tbuckley/cabot-search huggingface dataset:
Randomized multicenter phase II trial evaluating the sequencing of PD-1 inhibition with pembrolizumab (P) and standard platinum-based chemotherapy (C) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) (AFT-09).
Authors: Thomas A. Hensing, Xiaofei F. Wang, Junheng Gao, Tom Stinchcombe, Michael V. Knopp, Arkadiusz Z. Dudek, Stephen L. Graziano, Jyoti D. Patel, Bryan Faller, Konstantin H. Dragnev, David E. Kozono, Everett E. Vokes
Journal: Journal of Clinical Oncology (2019)

9088 Background: KEYNOTE-024 established single-agent P as a 1 st -line option for pts with metastatic NSCLC without targetable alterations and PD-L1 tumor proportion score (TPS) ≥ 50%. KEYNOTE-189 and 407 established concurrent C + P as a treatment option irrespective of PD-L1 expression. In this randomized phase II selection trial, we explored sequencing of C and P in this pt. population. Methods: Eligible pts were randomized 1:1 to (arm A) C (carboplatin (AUC 6) + pemetrexed 500 mg/m 2 (non-squamous) or paclitaxel 200 mg/m 2 (squamous)) x 4 cycles followed by P 200 mg x 4 cycles, or the reverse sequence (arm B) of P x 4 cycles followed by C x 4 cycles. After 8 cycles, pts on both arms were eligible to receive maintenance P for up to 24 months. Primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review. Secondary endpoints included progression free survival (PFS) per RECIST 1.1 and overall survival (OS). Efficacy endpoints were also evaluated by PD-L1 expression. Results: 89 pts (47 arm B &amp; 42 arm A) were enrolled and are included in the analysis (PD-L1 TPS 0/1-49%/≥50% = 24 pts (34%)/25 pts (36%)/21 pts (30%)). There was no significant difference in ORR (36% vs 38%, p = 0.829), median PFS (2.7 vs 5.5 months (mo), HR 1.25, 95% CI 0.77-2.02, p = 0.363) or OS (13.1 vs 19.8 mo, HR 1.25, 95% CI 0.69-2.25, p = 0.4573), arm B (Px4→C) vs arm A (Cx4→P). Multivariable Cox regression analysis demonstrated significant interaction between treatment and PD-L1 TPS ( &lt; 50% vs ≥ 50%) for PFS (HR 6.76, 95% CI 2.14-21.35, p = 0.0011) and a trend for OS (HR 5.02, 95% CI 0.92-27.55, p = 0.0632), arm B vs arm A. Incidence of grade ≥3 adverse events was 71% for arm A and 65% for arm B. No new safety signals were observed. Conclusions: In pts with stage IV NSCLC and PD-L1 TPS ≥ 50% there was an observed improvement in PFS and OS in favor of C followed by P vs P x 4 followed by C. Given small # of pts and trial design, this observation should be considered hypothesis-generating, but supports further exploration of sequential C + P in this setting. Support:Merck Sharp &amp; Dohme Corp.; https://acknowledgments.alliancefound.org Clinical trial information: NCT02591615.
The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis
Authors: Karthik Suresh, Jarushka Naidoo, Qiong Zhong, Ye Xiong, Jennifer Mammen, Marcia Villegas de Flores, Laura Cappelli, Aanika Balaji, Tsvi Palmer, Patrick M. Forde, Valsamo Anagnostou, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Cheng-Ting Lin, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Danoff, Franco D’Alessio
Journal: Journal of Clinical Investigation (2019)

Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown.To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements.We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape.We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.
Retrospective comparison of Cheson 2007 and Lugano classification criteria in independent review assessment of FDG-avid lymphomas.
Authors: Jayant Narang, Surabhi Bajpai, Rudresh Jarecha, Sayali Karve, Katarina Ludajic, Manish Sharma, Oliver Bohnsack
Journal: Journal of Clinical Oncology (2019)

e19015 Background: Revised Response Criteria in Malignant Lymphoma (Cheson 2007) and Lugano Classification are the most commonly used guidelines to assess response to treatment in lymphoma in clinical trials. While not drastically different from Cheson 2007, important clarifications and modifications were provided in Lugano Classification, specifically in the use of PET in response assessments. Methods: We retrospectively compared the blinded independent review of 25 subjects across multiple studies, assessed using Cheson 2007 and Lugano Classification on separate case report forms by the same reviewer per subject on 2 different dates. Focus was given on comparison of endpoint assessments of Progression-Free Survival (PFS), Duration of Complete Response (DOCR) and Duration of Response (DOR). Results: Assessments using Lugano Classification showed increased DOCR in 12% (3 out of 25), and DOR in 24% (6 out of 25) of the subjects. Cheson 2007 showed better DOR in 8% (2 out of 25) of the subjects. For PET positivity, Lugano Classification requires comparison with liver and mediastinal blood pool, whereas Cheson 2007 requires comparison to background or mediastinal blood pool. The results suggest that this difference in assessment of PET positivity (blood pool versus liver) leads to achieving Complete Response (CR) earlier, leading to longer DOCR and DOR when assessed using Lugano Classification compared to Cheson 2007. Lugano Classification also showed longer PFS in 16% (4 out of 25) of the subjects. When Progressive Disease (PD) was due to identification of new lesion(s), the two criteria showed similar PFS; however, when PD was due to lesion measurements and PET positivity assessment, Lugano Classification showed a longer PFS. Better PFS in Lugano Classification was observed because enlarging lymph nodes do not always show increased PET activity. Conclusions: In Independent review assessments for FDG avid lymphoma, using Lugano Classification showed better DOCR, DOR and PFS as compared to Cheson 2007. Further studies with increased number of subjects and intra-reader variability assessments are warranted to investigate the two criteria.
Digoxin as an inhibitor of global hypoxia inducible factor-1α (HIF1α) expression and downstream targets in breast cancer: Dig-HIF1 pharmacodynamic trial.
Authors: Aditya Bardia, Cesar Augusto Santa-Maria, Lisa K. Jacobs, Ashley Cimino-Mathews, Peng Huang, Stuart Russell, Melissa Camp, Mehran Habibi, Julie R. Lange, Stacie Jeter, Penny Powers, Shannon Slater, Edward Gabrielson, Michael Anthony Carducci, Gregg Semenza, Vered Stearns
Journal: Journal of Clinical Oncology (2013)

TPS1144 Background: Unlike normal cells, tumor cells thrive in a hypoxic microenvironment, and intratumoral hypoxia correlates with increased tumor invasiveness, metastasis, and poor prognosis in cancer. The hypoxic microenvironment is primarily mediated through HIF1α, a transcription factor for over 200 genes involved in cellular metabolism, proliferation, and angiogenesis. In pre-clinical models, cardiac glycosides, including digoxin, act as potent inhibitors of HIF1α protein synthesis and expression of HIF1α target genes (Zhang et al, PNAS 09). Methods: Trial design: The proposed study is a randomized, controlled, two arm, pre-surgical study. Eligible patients include women with stage I-III carcinoma of the breast scheduled to undergo definitive surgery, tumor size ≥ 1cm, grade 2/3 or Ki-67 ≥ 10%, normal organ function, and no known cardiac arrhythmias. Participants will receive oral digoxin daily, or no therapy, for 14 days (±4 days) prior to scheduled surgery. Trial Objectives: 1) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces HIF1α expression by IHC and mRNA or its target genes (VEGF, CA-9, and GLUT1) in breast cancer tissue. 2) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces levels of serum VEGF &amp; PAI-1, reduces tissue Ki-67 expression, and modulates proteomic profiles of breast cancer tissue. 3) To assess safety and tolerability of digoxin therapy in the pre-surgical setting. Statistical methods: The primary hypothesis is that 2 weeks of digoxin therapy will reduce the level of HIF1α expression in breast cancer tissue assessed by pathologists blinded to the treatment assignment. Our preliminary study shows the mean HIF1α expression level is 2.43. A 33% reduction would be considered clinically relevant. Allowing for up to 20% attrition, a total sample size of 64 will provide more than 85% power to detect 33% reduction with a two-sided significance level of 0.05. Target accrual: 64 (32 each arm). Funding and Acknowledgement: Dept. of Defense, Commonwealth Foundation, ASCO YIA. Contact Person: Dr. Vered Stearns, Email: vstearn1@jhmi.edu .ClinicalTrials.gov Identifier: NCT01763931. Clinical trial information: NCT01763931.
A phase 1/2, open-label, dose-expansion study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) in patients with previously untreated metastatic pancreatic cancer
Authors: Z. Wainberg, P. Boland, C. Lieu, F. Dayyani, T. Macarulla, B. Zhang, B. Belanger, Y. Moore, T. Wang, F. Maxwell, A. Dean
Journal: Annals of Oncology (2019)
Coated cationic lipid-nanoparticles entrapping miR-660 inhibit tumor growth in patient-derived xenografts lung cancer models
Authors: Massimo Moro, Daniela Di Paolo, Massimo Milione, Giovanni Centonze, Viviana Bornaghi, Cristina Borzi, Paolo Gandellini, Patrizia Perri, Ugo Pastorino, Mirco Ponzoni, Gabriella Sozzi, Orazio Fortunato
Journal: Journal of Controlled Release (2019)

