bluuebunny/crossref_metadata_2025 huggingface dataset:
VONC: A solution for the clinical assessment of somatic genomic alterations.
Authors: Kueffner Robert , Li Hui , Cheung Kakit , Fink Marc , Soens Zachry , Wang Jinlian , Siddiqui Osman , Thiumurthi Umadevi , Uzilov Andrew , Song Chunying , Villar Joaquin , Pollock Andrew , Jeganathan Bharath , Zimmermann Michelle , Kip Nefize Sertac , Rossi Michael , Schadt Eric , Li Dan , Hantash Feras , Chen Rong
Published: May 2019

e13155

Background: Next generation sequencing (NGS) technology is transforming the diagnosis and treatment of cancer. However, the massive scale of data has overwhelmed pathologists who need streamlined tools to process this data, automate report generation and minimize human errors. Methods: We developed the Variant interpretation station for ONCology, VONC, as an end-to-end solution for moving from NGS whole exome and transcriptome data to actionable clinical reports that support cancer diagnosis, prognosis, and personalized treatment strategies for solid and hematologic malignancies. Results: VONC integrates all steps for moving from raw NGS data, variant calling and LIMS, to comprehensive annotation of variants. The main functional feature of VONC is a transparent process that effectively combines automated and expert curation to identify clinically relevant and actionable driver variants. VONC also enables efficient management of multi-group, -role, -system and -site curation processes. In contrast to current tools, VONC handles all somatic and constitutional genomic alterations including SNV, indel, CNV, fusion, splicing, and gene expression. Key data sources include 1) 350,000 variants for 50 tumor types across 57,000 sequenced cancer patients; 2) variant frequencies estimated from 1.5M cancer patients; 3) expert curated literature evidence from 16,818 papers covering 26,496 alterations spanning 2,448 cancer driver genes; and 4) curated database of FDA-approved drugs and recruiting clinical trials. VONC presents a prioritized list of variants in oncogenes and tumor suppressors through functional (literature-based) and structure-based (hotspots) algorithms. This is coupled to all supporting information necessary for clinical decision making. Curators can quickly screen variant type, QC metrics, and frequency in sequencing cohorts of cancer patients as well as healthy subjects. Within minutes, variants can be triaged and annotated with FDA approved, NCCN guidelines reported, or literature supported therapeutics, including resistance and contraindicated. Conclusions: VONC is a clinically-ready tool with an intuitive end-user interface tailored for the rapid assessment of variants in cancer patients, to facilitate personalized cancer medicine in a high-throughput laboratory.
Enhanced family history screening is crucial to individualized cancer surveillance.
Authors: Clift Kristin , Macklin Sarah K , Wallace Michael B , Presutti R. John
Published: May 2019

e13161

Background: Capturing family health history is a simple and cost-effective way to identify individuals at increased risk for hereditary cancers. Several barriers exist to family history collection in the clinical setting. Self-reported histories can be limited, inaccurate or static. Physicians are often overwhelmed with data and “alert fatigue.” These complex factors make it difficult to quantify hereditary risks. Patients with increased genetic predisposition may be missed and may not receive individualized cancer surveillance measures. Methods: A practice improvement project was implemented at Mayo Clinic Florida to enhance family history screening. A questionnaire and simple scoring algorithm were developed to prompt referral for genetic counseling. This tool was pilot tested in a multi-specialty gastroenterology clinic. The questionnaire was administered in the waiting room (tablet interface). Patients with significant risk factors identified were contacted and offered genetic counseling. Results: Currently, 291 patients have completed the questionnaire. Thirty of the 60 patients identified to have significant familial risk factors met with a genetic counselor. Of the twenty who completed genetic testing, 9 patients received one or more variants of unknown significance. Two pathogenic variants were identified. One patient was molecularly confirmed to have multiple endocrine neoplasia type 2, which can allow for cascade screening in her unaffected sibling. A pathogenic ATM variant was found in a patient with a recent personal history of pancreatic cancer. The result prompted consideration of platinum based chemotherapy and/or PARP inhibitors in her cancer management. She has had a visible response thus far with the treatment. Her sister implemented a new surveillance regimen after testing positive for the familial variant. Conclusions: Enhanced family history screening is a low cost, effective method for the identification of patients who may benefit from hereditary cancer screening and genetic testing. Increased attention to family history is a vital component of precision medicine in any care setting.
National trends in the use of immunotherapy in the up front management of glioblastoma.
Authors: White Richard , Abel Stephen , Hasan Shaakir , Verma Vivek , Ranjan Tulika , Karlovits Stephen , Wegner Rodney E
Published: May 2019

