tbuckley/cabot-search huggingface dataset:
Effect of combination immunotherapy on tumor growth, survival, and intratumoral immune infiltration in transgenic murine model of melanoma.
Authors: Robyn Denise Gartrell, Zoe Blake, Camden L Esancy, Rolando Perez-Lorenzo, Emanuelle Rizk, Yichun Fu, Chen Yang, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2018)

e21610 Background: Talimogene Laherparepvec (T-Vec), a modified Herpes Simplex Type I (HSV I) virus, is the first oncolytic virus to be FDA approved for the treatment of cancer. T-Vec has two proposed mechanisms of action: direct cell lysis and immune activation. Combination immunotherapy using T-Vec and immune checkpoint blockade has shown promise in clinical trials. Use of transgenic murine models allows for evaluation of combination immunotherapy and the ability to study the immune tumor microenvironment (TME). Methods: In a transgenic murine model (BRAFCAPTEN-/-), melanoma tumors were induced and tumor bearing mice were randomized into six treatment groups comparing combinations of BRAF inhibition (BRAFi), α-PD1, and T-Vec. Tumors were measured twice weekly. Flow cytometry and quantitative multiplex immunofluorescence (qmIF) were performed at end of study. Quantitation of mRNA transcripts using the NanoString assay was performed at 30d of treatment to assess immune TME. Results: Mice treated with the triple combination BRAFi+α-PD1+T-Vec have decreased tumor growth compared to BRAFi alone (p = 0.0141). Mice treated with triple combination have prolonged survival compared to mice treated with control (p < 0.0001). Flow cytometry shows an increase in percent CD8+/CD3+ cytotoxic T cells (CTLs) (p < 0.0001) and a decrease in percent of FOXP3+/CD4+ T regulatory cells (Tregs) (p < 0.0001) in tumors treated with T-Vec compared to mice not treated with T-Vec. QmIF analysis shows a qualitative increase in immune cells in triple combination group compared to control, quantitative analysis ongoing. NanoString at 30d post treatment shows an increase in Th1 and interferon related genes, including CD8a, CXCL9, CCL5, gzmA and gzmB in mice receiving T-Vec. Conclusions: Our findings show that BRAFi+α-PD1+T-Vec combination therapy is more effective than any single treatment in controlling tumor growth. T-Vec increases tumoral infiltration of CTLs, decreases intratumoral Tregs, and activates a Th1 transcription program in the TME. This study provides rational basis to combine targeted agents, oncolytic virus and checkpoint inhibitors in the treatment of melanoma.
Study on the relationship between microsatellite status and clinicopathological characteristics of colorectal cancer patients after surgery.
Authors: Meili Chen, Lin Li, Lixia Yu, Baorui Liu, Xiaoping Qian, Jia Wei, Mi Yang
Journal: Journal of Clinical Oncology (2018)

e15645 Background: Microsatellite status plays an important role in prognosis and treatment of colorectal cancer. However, the association of microsatellite status with clinicopathological features of colorectal cancer patients after surgery remains controversial. Methods: This study collected 572 colorectal cancer cases with clear pathological diagnosis and clinicopathological features from Department of Pathology, Nanjing Drum Tower Hospital from June 2014 to June 2017. The microsatellite status and RAS mutations were detected by polymerase chain reaction., Ki67, EGFR , MGMT and Lgr5 have been detected by immunohistochemistry. The clinicopathological features have been analysed based on the microsatellite states. Results: In this study, we found MSI-H in 7.0% of all patients, and 93.0% cases with MSS/MSI-L.Compared with MSS and MSI-L colorectal cancer cases, MSI-H colorectal cancer cases have the following characteristics: (1) more likely located in the right colon; (2) the incidences of different age levels were comparable; (3) at early cancer stage (I/II) (P = 0.003); (4) a lower proportion of lymph node metastasis (P = 0.023); (5) a lower proportion of cancerous nodules (P = 0.005); (6) lower mutation rate of KRAS (P = 0.004) and no mutation of NRAS were found in MSI-H colorectal cancer. There was no significant difference in the positive rates of MGMT, EGFR, Lgr5 and ki67 between the two groups. Conclusions: The microsatellite status was associated with patient age, proximal location, cancer stage and lymph node invasion. MSI-H patients may have a better prognosis. And the lower mutation rate of KRAS/NRAS and higher methylation rate of MGMT were found in MSI-H cases. Our results will provide the basis for individual diagnosis and treatment of colorectal cancer.
