tbuckley/cabot-search huggingface dataset:
Immune cell concentrations among the primary tumor microenvironment in colorectal cancer patients predicted by clinicopathologic characteristics and blood indexes
Authors: Guifang Guo, Yixing Wang, Yixin Zhou, Qi Quan, Yijun Zhang, Haohua Wang, Bei Zhang, Liangping Xia
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune cells play a key role in cancer progression and treatment. It is unclear whether the clinicopathologic characteristics and blood indexes of colorectal cancer (CRC) patients could predict immune cell concentrations in the tumor microenvironment. <h3>Methods</h3> CRC patients with detailed data and tumor tissue who visited Sun Yat-sen University Cancer Center between April 1, 2004, and September 1, 2017, were enrolled. The densities of CD3+ and CD8+ T cells examined by immunohistochemistry in both the core of the tumor (CT) and the invasive margin (IM) were summed as the Immunoscore. The relationships between the Immunoscore and clinicopathologic characteristics and blood indexes, including tumor biomarkers (carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA 19–9)), inflammatory markers (lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (ALB), neutrophils, lymphocytes, monocytes, platelets, NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and LMR (lymphocyte-to-monocyte ratio)) and lipid metabolism markers (cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB)), were analyzed using SPSS. <h3>Results</h3> Older patients had lower CD3+ and CD8+ T cell expression in the IM and a lower Immunoscore than did younger patients. CD8+ T cell expression in the IM and the Immunoscore were lower in right-side tumors than in left-sided tumors. High CD8+ T cell expression in the CT was found in the T4 stage group. The higher the CEA level in the blood, the fewer CD8+ T cells were in the CT. Either fewer monocytes or a higher LMR in the blood, the larger number of CD3+ T cells in the CT. The more ApoA1 was in the blood, the more CD3+ T cells were in both the CT and the IM. <h3>Conclusion</h3> Age, T stage, tumor location, CEA, monocytes, LMR and ApoA1 could reflect immune cells infiltrating the tumor microenvironment of CRC.
68Ga–Prostate-Specific Membrane Antigen-11 PET/CT
Authors: Göksel Alçin, Cihan Gündoğan, İlhan Nahit Mutlu, Tevfik Fikret Çermik
Journal: Clinical Nuclear Medicine (2019)

Abstract A 77-year-old man with newly diagnosed prostate adenocarcinoma with a total prostate - specific antigen level of 6.4 ng/mL and Gleason score 7 (4 + 3) was referred to 68 Ga–prostate-specific membrane antigen-11 (PSMA) PET/CT for initial staging. An intense focal PSMA uptake was shown in the right peripheral zone of the prostate gland consistent with the primary tumor. Additionally, PET/CT demonstrated a PSMA-avid soft tissue mass in the left cerebellopontine angle. The patient had a history of left-sided sensorineural hearing loss.
Abstract 12455: The Impact of Endovascular Therapy for TASC D lesions
Authors: Yukiko Mizutani, Kenji Suzuki, Yoshimitsu Soga, Osamu Iida, Daizo Kawasaki, Yasutaka Yamauchi, Keisuke Hirano, Ryoji Koshida, Daisuke Kamoi, Junichi Tazaki, Michiaki Higashitani, Yoshiaki Shintani, Shinya Okazaki, Terutoshi Yamaoka, Nobuhiro Suematsu, Taketsugu Tsuchiya, Yusuke Miyashita, Hiroki Takahashi, Norihiro Shinozaki, Naoto Inoue, Taiichiro Meguro
Journal: Circulation (2013)

