tbuckley/cabot-search huggingface dataset:
Abstract 3147: A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer
Authors: Wenyun Li, Fengmei Pi, Xiaoxia Liang, Taiyuan Cao, Yiheng Lin, Xiaohui Zhai, Mengli Huang, Hao Qin, Chan Gao, Shangli Cai, Xianrui Wu, Jian Xiao, Ping Lan
Journal: Cancer Research (2019)

Abstract Background: Microsatellite instability (MSI) has become a critical predictive and prognostic biomarker in multiple cancers. The mainstream MSI-detecting techniques, immunohistochemistry (IHC) and polymerase chain reaction (PCR), may have trouble profiling an expanded panel if tissue samples are not available in adequate quantity, depriving patients of treatment options, especially for those with advanced disease. Next generation sequencing, in contrast, allows for massively parallel examination of numerous targets in one single test. In this work, we developed a novel NGS-based assay to detect MSI in colorectal and gastric cancer (CRC/GC) and clinically validated its performance in comparison with IHC and PCR. Methods: Surgical or biopsy specimens collected from 104 CRC and 15 GC patients were examined for MSI status using IHC, PCR and NGS employing a novel algorithm. The concordance rates between the three techniques were assessed using z-test. Results: Of the 119 patients enrolled, 53.8% had metastases. IHC tests identified deficient MMR protein expression in 40 (33.6%) cases (dMMR), seven of which were microsatellite stable (MSS) using both PCR and NGS. A discrepancy was also observed for one MMR-proficient (pMMR) case where NGS and IHC consistently produced negative results (pMMR/MSS), while PCR reported a MSI-high (MSI-H) status. The NGS method demonstrated 97.1% (33/34) sensitivity and 100% (85/85) specificity compared to PCR,and 82.5% (33/40) sensitivity and 100% (79/79) specificity compared to IHC. The concordance rate was 99.1% between NGS and PCR, and 94.1% between NGS and IHC. Of the 33 dMMR/MSI-H patients, 30.3% harbored germline defects, suggestive of Lynch Syndrome. In addition, in line with previous reports, the dMMR/MSI-H subset showed a significantly higher median tumor mutational burden (TMB) than the pMMR/MSS patients (P=0.0039). Conclusion: Our NGS-based approach is reliable and robust for MSI status determination in CRC/GC. Citation Format: Wenyun Li, Fengmei Pi, Xiaoxia Liang, Taiyuan Cao, Yiheng Lin, Xiaohui Zhai, Mengli Huang, Hao Qin, Chan Gao, Shangli Cai, Xianrui Wu, Jian Xiao, Ping Lan. A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3147.
The use of first, second and beyond line chemotherapy for metastatic pancreatic ductal adenocarcinoma at the Royal Marsden Hospital
Authors: O. Butters, F. Swann, I. Leslie, K. Young, K. Kouvelakis, D. Watkins, S. Rao, I. Chau, D. Cunningham, N. Starling
Journal: Annals of Oncology (2019)
Abstract 299: Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers
Authors: Mahta Samizadeh, Debashree Chakrabarti, Yuhan Zhu, Robert Louis Treuting, Johanne Kaplan, William Siders, Jamie D. Barber
Journal: Cancer Research (2019)