P01.116 Treatment with Dabrafenib in a patient with BRAF mutated recurrent ganglioglioma
Authors: F Pasqualetti, A Gonnelli, A Molinari, M Cantarella, R Mattioni, D Baldaccini, M Grazzini, F Paiar, R Rudà, R Soffietti
Journal: Neuro-Oncology (2018)

Gangliogliomas are rare tumor usually arising in the supratentorial region, WHO grade 1 or 2. In these tumors, BRAF mutation may constitute a driver genetic alteration and a biomarker of response to BRAF inhibitors. Dabrafenib is an oral inhibitor of BRAF and has shown to significantly improve progression-free survival in patients with BRAF mutated metastatic melanoma. In March 2015, after being diagnosed with left front-temporal enhancing mass, a 31-year-old lady was referred to the University Hospital of Pisa. In the previous two months, the patient had noticed motor aphasia and, due to the persistence of the symptoms, she was sent to the emergency room by the general practitioner. Previous history did not show any co-morbidity. An MRI displayed a fronto-parietal tumor with some contrast enhancement. The patient underwent craniotomy and subtotal tumor resection. Histopathology revealed a WHO grade I ganglioglioma and immunohistochemistry (IHC) documented focal expression of P-53, CD34, and ki-67 proliferation index of 3%. BRAF V600E mutation (Val600Glu(GTG◊GAG)) was detected by polymerase chain reaction. Postoperatively, the patient received radio-chemotherapy with temozolomide (60 Gy in 30 fractions), but 10 months later the patient experienced disease progression. A second surgery was performed without any neurological impairment. The disease monitoring with MRI revealed a partial tumor removal and the pathology confirmed the previous diagnosis. After second surgery, considering the Karnofsky Performance Status Score of 100, the young age and, the presence of BRAF mutation, our multidisciplinary team (in agreement with colleagues of the Neuro-Oncology Unit of the University of Turin) decided to administer the selective BRAF inhibitor Dabrafenib (75 mg twice per day for the first 21 days, then 150 mg twice per day). Since the beginning of the salvage systemic therapy, the patient did not experience treatment-related adverse events. Magnetic resonance performed two months after the start of Dabrafenib and then every three months showed a major response. After 15 months due to the persistent disease response and MRI, we decided to stop the administration of Dabrafenib. Three months after interruption of dabrafenib a new MRI detected a second disease progression being the patient asymptomatic, and we decided to restart the administration of Dabrafenib, which is ongoing. Despite the lack of literature on the use of Dabrafenib in Central Nervous System tumors, this case report provides evidence that Dabrafenib can be active in patients with ganglioglioma with BRAF mutation and confirms the safety related to this agent.
Evaluation of cancer risk in patients with periodontal diseases.