e13500

Background: Glioblastoma (GBM) carries an abysmal prognosis. Current standard of care involves an aggressive multimodality approach including surgical resection followed by adjuvant chemoradiation. Despite this approach, overall survival remains poor and treatment approaches continue to evolve. Given the successes of immunotherapy in other disease sites, implementation in GBM management may improve outcomes. Methods: We conducted this NCDB-driven retrospective study to analyze treatment trends and outcomes from 2004-2015 with respect to GBM and immunotherapy. We queried the NCDB diagnosed between 2004-2015 with GBM and excluded patients treated without surgery, extracranial radiation, or chemotherapy as well as those lost to follow up. Results: Of the 39,317 eligible patients in this study, 511 were treated with immunotherapy and 38,806 lack thereof. Median overall survival for all patients was 15 months with a 2 and 5 year survival rate of 29% and 8%, respectively. Factors positively influencing delivery of immunotherapy included younger age, higher income, facility location in a metropolitan location, greater distance to the treatment facility, treatment at an academic facility, treatment outside of the years 2007 to 2009, and Caucasian race. On propensity matched analysis, survival was 18 months and 17 months with and without immunotherapy, respectively (p = 0.15). Higher comorbidity, lower income, and male gender predicted for worse survival. Conclusions: The results of the NCDB analysis showed an initial decrease and then increase in the use of immunotherapy in the management of GBM. Propensity-matched and –adjusted analyses did not show an overall survival benefit, consistent with data from randomized trials.
Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to brain tissue using drug-embedded biodegradable nanofibers.
Authors: Liu Shih-Jung , Tseng Yuan-Yun
Published: May 2019

e13501

Background: Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor cell resistance to chemotherapy. Methods: We developed bilayered poly[(d,l)-lactide- co-glycolide] nanofibrous membranes that enable the sequential and sustained release of carmustine [or bis-chloroethylnitrosourea (BCNU)], irinotecan, cisplatin, and combretastatin by employing an electrospinning technique. An elution method and a high-performance liquid chromatographic assay were employed to characterize the in vitro release behaviors of pharmaceuticals from the nanofibers. Results: The experimental results showed that the drug-eluting nanofibers exhibited a sequential drug release behavior, with the release of high concentrations of BCNU, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then placed into the cerebral cavity of rats after operative craniectomy was performed, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. A histological examination revealed the progressive atrophy of brain tissues without inflammatory reactions. Conclusions: Biodegradable drug-eluting nanofibers can be manufactured for the long-term sequential delivery of various chemotherapeutic and antiangiogenic agents in the cerebral cavity, which can potentially enhance the therapeutic efficacy of glioblastoma multiforme treatment and prevent toxic effects resulting from systemic administration.
Comparison of two dose calculation methods of intra-arterial carboplatin in the treatment of recurrent glioblastoma multiforme.
Authors: Boilard Brigitte , Hinse Alexandra , Beaulieu Karianne , Marcotte Florence , Fortin David , Lacasse Marie-Constance , joly-Mischlich Thomas , Ferland Gabrielle
Published: May 2019

e13503

Background: Glioblastoma is a deadly brain cancer, and as part of the natural evolution, its relapses will mostly occur 32 to 36 weeks after the initial diagnosis. The standard of care for recurrent glioblastomas is not well defined and multiple options exist. Intra-arterial chemotherapy as one option is currently practiced at the Centre hospitalier universitaire de Sherbrooke, the only center doing this procedure in Canada. The aim of this study is to evaluate the impact of using the area under the curve (AUC) or body surface area (BSA) dosing formula to guide intra-arterial carboplatin administration. It was designed to explore the relation of two dose calculation methods on efficacy and toxicity, determined by progression-free survival (PFS) and hematologic toxicity, respectively. Methods: A retrospective observational study was conducted, which includes adult in-patients who received intra-arterial carboplatin for recurrent glioblastoma from June 1st, 2000 to December 31st, 2017. It examined the associations of the method used to calculate the doses, in mg or mg/mL x min-1, with clinical outcomes. Results: One hundred ninety patients were included in the analysis. For the primary endpoint, an exposure greater than 6 of AUC was found potentially harmful in terms of efficacy compared to AUC under 6 (HR 0.529, p = 0.0044). In terms of toxicity, a higher AUC is highlighted to correlate with a slightly higher incidence of thrombocytopenia and neutropenia (OR 1.051 p = 0.0271; OR 1.072 p = 0.049). No significant association between toxicity and dose calculated with BSA could be established. Conclusions: AUC greater than 6 is detrimental in terms of effectiveness according to progression free survival. Moreover, AUC could be used to predict neutropenia and thrombocytopenia. However no significant predictions were found using BSA method. We recommend the use of AUC method in intra-arterial carboplatin instead of BSA method since the latter was not statistically related to toxicity. A prospective trial comparing the two dosage methods would be needed.
Targeting the androgen receptor as a novel therapeutic strategy for high-grade gliomas by suppressing glioma cancer stem cells.
Authors: Zhao Nan , Ahmed Shaheen , Wang Fei , Dominick DiMaio J , Lin Chi , Zhang Chi
Published: May 2019