Background: Recently, the application of endovascular therapy (EVT) for aortoiliac lesions has been expanded. ESC guideline mentions that endovascular-first strategy is recommended in all aortoilia...
Transcriptional inhibition of Notch signaling using cell penetrating fusion proteins.
Authors: Agamemnon A. Epenetos, Silvia Colucci, Mahendra Deonarain, Spyros Stylianou
Journal: Journal of Clinical Oncology (2012)

e13525 Background: Notch signalling is deregulated in a number of cancers and is possibly involved in cancer stem cell development. It is postulated that cancers such as breast can become addicted to Notch signalling presenting opportunities for tumour-specific intervention. Due to the presence of at least 4 cell surface receptors that mediate Notch signalling, conventional targeting agents such as monoclonal antibodies cannot inhibit them all. As all the signalling cascades converge on the Notch transcriptional complex (NTC) in the nucleus, inhibition of gene expression by disrupting this machinery is an attractive strategy to overcome this redundancy. Methods: Towards this, we have developed a fusion protein based on the potent cell penetrating protein (CPP) antennapedia (Antp) recombinantly fused to a dominant-negative truncated mastermind-like protein (DN-MAML) called TR4. We have also developed a method of incorporating CPP to deliver intracellular antibody fragments against nuclear targets such as Notch and mastermind. Results: The Antp-DN-MAML protein (TR4) has similar potency to many of the gamma-secretase inhibitors being developed against this pathway but more specific for the NTC.TR4 can inhibit tumour cells in vitro and in vivo and provide some insight into the mechanism of action. Also such intracellular targets are accessible to antibodies, provided they are delivered using CPP such as antennapedia. Conclusions: .As a model system, scFvs have been raised to key epitopes in the NTC which can lead to complex inhibition and the same downstream effects as TR4.In addition, we further demonstrate that there is a more general approach to trascription factor inhibition using single-chain Fvs fused to Antp
Catheter ablation did not reduce CV events and mortality more than drug therapy in symptomatic AF
Authors: Gaetano Santulli
Journal: Annals of Internal Medicine (2019)

Source Citation Packer DL, Mark DB, Robb RA, et al; CABANA Investigators. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019. [Epub ahead of print]. 30874766
Use of TMB and PD-L1 to predict outcomes of checkpoint inhibitor treatment.
Authors: Paul B. Robbins, Tina Krieger, Isobel Pearson, Judith Bell, Jim P. Doherty
Journal: Journal of Clinical Oncology (2019)

150 Background: Medical practice is moving toward a more tailored, patient-centric one with precision medicine (biomarker)-guided therapies. Studies have evaluated ways of applying precision medicine to cancer therapies, and the use of several biomarkers has shown promise. The potential value of tumor mutational burden (TMB) and/or programmed death-ligand 1 (PD-L1) biomarkers to enhance the prediction of which patients are most likely to respond to checkpoint inhibitors has been explored in many studies. The objective of this literature review was to identify and summarize these studies. Methods: Literature searches were performed using electronic medical databases (MEDLINE, Embase, and BIOSIS) and internet searches of specified sites. Bibliographies of key systematic literature reviews and meta-analyses were reviewed for studies of interest. Due to the volume of literature for various cancer types, studies with a sample size of &lt;50 patients were excluded. Results: The review identified 27 trials in non-small cell lung cancer (NSCLC), 39 trials in melanoma, 10 trials in urothelial cancer, and 5 trials in renal cell cancer indications. Studies also were identified in other cancer types (eg, colorectal, breast, and gastric cancer and Merkel cell carcinoma [MCC]). TMB as a predictor of outcomes was evaluated in 12 trials, including 6 in NSCLC. A TMB of ≥10 mutations per megabase was shown to be an effective biomarker in the CheckMate 227 study. PD-L1 was found to predict response in melanoma and all types of NSCLC other than squamous (Checkmate-017). However, prediction of response was not a prespecified analysis in some PD-L1 studies; other studies had small sample sizes and wide CIs. A clear predictive trend for PD-L1 was not identified in renal, breast, or gastric cancer or MCC. Conclusions: On the basis of the data in this review, assessment of TMB and PD-L1 biomarker expression may enhance the prediction of response to checkpoint inhibition in some tumors, such as NSCLC and melanoma. In this rapidly growing area of research, further exploratory biomarkers are being investigated, such as tumor-infiltrating lymphocytes and KRAS and BRAF mutations, that may provide insight on the potential efficacy of a treatment in a given patient.
FPT155-001: A phase Ia/Ib study of FPT155 (CD80-FC) in patients with advanced solid tumors.
Authors: Michael Millward, Hui Kong Gan, Anthony M. Joshua, James Chun-Yen Kuo, Amy Prawira, Gary Edward Richardson, Susannah D. Barbee, Sandeep P. Inamdar, Kristen L. Pierce, Mona Qureshi, Lisa Horvath
Journal: Journal of Clinical Oncology (2019)