Authors: Deniz Can Guven, Omer Dizdar, Abdullah Cevdet Akman, Ezel Berker, Emre Yekeduz, Furkan Ceylan, Batuhan Baspinar, Ilgın Akbiyik, Burak Yasin Aktas, Deniz Yuce, Mustafa Erman, Mutlu Hayran
Journal: Journal of Clinical Oncology (2018)

e13571 Background: Periodontal diseases has been linked to various systemic diseases including cancer. In this study, we aimed to investigate the risk of cancer among patients with any periodontal disease who were referred to the Periodontology Unit of our hospital and compared the results with the incidences of the similar age and gender groups from Turkish National Cancer Registry (TCNR) data. Methods: Patients diagnosed with any periodontal disease at Hacettepe University Periodontology Department between 2007 and 2012 were assessed and data on the diagnosis of any cancer after periodontal disease were collected from patient files. Patients ≤50 years of age and those with a prior cancer diagnosis were excluded. The age- and gender-standardized incidence rates (SIR) were calculated by dividing the number of observed cases by the number of expected cases from TCNR 2013 data. Results: A total of 5199 patients with periodontal disease (gingivitis or periodontitis) were included in the study. Median follow-up was 7,2 years. On follow-up, 319 new cases of cancer were detected. Patients with periodontal diseases had 17% increased risk of cancer compared with the expected counts at the corresponding age and gender group (SIR 1,17; 95% CI 1,04-1,3, p = 0,006). The increased cancer risk was statistically significant in women (SIR 1,24; 95% CI 1,05-1,45, p = 0,008) but not in men (SIR 1,11; 95% CI 0,95-1,28, p = 0,197). Among women with periodontal disease, the risk of breast cancer (SIR 2,19; 95% CI 1,71-2,77, p < 0,001) and head and neck cancer (SIR 4,71; 95% CI 2,19-8,93 p < 0,001) were significantly increased. Among men, the risk of prostate cancer (SIR 3,75; 95% CI 0,95-10,21 p < 0,001) and head and neck cancer (SIR 3,55; 95% CI 1,87-6,17 p < 0,001) and hematological cancers (SIR 1,76; 95% CI 0,97-2,93 p = 0,04) were significantly increased compared with general population. Conclusions: This study showed that periodontal diseases were associated with increased risk of breast and head and neck cancer in women, and prostate and head and neck cancer and hematological cancers in men. Besides other well-known benefits for overall health, providing oral/dental health should also be considered and employed as a cancer prevention measure.
Serum microRNA expression during neoadjuvant chemoradiation for rectal cancer.
Authors: Stephanie Hui-Su Lim, Emilia Ip, Wei Chua, Weng Ng, Christopher Henderson, J-S Shin, Benjamin Howell Lole Harris, Alessandro Barberis, Mark Cowley, Paul L. De Souza, Kevin Spring
Journal: Journal of Clinical Oncology (2017)

e15081 Background: Changes in microRNA (miRNA) expression during treatment for locally advanced rectal cancer (LARC) may provide insight into disease biology and potentially act as predictive biomarkers. We investigated 112 miRNAs in serum during neoadjuvant chemoradiation for LARC. Methods: Serum was collected at baseline, week 3 and at completion of chemoradiation from 40 prospectively recruited patients with LARC. Responders were classed as tumour regression grade (AJCC classification) 0 or 1 and non-responders as 2 or 3. Serum was also collected from 20 healthy controls. RNA extraction was performed using the Norgen total RNA purification kit. Reverse transcription and pre-amplification were performed according to Taqman OpenArray MicroRNA Panels manufacturer's instructions. QuantStudio12K platform was used for miRNA array qPCR. The delta-delta-Ct method was used to identifiy differentially expressed miRNAs, normalised against U6 snRNA. Analysis was performed in R using paired t-statistics and the Benjamini-Hochberg False Discovery Rate for multiple hypothesis testing adjustment, with q &lt; 0.05 for significance. Enriched KEGG pathways were identified using DIANA, based on verified gene targets of each miRNA from Tarbase. Results: Four miRNAs (miR-125b-1, miR-1183, miR-130a, miR-375) were differentially expressed in baseline patient samples compared to controls. From baseline to completion of treatment, three of these - miR-125b-1, miR-1183, miR-130a were downregulated by more than 2-fold. Comparing responders and non-responders, miR-130a was significantly downregulated in the non-responders only. Conclusions: miR-125b-1, miR-1183 and miR-130a are significantly downregulated in patients with LARC during chemoradiation. These miRNAs are known to target key colorectal cancer genes such as ATM and CHEK1, which have been implicated in chemoradiation resistance. miR-130a warrants further investigation as a predictive biomarker, being downregulated in patients with a poor response to therapy. Work is ongoing, investigating these miRNA targets in the solid tissue in these patients. To our knowledge, this is the first study to profile potentially predictive miRNA changes during chemoradiation in LARC.