Abstract Depending upon the definition used, as many as half of all cancers diagnosed are considered rare cancers, and most rare cancer patients would greatly benefit from additional therapies. Repurposing of drugs for use in oncology represents an attractive strategy for the rapid development of therapies that address the significant unmet medical need that remains for rare cancers. The FDA-approved anti-helminthic drug mebendazole (MBZ) has been reported to affect several biological pathways involved in tumor growth and metastasis. Based on this activity, multiple rare cancer tumor cell lines including neuroblastoma, carcinoid tumors, esophageal adenocarcinoma, gastrointestinal stromal tumors, leiomyosarcoma, pheochromocytoma, and mesothelioma were analyzed for their susceptibility to MBZ treatment alone or in combination with standard chemotherapeutic agents in vitro. Cultured cells exposed to increasing concentrations of MBZ alone showed a significant decrease in cell viability with IC50s ranging from 0.09-2.2 μM. To evaluate efficacy of MBZ in an additional model system, an ex vivo 3D assay using gastric cancer primary cells isolated from two patient-derived xenograft (PDX) models was performed. Cells were seeded in 3D cultures and treated for seven days with MBZ at nine different doses in triplicate. IC50s were determined to be 0.74 and 0.76 μM indicative of significant potency. These results along with the in vitro data generated using cell lines suggest that MBZ may represent an effective anti-cancer agent across multiple rare cancer indications. However, since tumor cells can often evade or develop resistance to single agent therapy, the potential for synergistic combinations with chemotherapeutic agents was also explored in vitro. Cells were plated in triplicate and treated with a range of concentrations of MBZ and relevant chemotherapeutic agents in a complete Latin square. Combination indexes (CI) were determined based on the method described by Chou and Talalay. Several synergistic drug combinations were identified with CI values ranging from 0.008 to 0.428 (CI &amp;lt; 0.9 indicates synergy). Overall, our results indicate that synergistic combinations of MBZ and chemotherapy agents represent a promising strategy for the treatment of rare cancers. Citation Format: Mahta Samizadeh, Debashree Chakrabarti, Yuhan Zhu, Robert Louis Treuting, Johanne Kaplan, William Siders, Jamie D. Barber. Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 299.
Abstract 21371: Derivation and Validation of a Simple Exercise-Based Algorithm for Prediction of Genetic Testing in Relatives of LQTS Probands
Authors: Raymond Sy, Ishvinder Chattha, Christian vanderWerf, Priya Chockalingam, Arthur A Wilde, Sami Viskin, Arnon Adler, Jeffrey S Healey, Vijay Chauhan, Mark Perrin, Michael H Gollob, Andrew Krahn
Journal: Circulation (2010)

Introduction: Genetic testing can confirm LQTS in asymptomatic relatives of patients with an identified mutation. However, genetic testing is costly and subject to availability. The accuracy of a s...
The myeloma-developing regimens using genomics (MyDRUG) master protocol.
Authors: Daniel Auclair, Kenneth Carl Anderson, David Avigan, Giada Bianchi, Noa Biran, Maria Chaudhry, Hearn J. Cho, Maggie Furlong, Craig C. Hofmeister, Ankit J. Kansagra, Amrita Y. Krishnan, Jeremy Todd Larsen, Gregory Joshua Orloff, Ravi Vij, Peter Michael Voorhees, Andrew Jenho Yee, Jing Christine Ye, Jeffrey A. Zonder, Sagar Lonial, Shaji Kumar
Journal: Journal of Clinical Oncology (2019)

TPS8057 Background: Multiple myeloma (MM) is the second most prevalent blood cancer, representing approximately 1% of all cancers. Although overall survival has improved in recent years due to new approved agents, the vast majority of MM patients (pts) ultimately stop responding to treatment. Moreover, about a quarter of MM pts characterized as “high risk” experience limited benefit from existing treatments. Seminal genomic sequencing research efforts, such as the MMRF CoMMpass study, have highlighted that a large number of MM cases harbor potentially actionable oncogenic molecular alterations and published reports on small numbers of cases suggest that Precision Medicine (PM) interventions clinically targeting such actionable drivers may benefit MM pts. These results suggest that PM approaches in MM are possible and should be further studied clinically. To that end, we have launched MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual pt’s genomics. Methods: This study is a Phase I-II, multicenter master protocol in functional high risk MM patients (i.e patients having progressed from baseline treatment within 18 months without maintenance or 3 years on maintenance) with 1-3 prior lines of therapy. Patients are screened for actionable genomic alterations on the CLIA-grade MI-ONCOSEQ platform. Patients with actionable alterations are assigned to the appropriate targeted agent used in combination with a backbone regimen ixazomib, pomalidomide and dexamethasone (IPd), whereas patients without such alterations go on an immune arm (see Table). Inclusion criteria include measurable disease (as measured by M-protein and FLC) and acceptable hematologic and metabolic functions. A maximum of 12 evaluable pts will be accrued onto the phase I portion of each arm and an additional 21 evaluable phase II pts will be accrued onto each arm for a total of 27 evaluable pts at the MTD combination dose. The primary objective of the study is to evaluate ORR per IMWG consensus criteria. Secondary objectives are to assess adverse events (AEs), progression-free survival, and overall survival (OS). Experimental correlative aims include assessing molecular or clonal response, molecular and immune signatures of resistance/response, MRD. Clinical trial information: NCT03732703. [Table: see text]
The efficacy of ibrutinib-based combination therapy for mantle cell lymphoma: A systematic review.
Authors: Prem Thirunagari, Aida Siyahian, Ahmad Iftikhar, Ahsan Wahab, Afia Ashraf, Ammara Majeed, Nadia C Nunes Cavalcante Parr, Atlantis Dawn Russ, Abhijeet Kumar, Faiz Anwer
Journal: Journal of Clinical Oncology (2019)