e13504

Background: Glioblastoma (GBM) is the most aggressive and most common type of primary brain malignancies with median overall survival being only 20.9 months. The incidence of GBM is 50% greater in men than in women, and GBM transplanted into animals grow at a slower rate in females compared with males. Gender difference in GBM indicates that sex hormones such as androgen receptor (AR) may be involved in the tumorigenesis of GBM. A newer generation of AR antagonist, Enzalutamide, is available for prostate cancer treatment in clinic and can pass the blood-brain barrier, thus a good candidate for GBM treatment. Methods: Cell proliferation assay, cell cycle analysis, and cell apoptosis assay were performed on different GBM cell lines after Enzalutamide treatment. After treating GBM cells with or without Enzalutamide in mono-layer cell culturing or tumor spheres, cancer stem cell sub-population (CD133+ cells) in different groups was compared using flow cytometry. After enriching GBM cancer stem cells by sorting CD133+ U87MG cells out, cell proliferation assay was performed on CD133+ U87MG cells. Western blotting was performed comparing marker gene expression levels including CD133 and c-Myc with total protein isolated from GBM cells treated with Enzalutamide at different time points. A syngeneic orthotopic GBM mouse model was used for in vivo study. The size of tumors in the brain was monitored weekly with and without Enzalutamide treatment by in vivo imaging system for the luciferase activities. Results: Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Enzalutamide induced apoptosis of GBM cells as well as arrested the cell cycle at G2/M phase in a cell cycle that has a potential of radio-sensitizing effect. Enzalutamide decreased the cancer stem cells population both in cultured mono-layer cells and in tumor spheres. Enzalutamide inhibited the proliferation of CD133+ U87MG cells after four days’ treatment. c-Myc is a proto-oncogene and required for maintenance of GBM cancer stem cells. Both CD133 and c-Myc expression levels decreased in GBM cell lines after Enzalutamide treatment in a time-dependent manner. Conclusions: Enzalutamide targets cancer stem cells and inhibits the proliferation of GBM.
Aberrant miRNA expression in glioma.
Authors: Pushkin Anton , Kit Oleg I. , Rostorguev Eduard Evgenevich , Porksheyan David H. , Kuznetsova Natalya S. , Kavitskiy Sergey E.
Published: May 2019

e13506

Background: Gliomas are the most common type of primary brain tumors, with a high level of recurrence and mortality. The purpose of the study was to determine the expression profile of micro-RNA targeting components of the Hedgehog, Notch, Wnt, EGFR, TGFβ, HIF1α signaling pathways according to MirTarBase, miRDB, TargetScan. Methods: The study included 30 patients (15 women and 15 men) aged 27 to 76 years with histologically verified glial brain tumors. The RT2-qPCR method in operational biopsy specimens determined the relative expression of 12 micro-RNAs: hsa-miR-17-3p, hsa-miR-20a-3p, hsa-miR-326, hsa-miR-330-3p, hsa-miR- 107, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-146a-5p, hsa-miR-29a-3p, hsa-miR-92a-1-5p, hsa-miR-26b-3p, hsa-miR-96-5p. Hsa-miR-7-5p and hsa-miR-126-3p were used as reference micro-RNA. Results: A statistically significant increase in the expression of hsa-miR-143-3p, hsa-miR-146a-5p and hsa-miR-92a-1-5p by 2, 2.2 and 2.9 times, respectively, was found, as well as a decrease in the expression of hsa-miR-330- 3p by 4.1 times in tumor tissue of the brain relative to normal tissue (p < 0.05). Reduced expression of micro-RNA hsa-miR-330-3p may increase the activity of the VEGFA gene, which leads to intensive vascularization of the tumor. In addition, hsa-miR-330-3p is a validated negative regulator of the E2F1 gene known as a regulator of the cell cycle and tumor suppressor proteins. The TRAF6 gene is the direct validated target of hsa-miR-146a-5p, and its overexpression is associated with the patient's chemoresistance to temozolomide. Increased hsa-miR-143-3p micro-RNA expression can reduce the activity of the EGLN1 gene that also mediates the adaptation of tumor cells to hypoxic conditions. Hsa-miR-92a-1-5p micro-RNA is a negative regulator of PTEN gene expression. Conclusions: A significant decrease in hsa-miR-330-3p expression and an increase in hsa-miR-146a-5p, hsa-miR-143-3p, and hsa-miR-92a-1-5p, which was found in gliomas, can potentially be used to develop prognostic markers and therapeutic targets for targeted therapy.
Bevacizumab-associated intracerebral hemorrhage in patients with CNS malignancy: A single-center retrospective cohort study.
Authors: Clarke Nathan , Ruff Michael
Published: May 2019