TPS42 Background: Despite recent advances in immunotherapy, many patients with advanced solid tumors are refractory to available therapies or eventually relapse. Novel immune therapies are needed with differentiated mechanisms of action that result in improved response rates and durability across a broad range of tumors. FPT155 is a first-in-class therapeutic being developed to meet this need. FPT155 is a recombinant fusion protein composed of the extracellular domain of human CD80 fused with the Fc domain of human immunoglobulin G1. It is designed to act as a potent stimulator of anti-tumor immunity through CD28 and thereby co-stimulate T cell responses only in the presence of antigenic T cell receptor (TCR) signaling. FPT155 alone does not induce spontaneous cytokine release by primary human immune cells, in contrast to a CD28 superagonist antibody that exerts TCR stimulus-independent activity. FPT155 also blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T cell activation. A murine surrogate of FPT155 is a potent inhibitor of tumor growth that induces complete tumor regression in multiple tumor models, including models that are insensitive to anti-PD1 or anti-CTLA4. Methods: The FPT155-001 study is a Phase 1a/1b open-label, multicenter, dose escalation and expansion study to evaluate the safety and tolerability of FPT155 monotherapy. Phase 1a dose escalation includes an accelerated titration design followed by a standard 3+3 design until the recommended dose for Phase 1b is determined by evaluation of all available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Eligible patients with advanced solid tumors who are refractory to all standard therapy for their malignancy will be enrolled in Phase 1a. Phase 1b dose expansion will enroll patients with select tumor types. The primary endpoint is safety in both phases. Key secondary endpoints in Phase 1a include characterization of the FPT155 PK profile and immunogenicity. Key secondary endpoints in Phase 1b include objective response rate, duration of response, progression free survival, and disease control rate. The FPT155-001 trial opened for enrollment in October 2018 and is in progress. Clinical trial information: Submitted - awaiting registration number.
A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).
Authors: Evan W. Alley, Tawee Tanvetyanon, Thierry Marie Jahan, Leena Gandhi, Tobias Peikert, James Stevenson, Katia Schlienger, Weiqun Liu, Nitya Nair, Somayeh Honarmand, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2019)

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.
Predictive model for survival and toxicity in early-phase trials in hematology.
Authors: Rahima Jamal, Bingshu E Chen, Gergana Hristova, Lesley Seymour, Sarit E. Assouline
Journal: Journal of Clinical Oncology (2012)

2547 Background: Strict criteria are used to limit toxicity for patients (pts) enrolled in phase I/II clinical trials, but the ability to survive beyond 12 weeks, a common inclusion criterion, is subjective and error-prone. A prognostic score with 3 variables was designed and validated as an independent predictor of OS in pts with solid tumors included in phase I trials (Arkenau, JCO 2009). We examined the ability of objective measures to predict OS and risk of grade ≥3 toxicity in pts with hematologic malignancies enrolled in early-phase trials. Methods: A retrospective analysis was conducted on 290 pts in Phase I (79 pts) and II (211 pts) trials from the NCIC - Clinical Trials Group and our institution from 1995 to 2009. Only pts with survival data up to 90 days were included. Univariate model (UVA) was used to identify factors significantly associated with OS. A Cox proportional hazards model (MVA) included all factors identified from the UVA. Six prognostic factors were identified in the MVA, and each assigned a score of 0 or 1. Pts were categorized as high or low risk based on the total scores that they received, ≥3 were assigned to the high risk group, and a ≤2 to the low risk group. Kaplan-Meier method was used to generate the survival distribution for the high and low risk groups. Multivariate logistic regression was used to identify the risk factors for grade ≥3 toxicity. Results: The overall median survival was 238 days (95% CI 237 to 331), and 27% of pts had grade ≥ 3 toxicity. In the MVA, albumin (alb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lymphocytes, platelets (plts) and diagnosis were significantly associated with OS. Pts in the low risk group had a median survival of 10.6 months, relative to 2.4 months among pts in the high risk group. Survival at 90 days was 80% in lower risk vs. 36% in the high risk group. In addition, the MVA for toxicity showed that alb, ALP, LDH, plts and performance status were significantly associated with grade ≥3 toxicity. Conclusions: Our model predicts OS, 90 day survival and risk of grade ≥ 3 toxicity among pts with hematologic malignancies entered in Phase I/II trials. Future work will include a linear predictor score based on MVA to refine the prediction model. The model will also be validated using another dataset.
Addition of Cyclophosphamide to Pomalidomide and Dexamethasone in Case of Suboptimal Response to Pomalidomide and Dexamethasone Alone in Relapsed and/or Refractory Multiple Myeloma: Results of the GMMG-Perspective Trial
Authors: Katja C. Weisel, Hans Jürgen Salwender, Christof Scheid, Manola Zago, Britta Besemer, Mathias Hänel, Jan Dürig, Markus Munder, Hans-Walter Lindemann, Anja Seckinger, Christina Kunz, Axel Benner, Dirk Hose, Anna Jauch, Lothar Kanz, Hartmut Goldschmidt
Journal: Blood (2017)
Added Value of Myocardial Blood Flow Quantification and Calcium Scoring During CZT SPECT Myocardial Perfusion Imaging for Coronary Artery Disease Screening
Authors: Matthieu Bailly, Frédérique Thibault, Maxime Courtehoux, Gilles Metrard, Maria-Joao Ribeiro
Journal: Clinical Nuclear Medicine (2019)