Personalized gene expression profiling-guided (MAGE) therapy in resistant sarcomas. Preliminary data.
Authors: Manuel Sureda, Ramon Gonzalez Manzano, Elena Ma Martínez, Francisco J. Fernández-Morejón, Joseba Rebollo, Aurora Crespo, Belen Valenzuela, Josep Farre, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2016)

e14028 Background: Genomic-based profiling of tumors constitutes an encouraging approach that favors the selection of active regimens minimizing the possibility of futile therapies. Previous experience with this technique has been reported (ASCO'12 # 3,064; Am J Clin Oncol. 2014). In relapsed or disseminated sarcomas resistant to doxorrubicin and/or ifosfamide there are not good therapeutic options. MAGE represents a way to explore new personalized regimes to treat these patients. Methods: Pts with previously treated progressive sarcomas of different histologies and non bone metastatic lesions had immediately frozen biopsies, RNA isolation and quality validation after confirmation of viable tumor in more than 30% of the sample. mRNA was hybridized to a whole human genome oligonucleotide microarray. Genes related to the sensitivity and resistance profile for the most frequently used drugs were studied in tumor and normal tissue to evaluate the differential expression associated with malignant phenotype. Therapy was selected according to MAGE profiling, drug availability, and patient's acceptance. Results: From Mar 2011 to Set 2015, 13 procedures of MAGE were performed in 11 pts. Previous treatment included at least surgery, radiotherapy and chemotherapy with DOX/IFX. MAGE profiling revealed a median of 8 (5-10) potentially active drugs, including chemotherapy and TKIs, most of them commercially available. 3 partial responses were observed, in a pt with synovial sarc treated with 177Lu-somatostatin (13 m), in a pt with FMH (8 mo, gemcitabine/imatinib/temodal) and in a pt with angiosarc (4 mo, metronomic CTX plus pazopanib). Two additional cases were treated as
NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT.
Authors: Adi Diab, Michael E. Hurwitz, Daniel C. Cho, Vassiliki Papadimitrakopoulou, Brendan D. Curti, Scott S. Tykodi, Igor Puzanov, Nuhad K. Ibrahim, Sara M. Tolaney, Debu Tripathy, Jianjun Gao, Arlene O. Siefker-Radtke, Wendy Clemens, Mary Ann Tagliaferri, Scott N. Gettinger, Harriet M. Kluger, James M. G. Larkin, Giovanni Grignani, Mario Sznol, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2018)

3006 Background: PIVOT is an ongoing, open-label, phase 1/2 study of NKTR-214 (214; CD122-biased agonist) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (MEL, RCC, NSCLC, TNBC, and UC). 214 monotherapy increases newly proliferative CD8+ T cells in tumors and increases cell surface PD-1 and PD-L1 expression, demonstrating a potentially synergistic mechanism with anti-PD-1 therapy. Methods: In P1 dose escalation, pts received 214 (0.003, 0.006 or 0.009 mg/kg) with N (240 mg or 360 mg) administered IV as outpatient Q2W or Q3W; in P2 expansion, the RP2D of 214 (0.006 mg/kg) with N (360 mg) Q3W was administered concurrently. Response was assessed Q8W by RECIST v1.1. Matched tumor samples were evaluated for changes from baseline in immune cell populations, gene expression, and T cell receptor repertoire. Tumor baseline and on treatment PD-L1 protein expression was assessed (28-8 IHC assay). Results: As of 7FEB2018, 162 pts (P1, n = 38; P2, n = 124) were evaluable for safety. The most common TRAEs of all grades at the RP2D ( > 25%) in pts were flu-like symptoms (63%), fatigue (39%), rash (38%) and pruritus (30%). G3+ TRAEs at the RP2D were 11%. No pts discontinued treatment or died from TRAEs. A total of 60 IO-treatment naïve stage IV pts (P1, n = 30; P2, n = 30) were efficacy evaluable (≥1 scan) (23 MEL, 24 RCC, 6 NSCLC, 4 UC, 3 TNBC). 