e13509

Background: Gliomas are a known risk factor for the development of spontaneous intracranial hemorrhage (ICH) independent of therapies directed against them, with studies reporting an incidence of 1.9-3.8%. Bevacizumab (BEV) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) FDA approved for recurrent glioblastoma. ICH is commonly considered to be a potential adverse effect of BEV use in patients with glioma, with previous retrospective studies describing incidence of intracerebral hemorrhage ranging from 1.9-3.3%. Methods: We performed a single center (Mayo Clinic, Rochester, MN) retrospective chart review of all patients who received BEV therapy at our institution for a diagnosis of primary CNS malignancy. We used ICD-9 and ICD-10 codes to identify adult patients with primary CNS neoplasms that subsequently developed ICH. Results: We screened 10,507 adult patients with a diagnosis of primary CNS neoplasm treated at our center from 01/31/2008 to 12/31/2018 and found 644 patients treated with bevacizumab. Of these, 23 (3.6%) suffered an ICH within 12 weeks of a BEV infusion (median 9 days post infusion, 1-24 IQR). The dose of BEV in all hemorrhages was either 10 mg/kg every two weeks (n = 21) or 15 mg/kg every three weeks (n = 2). No patients treated with infusions at 7.5 mg/kg every three weeks (n = 79) or 5 mg/kg every two weeks (n = 17) suffered ICH events, however this did not meet significance (P = 0.06) when compared to patients on 10 mg/kg or above. The median ICH score was 1 (0-2 IQR). There was an increase in ECOG scores documented at clinical follow up following the hemorrhage compared to the pre-hemorrhage functional status (ECOG 3.28 versus 1.2, p = < 0.0001), with 13 patients (56%) having developed severe debility or death (ECOG 4 n = 3, ECOG 5 n = 10). Conclusions: In our single-center cohort of patients with a primary diagnosis of CNS neoplasms treated with BEV, ICH occurred in 3.6% of patients. Those who experienced an ICH in proximity to BEV infusion had significant morbidity and mortality with a clear decline in functional status. There was a signal of dose response as far as ICH incidence in our cohort with dosages 10 mg/kg per infusion or above.
The use of metformin to enhance radiation effects on M1 macrophage subtype polarization in bone marrow-derived macrophage in glioblastoma tumor environment.
Authors: Wang Fei , Zhao Nan , Lin Chi , Zhang Chi
Published: May 2019

e13513

Background: Given the clinical relevance of tumor-associated macrophage (TAM) with its pro-tumor role and as a cell type compromising a large portion in glioblastoma (GBM), reversing the imbalance of TAM polarization in the tumor environment has emerged as a promising novel field for GBM treatment. Radiation therapy (RT) is the standard treatment for GBM patients after surgery, which has been shown to transiently induce M1 polarization of macrophage (M1Ø). Recent studies suggested that metformin could also promote M1Ø in tumor microenvironment. We thus postulate that metformin may enhance and sustain the M1-inducing effect of radiation in GBM. Methods: We first examined the polarization effect of metformin (0.1mM, 1mM and 2mM) on mouse bone marrow-derived macrophage (BMDM) cultured in GBM tumor environment, including media conditioned by GBM cells in monolayer culture or tumor spheres as well as in trans-well co-culturing system. We irradiated GBM cells with different doses (2 Gy, 8 Gy, and 20 Gy) after the treatment of Metformin at various time points; then we used conditioned media to treat BMDM either cultured alone or co-cultured with GBM cells in trans-well system for 24 or 48 hours. A separate set of experiment was conducted by first irradiating GBM cells and then co-culturing them with BMDM at 24 or 48 hours after radiation with metformin added at the start of co-culture. Percentage of various subtypes of BMDM was calculated after flow cytometry. Results: High concentrations of metformin (1mM and 2mM) significantly increased M1Ø and inhibited M2Ø in all culture conditions. Co-culture with irradiated GBM cells or treatment with medium conditioned by irradiated GBM cells could temporally induce M1Ø polarization in BMDM, with the effects being RT dose-dependent. Metformin at high concentrations further promoted M1Ø and suppressed M2Ø polarization in those conditions mimicking tumor microenvironment. This enhancing effect was sustained for at least 48 hours. Conclusions: Metformin at mili-molar concentrations significantly enhances the effects of radiation on M1Ø polarization in BMDM in vitro.
Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.
Authors: Campian Jian Li , Kapoor Vaishali , Griffith Kaylan , Mahadevan Anita , Collins Andrea , Thotala Sukrutha , Jash Arijita , Hu Tong , Lee Byung Ha , Choi Donghoon , Yang Se Hwan , Hallahan Dennis , Chheda Milan G , Thotala Dinesh
Published: May 2019

e13516

Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival < 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.
Intracerebral immunotherapy for brain tumors.
Authors: Carillio Guido , Santaguida Luigi , Di Paola Eugenio Donato , Lavecchia Anna Maria , Vescio Virginia , Iannello Alfonso , Molè Rosa , Serrao Maria Gabriella , Mirabelli Rosanna , Mauro Giuseppe , Molica Stefano
Published: May 2019