Lung cancer is the leading cause of cancer-related deaths. Late diagnosis and inadequate therapies contribute to poor outcomes. MicroRNAs (miRNAs) are small non-coding RNAs and are involved in lung cancer development. Because miRNAs simultaneously regulate several cancer-related genes, they represent an interesting therapeutic approach for cancer treatment. We have developed Coated Cationic Lipid-nanoparticles entrapping miR-660 (CCL660) and intraperitoneally administered (1.5 mg/Kg) twice a week for four weeks into SCID mice carrying subcutaneously lung cancer Patients Derived Xenografts (PDXs). Obtained data demonstrated that miR-660 is down-regulated in lung cancer patients and that its replacement inhibited lung cancer growth by inhibiting the MDM2-P53 axis. Furthermore, systemic delivery of CCL660 increased miRNA levels in tumors and significantly reduced tumor growth in two different P53 wild-type PDXs without off-target effects. MiR-660 administration reduced cancer cells proliferation by inhibiting MDM2 and restoring P53 function and its downstream effectors such as p21. Interestingly, anti-tumoral effects of CCL660 also in P53 mutant PDXs but with a functional p21 pathway were observed. Stable miR-660 expression inhibited the capacity of H460 metastatic lung cancer cells to form lung nodules when injected intravenously into SCID mice suggesting a potential role of miR-660 in metastatic dissemination. To investigate the potential toxic effects of both miRNAs and delivery agents, an in vitro approach revealed that miR-660 replacement did not induce any changes in both mouse and human normal cells. Interestingly, lipid-nanoparticle delivery of synthetic miR-660 had no immunological off-target or acute/chronic toxic effects on immunocompetent mice. Altogether, our results highlight the potential role of coated cationic lipid-nanoparticles entrapping miR-660 in lung cancer treatment without inducing immune-related toxic effects.
Effect of PARP inhibitors on sensitivity of lung and breast cancer cells to trans-platinum as compared to cis-platinum.
Authors: Radmila Jankovic, Sinisa Radulovic, Sandra Arandjelovic, Lana Filipovic
Journal: Journal of Clinical Oncology (2013)