22/30 P2 pts had only 1 scan. ORR (CR+PR) and DCR (CR+PR+SD) in 23 MEL (1L) pts was 52% and 78%. 18/23 MEL pts had known PD-L1 status. ORR was 5/9 (56%) for PD-L1(+) pts and 4/9 (44/%) for PD-L1(-) pts. ORR and DCR in 24 RCC (1L) pts was 54% and 79%. 20/24 RCC pts had known PD-L1 status. ORR was 4/7 (57%) for PD-L1(+) pts and 7/13 (54%) for PD-L1(-) pts. ORR and DCR in 6 NSCLC (1-2L) pts was 50% and 67%. 5/6 pts had known PD-L1 status. ORR was 3/5 (60%) in PD-L1(-) pts. ORR and DCR in 4 UC (1L) was 75% and 100%. ORR/DCR in 3 TNBC (1- 2L) pts was 33%. In 60 evaluable pts, 32/32 responses are ongoing (0.3+ to 12.0+ mos) with 45/60 pts still on treatment. Conclusions: 214 plus N was well-tolerated with no TRAE discontinuations. Preliminary efficacy shows encouraging ORR/DCR with responses observed in 5 of 5 tumor types in I-O treatment naïve 1-2L pts. Updated data to be presented. Clinical trial information: NCT02983045.
P05.72 Single-step resection of spheno-orbital meningiomas and orbital reconstruction using customized CAD/CAM implants
Authors: B Krischek, L Goertz, M TImmer, R Goldbrunner, P Stavrinou
Journal: Neuro-Oncology (2018)

Computer-aided design and manufacturing (CAD/CAM) implants are fabricated based on volumetric analysis of computed tomography (CT) scans and are routinely used for the reconstruction of orbital fractures. We present three cases of patients with spheno-orbital meningiomas that underwent tumor resection, orbital decompression and orbital reconstruction with patient specific porous titanium or acrylic implants in a single procedure. The extent of bone resection of the spheno-orbital meningiomas was planned in a virtual three-dimensional (3D) environment using preoperative thin-layer CT data. The anatomy of the orbital wall in the resection area was reconstructed by superimposing the contralateral unaffected orbit and by using the information of the neighboring bony structures. The customized implants were designed in the desired size and shape using computer-aided manufacturing. Furthermore, a corresponding craniotomy template in the form of a frame was produced for precise craniotomy. All patients presented with a spheno-orbital meningioma and an exophthalmus. After osteoclastic craniotomy with the drilling template orbital decompression was performed. The cranioplasty implant fitted tightly in all three cases and could be easily fixated with mini-plates and screws, although in one case a reoperation was necessary for additional resection, as well as drilling and repositioning of the implant. The postoperative CT scans showed an accurate reconstruction of the orbital wall. After surgery, exophthalmos was substantially reduced and a satisfying cosmetic result was achieved in all patients. The concept of preoperative 3D virtual treatment planning and single-step orbital reconstruction with CAD/CAM-implants after tumor resection involving the orbit is well feasible and can lead to good cosmetic results.