e13522

Background: Immunotherapy is a promising approach for the treatment of brain tumors, but available data are still inconclusive. The main drawback is represented by transport across the blood–brain barrier of high molecular weight drugs. Convection-enhanced delivery (CED) has been designed to overcome some difficulties. We wondered whether a CED strategy based on the use of novel immune checkpoint inhibitors could be effective. Methods: Frameless biopsy by fluorescein tracer and neuronavigation-assisted system, followed by an injection of nivolumab 40mg/4mL into the brain lesion, were offered to patients with: a) high grade gliomas (HGG) inoperable or progressed during or after standard treatment (i.e. surgery and radio-chemotherapy); b) HGG at first diagnosis or after disease progression treated with radical surgery (nivolumab delivered in the surgical cavity after tumor removal); c) other brain tumors or solitary metastases judged suitable for surgical procedure. PD-L1 expression was assessed in all patients, but it was not a strict criterion for accrual. Standard therapy, usually based on chemotherapy, radiotherapy or both, was sequentially administered to patients able to tolerate such an approach. End-points were safety, response rate, disease control, predictive value of PD-L1 expression. This is a non-sponsored monocentric, real life, basket trial approved by Ethical Committee (EudraCT number: 2018-001560-33). Results: Since August 2018, 17 patients with brain tumors (16 HGG and 1 heavily pretreated medulloblastoma) and 5 patients with brain metastasis (of lung and gastrointestinal cancers) were enrolled. Median age was 63 years (range 26-83). After a median follow up of three months (range 1-6), all patients are alive and in good clinical conditions. No signs of neurologic toxicity due to intracerebral nivolumab were observed. Brain MRI performed at 4 to 12 weeks after nivolumab CED revealed findings suggesting a perivascular lymphocyte infiltration. Correlation between PD-L1 expression and treatment efficacy will be evaluated over time. Conclusions: Intracerebral nivolumab appears to be a feasible and safe option for patients with HGG and brain metastases at the dose investigated in the study. Long-term follow up could contribute to well understand the role of this strategy. Clinical trial information: 2018-001560-33.
Validation and revision of the RANO Leptomeningeal Metastasis Group scorecard for response assessment.
Authors: Le Rhun Emilie , Devos Patrick , Boulanger Thomas , Smits Marion , Brandsma Dieta , Ruda Roberta , Furtner Julia , Hempel Johann-Martin , Postma Tjeerd , Roth Patrick , Snijders Tom J. , Winkler Frank , Winklhofer Sebastian , Castellano Antonella , Hattingen Elke , Capellades Jaume , Van Den Bent Martin J. , Wen Patrick Y. , Bendszus Martin , Weller Michael
Published: May 2019

e13546

Background: The Response Assessment in Neuro-Oncology (RANO) group has proposed a scorecard to evaluate response assessed by magnetic resonance imaging (MRI) during treatment of leptomeningeal metastasis (LM). Methods: To validate the LM-RANO scorecard, cerebrospinal MRI of 22 patients with LM from solid tumors were rated by 10 neuro-oncologists and 9 neuroradiologists at baseline and during follow-up after treatment. The original scorecard and its instructions were sent to the raters. The inter-observer agreement for the evaluation of single items was assessed using the Krippendorff alpha coefficient. The agreement between numerical parameters including scores at baseline and at follow-up after treatment and total scores was determined using the intraclass coefficient of correlation (ICC). Results: Instructions of the scorecard were not clear for the majority of raters. The alpha concordance coefficients obtained for the rating of single items at baseline and at follow-up were low (Krippendorf alpha coefficient < 0.61 for all raters). The best concordances were noted for spinal nodules (0.60). The worst concordances were obtained for brain linear leptomeningeal enhancement and cranial nerve enhancement. The concordance was better among neuroradiologists than among neuro-oncologists. A poor agreement was also noted when evaluating changes between baseline and follow-up and for total scores (ICC < 0.65 for the best score for all raters). Conclusions: Assessing response of LM by MRI remains challenging. The definition of a measurable lesion and the determination of response were the most important challenges. A central review is therefore recommended for clinical trials in LM. Based on this study we propose a new scorecard that will require a similar assessment as conducted here.
Evaluation of prognostic role of inflammatory index in glioblastoma multiforme patients undergoing to concomitant radio-chemotherapy.
Authors: Fausti Valentina , Foca Flavia , Riva Nada , Bongiovanni Alberto , Gurrieri Lorena , Di Menna Giandomenico , Calpona Sebastiano , De Bonis Silvia Angela , Mercatali Laura , Spadazzi Chiara , De Vita Alessandro , Liverani Chiara , Miserocchi Giacomo , Cocchi Claudia , Dall'Agata Monia , Tosatto Luigino , Romeo Antonino , Amadori Dino , Martinelli Giovanni , Ibrahim Toni
Published: May 2019