Abstract Dedicated cadmium-zinc-telluride cardiac cameras have been shown to provide accurate measurements of absolute myocardial blood flow and flow reserve when PET is not available. We report the case of a 66-year-old woman who underwent 1-day stress/rest myocardial perfusion imaging (MPI) for coronary artery disease (CAD) screening. Relative MPI analysis was normal, whereas low-dose CT showed high calcium score. Myocardial blood flow and flow reserve were strongly impaired in all territories. Coronary angiography confirmed extended CAD. Flow parameters derived from cadmium-zinc-telluride SPECT MPI acquisition and calcium scoring can improve diagnostic accuracy and confidence of CAD.
Retrospective analysis of elderly patients with DLBCL: Single center experience with FIL.
Authors: Yasir Khan, Michael Del Rosario, Sherif Rezk, Thomas H. Taylor, Elizabeth Brem
Journal: Journal of Clinical Oncology (2019)

e19024 Background: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin’s Lymphoma (NHL). According to the SEER database, median age of diagnosis is 67 with 30% of cases diagnosed in patients greater than 75. 1/3 of patients older than 80 do not receive therapy for this potentially curable disease. The Lymphoma Italian Foundation (FIL) tool has been shown to help objectively identify elderly DLBCL patients most likely to benefit from therapy with curative intent. The tool identifies patients as “Fit,” “Unfit,” or “Frail” based on age, comorbidities, and ability to perform activities of daily living. We retrospectively applied the FIL tool to patients treated at our center to evaluate its efficacy in identifying elderly patients most likely to benefit from curative chemoimmunotherapy. Methods: Research protocol was approved by University of California, Irvine IRB. We identified patients with a diagnosis of systemic DLBCL and age ≥70 between January 1, 2010 and November 8, 2018. Medical charts were used to retrospectively apply the FILtool. Results: A total of 86 patients were identified. Mean age was 77. Ratio of germinal center (GC) DLBCL to non-GC was approximately 1:1. 23 patients were categorized as Fit, 8 as Unfit, and 55 as Frail. 96% of Fit, 100% of Unfit, and 91% of Frail patients were evaluated. Rates of complete responses (CR) to initial therapy with curative intent were 77% (17/22) in Fit, 88% (7/8) in Unfit, and 44% (22/50) in Frail patients. CR rate was not different between Fit and Unfit (p&gt;0.05), but the CR rate in Frail patients was significantly reduced compared to the other groups combined (p&lt;0.01). Among Fit and Unfit patients, only one death was treatment-related, but in the Frail group, 6 deaths were related to treatment. Conclusions: Our data suggest that the FILTool is useful in identifying Frail patients that perhaps should be treated with reduced dose-intensity. Additionally, our findings support that Fit and Unfit patients benefit from treatment with curative intent. Future studies will apply the FIL tool prospectively to further validate these findings. [Table: see text]
Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
Authors: Brian Giacopelli, Qiuhong Zhao, Amy S. Ruppert, Akwasi Agyeman, Christoph Weigel, Yue-Zhong Wu, Madelyn M. Gerber, Kari G. Rabe, Melissa C. Larson, Junyan Lu, James S. Blachly, Kerry A. Rogers, William G. Wierda, Jennifer R. Brown, Kanti R. Rai, Michael Keating, Laura Z. Rassenti, Thomas J. Kipps, Thorsten Zenz, Tait D. Shanafelt, Neil E. Kay, Lynne V. Abruzzo, Kevin R. Coombes, Jennifer A. Woyach, John C. Byrd, Christopher C. Oakes
Journal: Blood (2019)
A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers.
Authors: James J. Harding, Amita Patnaik, Victor Moreno, Mark Stein, Anna M. Jankowska, Nieves Velez de Mendizabal, Zhuqing Tina Liu, Mythili Koneru, Emiliano Calvo
Journal: Journal of Clinical Oncology (2019)