e19043 Background: Mantle Cell Lymphoma (MCL) is generally treated with rituximab (R) in combination with other drugs. However, treatment for relapsed or refractory (RR) MCL is challenging. For Ibrutinib (Ibr), we aim to determine the efficacy in combination therapy for newly diagnosed (ND) and RR MCL. Methods: Per PRISMA guidelines, a systematic review was performed using four databases. Results: Eleven studies with 363 patients were identified, most commonly studied regimens were ibrutinib in combination with R in 2 phase II studies and 2 studies on Ibr in combination with venetoclax. Ibr was also studied as part of the three-drug regimens in combination with bendamustine &amp; R, lenalidomide &amp; R, and obinutuzumab &amp; venetoclax. Ibr was studied in combination with other drugs such as palbociclib, ublituximab, and bortezomib as part of the two-drug regimens. Results summarized in Table. Adverse events included cytopenia, atrial fibrillation, septic shock, tumor lysis syndrome, and GI toxicities. Conclusions: Ibr in combination with R demonstrated the highest overall ORR and CR in treatment of ND MCL, whereas combination with venetoclax and obinutuzumab demonstrated highest overall ORR and CR in treatment of RR MCL. Additional studies are needed to further assess and confirm its role in treatment. [Table: see text]
TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
Authors: Tanya Siddiqi, Kathleen Anne Dorritie, Jacob Drobnyk Soumerai, Deborah Marie Stephens, Jason A Dubovsky, Heidi H. Gillenwater, Lucy Gong, Jerill Thorpe, Lin Yang, William G. Wierda
Journal: Journal of Clinical Oncology (2019)

7501 Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 10 6 or DL2 = 100 × 10 6 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10 −4 ) and by NGS in bone marrow (BM; 10 −6 ). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.
Abstract CT116: Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma
Authors: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, John Langlands, Anne Steino, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083’s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase I/II study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts. The dose-confirmation part (20, 30, and 40 mg/m2/day IV infusion on days 1-3 of a 21-day cycle) has been completed, and the expansion part has been initiated in up to 20 additional patients at 30 mg/m2/day IV infusion on days 1-3 of a 21-day cycle. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Trial design, enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, John Langlands, Anne Steino, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT116.
Abstract 1983: Cancer exosomes immunosuppressive activity in the absence of contaminating soluble factors is multifactorial
Authors: Shin La Shu, Junko Matsuzaki, Cheryl Allen, Yunchen Yang, Edward Hurley, Kunle Odunsi, Yun Wu, Marc S. Ernstoff
Journal: Cancer Research (2019)

Abstract Cancer derived exosomes, along with soluble factors such as growth factors, cytokines and chemokines have been identified as integral immunosuppressive pathways employed by cancer cells. Using melanoma cell lines as a model for generating human melanoma exosomes (HMEX), we studied the soluble factors associated with exosome purification methods. A Luminex 13-plex T cell activation kit was used to detect the presence of soluble factors in exosome isolates. We have demonstrated that combining Ultrafiltration and Size Exclusion Chromatography (REIUS method) can yield up to 58-fold more exosomes than ultracentrifugation (UC) with greatly reduced concentrations of contaminating soluble factors (IL-8: 4.6 pg/ml by REIUS versus 489 pg/ml by UC | IL-10: 1,052 pg/ml by REIUS versus 34,500 pg/ml by UC). A novel exosome-based Compact Surface Plasmon Resonance Biosensor demonstrated that REIUS-isolated exosomes abundantly express PD-L1 on their surface compared to UC-purified exosomes. These HMEX significantly inhibited a cloned NY-ESO tumor antigen-specific patient derived T cell function when co-cultured with a NY-ESO positive melanoma cell line for 4 h (IFN-γ positive T cell population: 78.5 ± 0.03 % versus 49.05 ± 0.07 %). Blocking with anti-PDL1 or anti-IL-10 failed to restore T cell function (IFN-γ production), while both anti-PD-L1 and anti-IL-10 antibodies partially reverse this suppression, thereby identifying IL-10 and PD-L1 as a novel collaborating inhibitory pathway. Taken together, we report that different exosome isolation methods impact the nature of the exosomes and contaminating soluble factors and should be chosen with caution. In addition, our data suggests a novel role for tumor-derived exosomes in the IL-10 and PD1-PDL1 axis crosstalk that impacts functional activity of T cells. Citation Format: Shin La Shu, Junko Matsuzaki, Cheryl Allen, Yunchen Yang, Edward Hurley, Kunle Odunsi, Yun Wu, Marc S. Ernstoff. Cancer exosomes immunosuppressive activity in the absence of contaminating soluble factors is multifactorial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1983.
Preclinical Alzheimer Disease—Early Diagnosis or Overdiagnosis?
Authors: Kenneth M. Langa, James F. Burke
Journal: JAMA Internal Medicine (2019)