INNV-31. USER EXPERIENCE WITH NEW, AESTHETICALLY IMPROVED TRANSDUCER ARRAYS FOR DELIVERY OF TUMOR TREATING FIELDS FOR GLIOBLASTOMA
Authors: Adrian Kinzel, Jai Grewal, Michael Graeb, Eilon Kirson
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are low-intensity, intermediate frequency alternating electric fields for glioblastoma. TTFields are administered using the Optune® system, comprised of two main components an electric field generator and insulated transducer arrays (TAs). The current TAs consist of 2 opposing pairs of TAs having ceramic disks arranged within a white adhesive bandage, designed to hold the TAs tightly to the shaved scalp. In response to patient and healthcare provider requests, NovocureTM evaluated tan colored TAs to minimize the stark appearance of white TAs for patients, making the TAs more amenable for use in public settings. MATERIALS AND This study was carried out in 25 newly diagnosed and recurrent GBM patients in Germany receiving Optune. Patients with KPS >70, caregiver support and skin intact at study initiation were asked to complete a questionnaire, which assessed patient satisfaction with the comfort, aesthetics and convenience associated with the tan TAs. Patients reported responses to questionnaire at day 0 (white arrays), days 7 and 28 (wearing the tan arrays). Median patient reported changes from baseline to Day 28 in responses in the questionnaire were compared using a Wilcoxon signed rank test. Patients reported the color of TAs to be an important attribute (p<0.011). The tan arrays were less conspicuous than white arrays (p<0.0052). Participants in Germany found tan color was neither too dark nor too light (p<0.001). Participants felt that wearing the tan arrays were significantly cooler than the white arrays. Optune is designed to be integrated into patients daily life. Results from phase 3 clinical trials showed a correlation between efficacy of TTFields and daily treatment duration. Therefore, improvements addressing patients user experience with the tan colored TAs, which minimize calling attention to the patients medical condition, may help to further improve treatment compliance and patient satisfaction.
An open-label phase 1 trial of the safety and efficacy of daily subcutaneous SPL-108 injections when used in combination with paclitaxel in patients with platinum-resistant, CD44+, advanced ovarian epithelial cancer.
Authors: Eugenia Girda, Alexandre Buckley de Meritens, Malcolm Finlayson, Aliza Leiser, David Nelson, Michael H. Silverman, Ruth Stephenson, Lorna Rodriguez-Rodriguez
Journal: Journal of Clinical Oncology (2018)

TPS5608 Background: Ovarian cancer often presents in advanced stages and is treated with platinum-based chemotherapy. However, many patients develop platinum-resistant disease with either failing to achieve clinical response or progressing within 6 months after completion of treatment. Our laboratory has shown that CD44 contributes to the development of chemotherapeutic resistance, through MDR1-dependent/P-glycoprotein mediated efflux of chemotherapeutic agents. Targeting CD44 or related signaling pathways inhibits tumor growth and relapse, and increases sensitivity to cytotoxic agents. SPL-108 is an 8-amino-acid peptide derived from single chain urokinase plasminogen activator that binds to CD44. In vitro and in vivo experiments showed that SPL-108 has therapeutic activity in models of ovarian and other cancers. Phase I trials with SPL-108 in healthy volunteers demonstrated no systemic adverse events; phase Ib trials in women with gynecologic cancers showed self-limited, mild or moderate adverse events with several subjects showing stable disease. Phase II trials in ovarian cancer patients showed improved time to disease progression with no grade 4 toxicity, 6.5% had grade 3 all of which were constitutional. In the current trial, SPL-108 would be used in combination with paclitaxel in an attempt to reverse efflux-mediated resistance to chemotherapy. Due to positive safety profile of SPL-108, the goal is to achieve improved efficacy without enhanced toxicity. Methods: Open-label 2-arm phase I trial. Arm I includes 6-12 patients, with a 3+3 design with 2 cohorts. Cohort 1 will receive daily 150-mg SPL-108 SQ, cohort 2 will receive twice-daily 150-mg SPL108; both cohorts will have concurrent administration of weekly paclitaxel of 80 mg/m2, on Days 1,8,15 of a 28 day cycle. Safety will be assessed and subjects without dose-limited toxicity continue 6 cycles, unless disease progression or unacceptable toxicity occurs. Arm II is the Exploratory Expansion Phase: 12 subjects receive SPL-108 daily dose determined in the Arm I Safety phase with concurrent 80 mg/m2 paclitaxel. Clinical trial information: NCT03078400.