12 Background: Combined targeting of both the TIM-3 and PD-L1 immune checkpoint pathways may improve efficacy. LY3321367 mAb targets TIM-3 on immune cells and LY3300054 mAb targets PD-L1 on tumor cells and tumor-infiltrating immune cells. This analysis presents safety, efficacy, pharmacokinetic (PK) and pharmacodynamics/soluble target engagement (TE) results from LY3321367 (anti-TIM-3) monotherapy and in combination with LY3300054 (anti-PD-L1) in patients (pts) with advanced cancer. Methods: This ongoing, open-label phase 1a/1b, dose escalation and expansion study enrolled pts with histologically confirmed advanced relapsed/refractory solid tumors. Pts received IV infusions of 3mg-1200mg LY3321367 Q2W monotherapy (Arm A) or 70mg-1200mg LY3321367 + 200mg-700mg LY3300054 Q2W combination therapy (Arm B). Primary objectives assessed safety and tolerability and determined the RP2D. PK, soluble target TE, anti-drug antibodies (ADAs), and clinical efficacy (RECIST v1.1) were also evaluated. Results: At data cutoff (3 August 2018), LY3321367 monotherapy was administered to 23 pts (Arm A); 18 pts received LY3321367 combination therapy (Arm B) as phase 1a dose escalation (3 mths median follow-up). Treatment-related AEs observed in Arms A and B were mild (Gr ≤2), except for 1 pt with Gr 3 anemia in Arm B (200 mg LY3321367 + 700 mg LY3300054). No dose limiting toxicities, dose limiting-equivalent toxicities, treatment-related SAEs, or deaths were observed in Arm A or B. For LY3321367, 68.2% (Arm A) and 88.2% (Arm B) of pts were positive for treatment-emergent ADAs. Despite ADAs, no effect on PK was noted; ADA titers were low, except for 1 pt with an infusion-related reaction. LY3321367 t 1/2 was ~22 days. Full TE was maintained 2 wks after 1200 mg dose; 600 mg Q2W maintained TE at steady-state. In Arm A, 2 pts had &gt; 20% tumor regression, 1 of which was later confirmed as a PR in a post-PD-1 SCLC pt. Conclusions: LY3321367 is well tolerated as a monotherapy and in combination with LY3300054. The RP2D for LY3321367 combination therapy is 1200 mg IV infusions Q2W for cycles 1-2; 600 mg infusions Q2W starting at cycle 3 onward. Clinical trial information: NCT03099109.
Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma
Authors: Matthew J. Frigault, Jorg Dietrich, Maria Martinez-Lage, Mark Leick, Bryan D. Choi, Zachariah DeFilipp, Yi-Bin Chen, Jeremy Abramson, Jennifer Crombie, Philippe Armand, Lakshmi Nayak, Chris Panzini, Lauren S. Riley, Kathleen Gallagher, Marcela V. Maus
Journal: Blood (2019)