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Abstract 4522: An in vitro 3D immune exclusion tumor model engineered in a layer-by-layer fashion
Authors: Kolin C. Hribar, Tracy Kleinheinz, Joanna Klementowicz, Susan Kaufman, Robert A. Blake, Celine Eidenschenk
Journal: Cancer Research (2019)

Abstract Recent immunotherapy failures in clinical trials have elucidated the affects of the tumor stroma on attenuating therapeutic response. In some cancers, the stroma consists of a collagen-rich fibrotic zone on the tumor periphery that traps infiltrating CD8+ T cells, allowing the tumor to evade immune cell-mediated death. Typically, animal models are employed to study complex physiology. However, known challenges to these methods include cost, duration and throughput. Thus, we sought to develop a 3D in vitro model that recapitulates the immune exclusion phenotype in a high throughput manner. We utilized a novel 3D cell culture platform, VersaGel and Symphony, to pattern tumor-stroma-immune compartments in a layer-by-layer fashion in 96-well plates. VersaGel is a chemically modified extracellular matrix that is amenable to light-induced crosslinking using the Symphony apparatus. Moreover, Symphony allows for discrete layers to be formed with any VersaGel/cell mixture, with defined 3D gel thicknesses (eg. 100µm, 250µm, 500µm) and areas in the plate (eg. 2mm, 4mm, or 8mm diameter discs). GFP-labeled MC38-ova (ovalbumin antigen) colon carcinoma cells were grown in 100µm thick 3D VersaGel with or without CFP-labeled mouse embryonic fibroblasts (MEF) layered on top for 4 days. After, OT-1-RFP CD8+ cells were added to the culture medium to assess their penetration depth and tumor cell death over 3 days. 3D cell analysis through the optically clear VersaGel was performed in situ using high content confocal microscopy, effectively quantifying RFP/CFP/GFP-labeled cells and DRAQ7-labeled dead cells using Z-stack analysis. In the control (tumor-only condition), OT-1 cells fully penetrated the tumor layer and induced cell death. In the experimental condition (with fibroblasts), it was found that the fibrotic stromal layer limited OT-1 penetration to the periphery of the 3D tumor, and, moreover, the total OT-1 cells increased relative to the control. Future analysis may include the utility of wild-type T cells and novel therapeutics targeting the stroma to activate the immune response. The results suggest a novel 3D immune exclusion model that integrates with high content confocal analysis and is amenable to immunotherapeutic screening and translational assessment. Citation Format: Kolin C. Hribar, Tracy Kleinheinz, Joanna Klementowicz, Susan Kaufman, Robert A. Blake, Celine Eidenschenk. An in vitro 3D immune exclusion tumor model engineered in a layer-by-layer fashion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4522.
Reply to S. Sorscher
Authors: Federico Innocenti, Fang-Shu Ou, Xueping Qu, Tyler Zemla, Donna Niedzwiecki, Rachel Tam, Shilpi Mahajan, Richard M. Goldberg, Monica M. Bertagnolli, Charles David Blanke, Hanna Sanoff, James Atkins, Blasé Polite, Alan P. Venook, Heinz-Josef Lenz, Omar Kabbarah
Journal: Journal of Clinical Oncology (2019)