e13549

Background: Hematologic markers of inflammation have been shown to be prognostic in different malignancies. Also in glioblastoma multiforme (GBM) a prognostic role has been demonstrated. The purpose of this study is to evaluate retrospectively the prognostic role of these markers in patients receiving a concomitant radio-chemotherapy after surgery. Methods: Sixty-five GBM patients have been treated with concomitant radio-chemotherapy after surgery at our institute from 2008 to 2017. Information on blood counts were carried out the day before starting therapy and after the day before the last cycle of chemotherapy. Neutrophil/lymphocyte ratio (NLR) and Platelet/lymphocyte ratio (PLR) were computed as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively. Systemic Inflammatory Index (SII) was calculated as platelet count × neutrophil count/lymphocyte count. The optimal cut-point was obtained using X-tile software version 3.6.1. Results: NLR and PLR baseline value didn’t show a statistic a statistically significant prognostic role in PFS or OS. Patients with baseline SII < 480 showed both better PFS and OS (OS: 22.1 VS 11.8 mo p-values 0.0516; PFS: 10.6 VS 5.7 mo p-values 0.0351). Patients aged < 60 years showed better PFS and OS. (PFS 10.3 VS 5.5 p-values 0.0501; OS: 20.6 VS 11.2 mo p-values 0.0124). Statistical significance for SII and age was maintained for both PFS and OS in multivariate analysis as shown in Table 1. Baseline values of NLR PLR and SII have also been correlated with the best response and ORR without showing statistical significance. Conclusions: This restorative study confirms the prognostic value of inflammatory indices in patients with GBM. Correlation analysis with the methylation status of MGMT is ongoing.[Table: see text][Table: see text]
Brain metastases as a first site of recurrence in patients on chemotherapy with controlled systemic cancers: An increasingly urgent clinical scenario.
Authors: O'Connell Kaelin , Romo Carlos G , Grossman Stuart A.
Published: May 2019

e13590

Background: As the treatment of non-central nervous system (CNS) malignancies improves, brain metastases (BM) are occurring more often in patients with controlled primary disease. In a retrospective analysis of 1953 patients with BM, 44.7% had a controlled primary tumor at the time of BM diagnosis. Given that prognosis after BM remains dismal, it is necessary to identify groups who might benefit from improved delivery of initial systemic therapy across the blood brain barrier (BBB). Methods: A retrospective literature review was conducted to estimate the proportion of patients with non-small cell lung cancer (NSCLC), breast cancer, and melanoma treated with chemotherapy in whom BM was the initial site of recurrence. Only studies explicitly reporting CNS metastasis with controlled extra-cranial (EC) disease on chemotherapy or reporting the first site of recurrence after chemotherapy were included. Results: Four studies of advanced NSCLC reported an average of 23% of patients who developed BM as an initial site of recurrence. Breast cancer cases varied by subtype with a range of 4 - 19%. In four papers reporting HER-2 status, an average of 14% of patients treated with traztuzumab had CNS metastasis with controlled EC disease. In three papers assessing patients with metastatic melanoma on chemotherapy, 4 – 25% initially progressed in the CNS. Conclusions: Of the 1024 patients treated with chemotherapy and achieving controlled systemic disease in this retrospective review, first recurrence in the brain was common: 23% in NSCLC, 12% in breast cancer, and 12% in melanoma. While chemotherapy controlled non-CNS disease, concentrations of these drugs were clearly subtherapeutic in the CNS. Preventing BM in patients with NSCLC, breast cancer, and melanoma will require novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in the treatment of the primary tumor. [Table: see text]
Risk factors for synchronous brain metastases: A National Cancer Database analysis.
Authors: Garcia Catherine R. , Slone Stacey A. , St Clair William H. , Durbin Eric B. , Pittman Thomas , Lightner Donita D. , Villano John L.
Published: May 2019

e13591

Background: Brain metastases (BM) are a significant source of disability and mortality in cancer patients. Investigations on the risk factors for their development are limited. We provide risk factors assessment using the largest cancer database. Methods: We analyzed the National Cancer Database from 2010-2014, for risk factors and survival outcomes in all patients with BM. Results: 4,650,963 tumor records were analyzed of which 88,274 were BM. Lung cancer accounted for 82.2%, breast cancer for 4.2%, melanoma for 3.5%, and urinary system tumors for 3.1% of cases. The majority of patients were males (51.6%), and whites (84.2%) with a median age of 65 years. A high index of comorbidities [Charlson-Deyo score (CDS) ≥3] was reported in 3.5% of patients. Lung primaries had the highest risk of BM (OR of 17.867), followed by melanoma (OR 1.946). Patients diagnosed at 70 years or older were less likely to present with BM, while patients diagnosed between 40 and 60 years were at increased risk. Other and unknown race were associated with an increased risk of BM compared to whites. Patients with a CDS of one or two had a decreased risk of presenting with BM compared to patients with scores greater or equal to three. Median overall survival was 5 months, with a 5-year survival rate of 5.2%. There was a decreasing risk of mortality, and increasing risk of receiving surgery, radiation, or chemotherapy per advancing year of diagnosis. Older age, white race, Hispanic origin, and higher CDS were risk factors for mortality. Conclusions: Higher number of comorbidities, younger age at diagnosis, and other races were associated with an higher risk of synchronous BM. The risk of mortality is decreasing, with a higher risk of receiving radiation, surgery, and/or chemotherapy. Median overall survival has increased in comparison to the Radiation Therapy Oncology Group Recursive Partitioning Analysis RPA studies (4.4 months).
Intraventricular radioimmunotherapy targeting B7H3 for CNS malignancies.
Authors: Kramer Kim , Pandit-Taskar Neeta , Donzelli Maria , Wolden Suzanne L. , Zanzonico Pat , Humm John , Haque Sofia , Souweidane Mark M. , Lewis Jason , Lyashchenko Serge K. , Larson Steven M. , Cheung Nai-Kong V.
Published: May 2019

