xia Yu , Prawira Amy 
Published: May 2019

e14006 Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy (RO). These features offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I, open-label dose escalation and expansion study in solid tumors (NCT03352531) began in Dec 2017, evaluating the safety and efficacy of AK105 administered IV q2w till confirmed progression (RECIST v1.1). For dose escalation, pts were enrolled at dose cohorts of 1, 3, and 10 mg/kg. Expansion of AK105 at the RP2D of 200 mg q2w is ongoing in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma; esophageal squamous-cell carcinoma; hepatocellular carcinoma (HCC); microsatellite instability-high (MSI-H) colorectal cancer. Results: As of 1 Feb, 2019, 34 pts (median age 66.5 years [30–79], female 44%, ECOG 0/1 ([68%/32%]) in cohorts of 1 mg/kg (n = 3), 3 mg/kg (n = 6), 10 mg/kg (n = 7), and 200 mg q2w (n = 18), received a median of 5 (1–29) doses of AK105. No DLTs were reported. Treatment-related adverse events (TRAEs) occurred in 41% of pts (G3 in 12% [4/34], no G4, treatment interruption in 9% [3/34]). Most frequent TRAEs ( > 5%) were hyperthyroidism (9%), hypothyroidism (6%), fatigue (6%), and rash (6%). PD-1 RO analysis showed that pts maintained full occupancy ( > 80%) for all dose levels. Of 25 evaluable heavily pretreated pts, ORR was 24% (6/25; 29% [4/14] in dose escalation and 18% [2/11] in expansion phase) and disease control rate (DCR) was 56% (14/25). Five responses are confirmed and ongoing (HCC, pancreatic carcinoma, cholangiocarcinoma, GBM, gastric adenocarcinoma), one is pending confirmatory scan (GEJ). Conclusions: The RP2D obtained from the dose escalation phase, reported safety profile and encouraging antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in classic Hodgkin lymphoma and nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in HCC. PD analysis is ongoing and expansion is ongoing at the RP2D. Clinical trial information: NCT03352531.
PD-L1 expression on circulating tumor cells and prognosis of breast cancer patients.
Authors: Wang Xuefei , Zhang Guochao , Sun Qiang 
Published: May 2019

e14028 Background: Nowadays programmed cell death (ligand) 1 (PD1/PD-L1) inhibitors in the clinic show benefit for appropriate patient. There are clinical trials for specific breast cancer patients. We all know that the prognosis of breast cancer is associated with CTC. However, PD-L1 expression on circulating tumor cells (CTC) is lack of research. It is crucial for the prediction and supervision of molecular-targeted therapy, while the predictive biomarker response to PD(-L)1 checkpoint inhibitors is lacking. So we tried to explore the relationship between overexpression of PD-L1 on CTCs and prognosis and clinicopathological features of breast cancer patients. Methods: We analyzed CTC and PD-L1 mRNA expression on CTC in 20 primary breast cancer patients, through mRNA probe hybridization. The relationship between clinicopathological features and PD-L1 expression on CTC was analyzed by chi square test. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with low PD-L1 expression. Results: The median follow-up time was 40 months (range, 36-43 months). Of the 20 patients, 15 had more than 1 CTC in 7.5ml peripheral blood. Among the 15 patients, each one has at least 1 CTC showing PD-L1. The expression of PD-L1 on CTC was divided into low expression, medium expression and high expression, then we gave 1 score for low expression, 2 score for medium expression and 3 score for high expression. PD-L1 high expression was total score≥3, while PD-L1 low expression was total score ＜ 3. We found PD-L1 expression on CTC is related to the tumor size(P = 0.012) lymph node status (P = 0.001) and PR status (P = 0.037). There was significant difference between T2 and T3 in large tumor group(P = 0.003), while in node status group statistical difference can be found in N1 vs N3(P = 0.000) and N2 vs N3(P = 0.015). Our data indicated that patients with high PD-L1 expression on CTC had poor overall survival(P = 0.004) compared to low PD-L1 expression on CTC (Table). Univariate Cox proportional hazards model analysis showed that high PD-L1 expression on CTC was an independent prognostic factor. Conclusions: PD-L1 on CTC is indeed associated with some poor clinicopathological features. High expression of PD-L1 on CTC is an independent prognostic factor for shorter survival. [Table: see text]
Quantification of activated and exhausted immune cell populations and simultaneous characterization of circulating tumor cells (CTCs) in peripheral blood of cancer patients receiving checkpoint inhibitor therapy.
Authors: Vansant Gordon , Krupa Rachel , Richardson Robin , Ontiveros Priscilla , Byun Jiyun , Landers Mark , Dittamore Ryan 
Published: May 2019

e14033 Background: Immune checkpoint inhibitors (ICIs) are becoming standard treatment options in many indications. However, a substantial portion of patients will not respond. Single biomarkers such as PD-L1 are insufficiently accurate to predict patient benefit. We sought to expand the Epic Sciences non-invasive liquid biopsy platform to identify predictive, peripheral blood biomarkers for ICIs using both molecular analyses of CTCs and immune cell changes. Methods: Blood samples from prostate, kidney, and bladder cancer patients treated with ICIs were collected at baseline and on-therapy and sent to Epic Sciences. Nucleated cells were plated on glass slides and stained with CTC (pan-CK, CD45, PD-L1 and DAPI) and immune panels for activation (CD4, CD8, Ki-67, and DAPI) and exhaustion (CD8, Ki-67, PD-1, Lag-3, Tim-3, and DAPI). Changes in populations of immune cells and circulating tumor cells were assessed using high throughput digital pathology. Results: CTCs were detected in 73% (24/33) patients, of which 12% (4/33) had PD-L1+ CTCs detected. No PD-L1+ CTCs were detected in the nine on-therapy samples tested. Of 14 patients with matched samples, 57% (8/14) patients had an increase in activated CD4+ leukocytes and 36% (5/14) patients had an increase in activated CD8+ leukocytes in on-therapy samples compared to baseline. The exhaustion assay was performed on a subset (6 of 14) of matched samples. In baseline and on-therapy samples, one patient had higher levels of exhausted CD8+ leukocytes compared to healthy donor controls, and two patients had lower levels versus controls. No change in exhausted CD8+ leukocytes was observed from baseline to on-therapy. Conclusions: We developed a liquid biopsy-based platform that can simultaneously measure biomarkers in CTCs and leukocytes from a single peripheral blood sample. Changes in activated and exhausted immune cell populations with ICI treatment were detected and PD-L1 expression on CTCs was evaluated. Efforts to further stratify immune and rare cell populations are ongoing.
Revisiting the ethics of phase 1 oncology trials in the era of precision medicine: A systematic review.
Authors: Mackley Michael Patrick , Fernandez Nicholas R , Fletcher Benjamin , Woolcott Christy , Fernandez Conrad Vincent 
Published: May 2019

e14060 Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.