e22115 Background: Poly(ADP-ribose) polymerase inhibitors (PARP-i) represent promising strategy in treatment of cisplatin resistant lung cancer and triple-negative breast cancer. We compared PARP inhibition by 3-aminobenzamide (3-AB) or NU1025, on activity of cis- and trans-platinum on NSCLC cells (A549) and breast cancer cells (MDA-MB-361), and correlated with p53 and ERCC1 status. Methods: Cell cycle distribution was determined by FACS-flow and PI-staining, while morphological changes were followed by light microscopy. ERCC1 siRNA transfection was performed by HiperFect reagent, and mRNA was analyzed by qRT-PCR. Protein expression levels were determined by Western blot. PARP-inhibition was quantified as NAD(P)H depletion using colorimetric XTT assay. Results: Trans-platinum compound with planar ammine ligands, trans-[PtCl 2 (4-acetylpyridine) 2 ] showed cytotoxic activity comparable to cis-platin and exhibited enhanced action in combination with PARP-i. 3-AB enhanced the activity of trans more efficient comparing to cis-platinum in MDA-MB-361 cells. At equitoxic concentrations corresponding to IC 50 values in A549 cells, cis-platin and trans-platinum compound differently affected cell survival in combination with PARP-i. XTT assay confirmed efficient inhibition of PARP activity at 200 μM NU1025 and 2 mM 3-AB in both cell lines. ERCC1 silencing in p53 proficient A549 cells, alone or in combination with NU1025, almost completely diminished resistance to trans-[PtCl 2 (4-acetylpyridine) 2 ], decreasing cell survival to 50 % following 24 h action and more than 85 % following 48 h treatment, comparing to siRNA/NU1025 treated control. By contrast, sensitivity to cisplatin was much less altered. Simultaneous alteration of ERCC1 and PARP itself did not affect cell cycle progression, but prolonged sub-G1 fraction by trans-platinum as well as G2-M fraction by cis-platin. Conclusions: PARP-inhibition enhanced tumor cell sensitivity to trans-platinum drug, stronger than cis-platinum. Knockdown of ERCC1 further increases sensitivity to platinum drugs, irrelevant to p53 status. Trans-platinum complexes should be further explored as good candidates for combining with PARP-i.
The anatomy and immunology of vasculature in the central nervous system
Authors: Panagiotis Mastorakos, Dorian McGavern
Journal: Science Immunology (2019)

Barriers between circulation and the central nervous system (CNS) play a key role in the development and modulation of CNS immune responses. Structural variations in the vasculature traversing different anatomical regions within the CNS strongly influence where and how CNS immune responses first develop. Here, we provide an overview of cerebrovascular anatomy, focusing on the blood-CNS interface and how anatomical variations influence steady-state immunology in the compartment. We then discuss how CNS vasculature is affected by and influences the development of different pathophysiological states, such as CNS autoimmune disease, cerebrovascular injury, cerebral ischemia, and infection.
Brain 123I-FP-CIT SPECT of a Holmes Tremor Due to Midbrain Pilocytic Astrocytoma
Authors: Nicolas Louarn, Dris Kharroubi, Aloÿse Fourquet, Marie Vidailhet, Aurélie Kas
Journal: Clinical Nuclear Medicine (2019)

Abstract A 24-year-old woman with an unresectable right mesencephalic pilocytic astrocytoma was treated with stereotaxic radiation therapy. Three months after a radiation therapy–induced bleeding, she presented a severe disabling low frequency rest and kinetic tremor involving the left upper limb, associated with dystonia, and a Holmes tremor was suspected. Thereby, we performed a 123 I-FP-CIT SPECT (DATSCAN) that revealed a normal distribution of radiotracer over the left striatum, whereas no binding was seen in the right caudate and putamen. This pattern was consistent with a right severe nigrostriatal dopaminergic denervation due to an ipsilateral red nucleus injury.
Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223
Authors: Carolina Jimenez Calvente, Masahiko Tameda, Casey D. Johnson, Hana del Pilar, Yun Chin Lin, Nektaria Adronikou, Xavier De Mollerat Du Jeu, Cristina Llorente, Josh Boyer, Ariel E. Feldstein
Journal: Journal of Clinical Investigation (2019)

Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated pro-inflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we have identified a novel role for neutrophils as key contributors to resolving the inflammatory response in the liver. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery and early fibrosis. These findings were associated with an impairment of the phenotypic switch of pro-inflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3 / miR-223 ratio. Mice with a deletion of the granulocyte specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by restoring miR-223 levels using a miR-223 3p mimic or infusing neutrophils from wildtype animals. Collectively, our findings reveal a novel role for neutrophils in the liver as resolving effector cells that induce pro-inflammatory macrophages into a restorative phenotype, potentially via miR-223.
Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
Authors: Pilar Esteve, Javier Rueda-Carrasco, María Inés Mateo, María Jesús Martin-Bermejo, Jonathan Draffin, Guadalupe Pereyra, África Sandonís, Inmaculada Crespo, Inmaculada Moreno, Ester Aso, Paula Garcia-Esparcia, Estrella Gomez-Tortosa, Alberto Rábano, Juan Fortea, Daniel Alcolea, Alberto Lleo, Michael T. Heneka, José M. Valpuesta, José A. Esteban, Isidro Ferrer, Mercedes Domínguez, Paola Bovolenta
Journal: Nature Neuroscience (2019)
Correction: ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis
Authors: Yun-Xin Lu, Huai-Qiang Ju, Ze-Xian Liu, Dong-Liang Chen, Yun Wang, Qi Zhao, Qi-Nian Wu, Zhao-lei Zeng, Hai-Bo Qiu, Pei-Shan Hu, Zhi-Qiang Wang, Dong-Sheng Zhang, Feng Wang, Rui-Hua Xu
Journal: Cancer Research (2019)

In the original version of [this article][1] ([1][2]), the immunostaining of Ki-67 (si#ME1 group of PDX#2 and PDX#3) in Fig. 5G was inadvertently duplicated during data arrangement. The image has been replaced with the intended image for Fig. 5G. The error does not affect the conclusion and has been
A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas
Authors: D. Laheru, C. Yeo, B. Biedrzycki, S. Solt, E. Lutz, B. Onners, I. Tartakovsky, J. Herman, R. Hruban, S. Piantadosi, E. Jaffee
Journal: Journal of Clinical Oncology (2007)

3010 Background: Pancreatic cancer remains the fourth leading cause of cancer related deaths in the US in 2006. Surgical resection provides the only possibility of cure. A standard adjuvant treatment approach for patients with resected disease has not yet been determined. We have developed an irradiated GM-CSF transfected allogeneic whole cell line pancreas adenocarcinoma vaccine. We have previously reported a follow-up 60 patient study in this same population using the highest bioactive vaccine dose identified in the initial phase I study. Methods: Single institution phase II study of 60 patients with resected pancreatic adenocarcinoma administered a total of 5 vaccines using two pancreatic cancer cell lines each delivering 2.5 X 10 8 cells ID. Vaccine one was administered 8–10 weeks following surgical resection. Patients subsequently were treated with 5-FU CI based chemotherapy integrated with radiotherapy. Patients who were disease-free one month after completion of chemoradiotherapy received vaccines 2–4, each 1 month apart. A fifth and final booster vaccine was administered 6 months after vaccine 4. The objectives of the study were: 1. To estimate overall survival and disease-free survival in patients with minimal residual disease treated with adjuvant chemoradiotherapy in sequence with the irradiated allogeneic GM-CSF transfected pancreatic tumor cell lines. 2. To characterize toxicities associated with intradermal injections of the vaccine. Results/Conclusions: The study completed enrollment of new patients in January 2005. Median follow-up for these patients is approximately 36 months. 1) The administration of a GM-CSF allogeneic pancreas cancer vaccine is safe and well tolerated; 2) The median survival is approximately 26 months. These results compare favorably with published data for resected pancreas cancer; 3) A matched cohort analysis comparing patients enrolled on this adjuvant vaccine study to the Johns Hopkins Surgery database of patients receiving surgery followed by chemoradiotherapy alone will be presented at this meeting; 4) Immune correlates will be presented at this meeting. No significant financial relationships to disclose.
Neuropeptide-like signaling in the microbiota-gut-brain axis
Authors: Sergueï O. Fetissov
Journal: Behavioral and Brain Sciences (2019)

Abstract For gut microbiota to influence behavior, microorganisms should be able to interfere with specific brain neurochemical circuitries. Understanding these molecular mechanisms is a key task in the new microbiota-gut-brain field. Recent studies have revealed that one major mechanistic link is the modulation of neuropeptide signaling by homologous bacterial proteins acting both directly and indirectly via production of neuropeptide-reactive immunoglobulins.