e13592

Background: Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with primary or metastatic CNS tumors. Methods: Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. Results: 57 patients (ages 2 – 54 years, median age 11.7 years) received 158 injections Primary CNS diagnoses included medulloblastoma (n = 23), ependymoma (N = 8), chordoma (n = 1), rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 3), ETMR (n = 3), glioblastoma multiforme (n = 1) , PXA (n = 1); metastatic tumors included sarcoma (n = 9), melanoma (n = 4), retinoblastoma (n = 2), and ovarian carcinoma (n = 1). Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting; 3 injections were associated with grade 3 toxicities requiring discontinuation of therapy including chemical meningitis (n = 2),and increasing communicating hydrocephalus (n = 1), Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (≥60 mCi). 16 patients remain alive including patients with high-risk malignancies including choroid plexus carcinoma, ETMR, recurrent ependymoma and recurrent medulloblastoma. Conclusions: We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and may have clinical utility in the treatment of primary and metastatic CNS tumors. Clinical trial information: NCT00089245.
Comparison of in vitro antitumor activity between SB3 (trastuzumab biosimilar, Ontruzant) and Herceptin combined with an antibody for subdomain II of HER2 in HER2-positive cancer cells.
Authors: Lee Jae Hee , Paek Kyungyeol , Kim Eunji , Kim Inhee , Jeong Juyeon , Kim Seokkyun
Published: May 2019

e14001

Background: The human epidermal growth factor receptor (HER) family plays a critical role in proliferation and survival of cancer cells. Trastuzumab is a recombinant humanized monoclonal antibody that blocks signaling pathways of HER2 tyrosine kinase receptor via binding to subdomain IV of HER2 extracellular domain. A subdomain II targeting therapeutic antibody (DII antibody, pertuzumab) binds to a different region on the same protein. A combination of the two different antibodies might provide a more effective antitumor activity without binding interference [1] . In this study, we evaluate in vitro antitumor activity of SB3 used in the same manner as Herceptin, in combination with a DII antibody that complements the mechanism of action of trastuzumab. [1] Nahta et al, [CANCER RESEARCH 64, 2343–2346, April 1, 2004]. Methods: Similarity assessment of in vitro antitumor activity between SB3 and Herceptin was performed on HER2-overexpressing breast and gastric cancer cells through analyzing HER2 dimerization, cell proliferation and survival activities, and antibody-dependent cellular cytotoxicity (ADCC) in the presence of a DII antibody. Combination index was calculated to evaluate the synergistic effect. Results: SB3 and Herceptin in combination with a DII antibody, showed similar in vitro inhibition rate for HER2/HER3 heterodimerization. The HER2-overexpressing breast and gastric cancer cells growth inhibition rate was similar whether SB3 or Herceptin was used in combination with a DII antibody. This effect was also shown in apoptosis activity by measuring caspase 3/7 expression. In terms of biological effect via Fc function, cell killing activity was assessed by ADCC assay in the presence of a DII antibody, and non-synergistic effect was shown with both SB3 and Herceptin. Conclusions: This study has concluded that SB3, as a trastuzumab biosimilar, demonstrates highly similar in vitro antitumor activity in experimental conditions when combined with a DII antibody, resulting in enhanced cell growth inhibition and apoptosis activities by inhibiting HER2 dimerization in HER2-positive cancer cells.
Safety and efficacy of repeated intra-hepatic artery and intravenous infusion of ET140202, a novel anti-AFP/MHC complex T-cell, in advanced hepatocellular carcinoma.
Authors: Peng Min , Li Na , Chang Chelsea , Yao Yi , Xu Bin , Zhang Yu , Liu Hong , Nejadnik Bijan , Song Qibin , Liu Cheng
Published: May 2019

e14013

Background: Despite the success in hematological malignancies, immunotherapy of solid tumors using redirected T cells such as CAR-T remains challenging due to the lack of a unique tumor antigen, inefficient trafficking of CAR T cells to tumor sites and the presence of immunosuppressive tumor microenvironment. ET140202 is a novel T-cell platform that targets AFP/MHC complex with GPC3-guided co-stimulation aiming to improve the specificity and efficacy. Herein we report a case study of ET140202 for a subject with AFP+ recurrent HCC previous treated with surgery and 2 TACE therapies. Baseline imaging showed multiple nodules on segment 7 of right lobe with enlarged lymph nodes in hepatic hilar region. Methods: From 9/25/18 to 1/29/19 the subject first received 2 intra-hepatic artery infusions (i.a.) of ET140202 T cells at the dose of 3×106 cells/kg followed by 4 i.v. infusions at the dose of 6×106 cells/kg. No lymphodepleting chemotherapy was given prior to T-cell infusion. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 2, 3, 4, 6, 9, 12 and 24. Results: Vital signs are normal after each infusion. No treatment-related Grade 2 or higher AEs observed. Grade 1 events that were possibly attributable to therapy included transient elevation of AST and bilirubin 58 days post the 1st infusion. Both events resolved in 4 days without treatment. The subject did not experience any clinical signs of CRS or neurotoxicity. Month 1, 2, and 3 follow-ups showed that the number and size of the liver nodules slowly increased overtime. Month 4 follow-up showed that the size of liver nodules decreased more than 50% of baseline and resulted in PR based on RECIST criteria. The AFP level elevated in the subject after infusion and reached the peak of 2097 ng/mL 55 days post 1st infusion, gradually dropped to 905 ng/mL on day 67, elevated to the 2nd peak of 2660 ng/mL and gradually decreased to 1235 ng/mL at the last follow-up on day 130. Conclusions: Repeated infusion of ET140202 T cells via i.a. and i.v. routes is safe and shows early sign of efficacy 4 months post initiation of the treatment in AFP+/HLA-A2+ HCC subject.
Effect on anti-tumor immunity and long-term memory CD8+ T-cell generation with a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine.
Authors: Hutchins Jeff , Tahiliani Vikas , Miriyala Jayalakshmi , Rose Jason , Dillon Patrick , Seavey Matthew M
Published: May 2019

e14016

Background: We are focused on developing and optimizing a next generation cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), into a single tumor cell line overexpressing a host of cancer associated neoantigens. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma cell line, stably transfected to express gp96-Ig, is being tested in a phase 1/2 clinical trial (NCT#02439450) for NSCLC. A similar line was generated that complements HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). Methods: To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines (mHS-110 and mHS-130) to activate and expand adoptively transferred ovalbumin specific T cells (OT-1) responding to tumor challenge with ovalbumin over-expressing, B16F10. To identify the best ratio of mHS-110 to mHS-130; multiple dose ratio and dose escalation studies were performed to measure T cell expansion (peripheral and intratumoral) in the context of tumor challenge. Results: CD8+ T-cell expansion was observed on day-7, post-priming, with greatest expansion seen for the 1 to 0.5 ratio. Animals were subsequently boosted 14-days post-priming; the 1 to 0.5 ratio combination gave the most consistent and robust expansion, peaking on day-21. Animals were then challenged with tumors s.c. and growth delay was monitored. Only the 1 to 0.5 and 1 to 4.5 ratio dose groups showed significant delay in tumor growth and weight. Spleen CD4+ and CD8+ T-cells, and CD8+ TILs all increased significantly, as compared to mHS-110 vaccination alone, for the 1 to 0.5 and 1 to 4.5 ratio dose groups. Conclusions: Only the 1 to 0.5 ratio dose group showed any long-term OT-1 expansion or longevity over all other dose ratios, strongly suggesting this is the best combination of gp96-Ig and OX40L-Ig expression for long-term anti-tumor memory generation. These results support the clinical translation of this approach of combining a T cell activation platform with costimulation.
Characteristics of POLE and POLD1 gene variations in Chinese cancer patients.
Authors: Yao Jianfei , Dang Shiying , Li Lifeng , Liu Xinyi , Liu Guifeng , Chen Shifu , Song Lele
Published: May 2019

e14031

Background: POLE and POLD1 gene variations have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutation burden (TMB), an effective indicator for response prediction in immunotherapy. Methods: In this study, we systematically studied the spectrum and characteristics of POLE and POLD1 gene variations from 1,392 Chinese cancer patients, and their correlation with existing immunotherapeutic markers and cancer associated genes. Results: We found that the frequency of POLE variations was not statistically different from that in COSMIC database, while the frequency of POLD1 variations in Chinese lung cancer patients was significantly higher than that in COSMIC database. Variations frequency analysis showed that c.857C > G and c.2091dupC were potential high frequency variations in Chinese cancer patients. Patients carrying POLE damaging variations were significantly younger, and patients carrying POLD1 damaging variations exhibited significantly higher frequency of MSI than POLE/POLD1 WT patients. Further studies found that patients carrying POLE exonuclease domain damaging variations, POLD1 exonuclease and non-exonuclease domain damaging variations exhibited significantly higher TMB than POLE/POLD1 WT patients, while no such difference was found in patients carrying POLE and POLD1 neutral variations. Moreover, patients with POLE exonuclease domain damaging variations showed significantly higher frequency of MMR gene and driver gene variations than POLE/POLD1 WT patients, including genes associated with RTK/RAS/RAF pathway. Patients with damaging POLD1 variations also exhibited higher frequency of MMR gene variations than POLE/POLD1 WT patients. The high frequency variant genes in patients with POLE exonuclease domain damaging variations or POLD1 damaging variations were associated with MMR, RTK/RAS/RAF, TGFβ, WNT, PI3K-Akt and TP53 pathways. Conclusions: This study identified key characteristics and domains of POLE and POLD1 gene variations that related to TMB, MSI, MMR gene variations and key driver gene variations, and provided theoretical and practical basis for patient selection based on POLE or POLD1 gene status in immunotherapy.