1,012 results on '"Reid Tony"'
Search Results
2. BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors
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Conley, Anthony P., Roland, Christina L., Bessudo, Alberto, Gastman, Brian R., Villaflor, Victoria M., Larson, Christopher, Reid, Tony R., Caroen, Scott, Oronsky, Bryan, Stirn, Meaghan, Williams, Jeannie, Burbano, Erica, Coyle, Angelique, Barve, Minal A., Wagle, Naveed, Abrouk, Nacer, and Kesari, Santosh
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- 2024
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3. Data Management 101 for drug developers: A peek behind the curtain.
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Oronsky, Bryan, Burbano, Erica, Stirn, Meaghan, Brechlin, Joanne, Abrouk, Nacer, Caroen, Scott, Coyle, Angelique, Williams, Jeannie, Cabrales, Pedro, and Reid, Tony
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Humans ,United States ,Data Management - Abstract
In drug development a frequently used phrase is data-driven. Just as high-test gas fuels a car, so drug development runs on high-quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States. It is intended to demystify CDM, which means nothing more esoteric than the collection, organization, maintenance, and analysis of data for clinical trials. The review is written with those who are new to drug development in mind and assumes only a passing familiarity with the terms and concepts that are introduced. However, its relevance may also extend to experienced professionals that feel the need to brush up on the basics. For added color and context, the review includes real-world examples with RRx-001, a new molecular entity in phase III and with fast-track status in head and neck cancer, and AdAPT-001, an oncolytic adenovirus armed with a transforming growth factor-beta (TGF-β) trap in a phase I/II clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this review is also included for easy reference.
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- 2023
4. CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency
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Phung, Abraham T., Shah, Jaimin R., Dong, Tao, Reid, Tony, Larson, Christopher, Sanchez, Ana B., Oronsky, Bryan, Trogler, William C., Kummel, Andrew C., Aisagbonhi, Omonigho, and Blair, Sarah L.
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- 2024
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5. A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation
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Jayabalan, Nanthini, Oronsky, Bryan, Cabrales, Pedro, Reid, Tony, Caroen, Scott, Johnson, Aishwarya M, Birch, Natalia A, O’Sullivan, John D, and Gordon, Richard
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Lung ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Humans ,Inflammasomes ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Inflammation ,Nucleotides ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy - Abstract
Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.
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- 2023
6. A Local and Abscopal Effect Observed with Liposomal Encapsulation of Intratumorally Injected Oncolytic Adenoviral Therapy
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Dong, Tao, Shah, Jaimin R, Phung, Abraham T, Larson, Christopher, Sanchez, Ana B, Aisagbonhi, Omonigho, Blair, Sarah L, Oronsky, Bryan, Trogler, William C, Reid, Tony, and Kummel, Andrew C
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Genetics ,Immunotherapy ,Cancer ,Biotechnology ,Gene Therapy ,adenovirus ,coxsackie and adenovirus receptor ,cancer immunotherapy ,TAV255 ,Oncology and carcinogenesis - Abstract
This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.
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- 2023
7. RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist.
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Oronsky, Bryan, Takahashi, Lori, Gordon, Richard, Cabrales, Pedro, Caroen, Scott, and Reid, Tony
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KEAP1 ,NFkB ,NLRP3 inflammasome ,Nrf2 ,RRx-001 ,antibody drug conjugate (ADC) ,nitric oxide - Abstract
RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or engineered as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a targeting moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This payload, which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide linker attached to a binding site, which correlates with the Fab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.
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- 2023
8. Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)
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Reid, Tony, Oronsky, Bryan, Caroen, Scott, Quinn, Mary, Williams, Jeannie, Cabrales, Pedro, and Abrouk, Nacer
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Cancer ,Clinical Trials and Supportive Activities ,Clinical Research ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Humans ,Azetidines ,Neoplasms ,Neoplasms ,Second Primary ,Nivolumab ,Pilot Projects ,RRx-001 ,CD-47 ,tumor associated macrophage ,vascular normalization ,nivolumab ,cold tumors ,NLRP3 inflammasome inhibitor ,bromonitrozidine ,Immunology ,Medical Microbiology - Abstract
BackgroundBromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options.MethodsThis single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03.ResultsTwelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination.ConclusionsThe combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted.Clinical trial registrationClinicalTrials.gov identifier, NCT02518958.
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- 2023
9. Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes
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Shah, Jaimin R, Dong, Tao, Phung, Abraham T, Reid, Tony, Larson, Christopher, Sanchez, Ana B, Oronsky, Bryan, Blair, Sarah L, Aisagbonhi, Omonigho, Trogler, William C, and Kummel, Andrew C
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Engineering ,Biomedical Engineering ,Cancer ,Biotechnology ,Gene Therapy ,Genetics ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,adenovirus ,cancer ,coxsackievirus and adenovirus receptor ,liposome ,transduction ,extrusion ,homogenization ,good manufacturing practice ,storage stability ,Biomedical engineering - Abstract
Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.
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- 2022
10. The small molecule NLRP3 inhibitor RRx-001 potentiates regorafenib activity and attenuates regorafenib-induced toxicity in mice bearing human colorectal cancer xenografts.
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Reid, Tony, Oronsky, Bryan, Abrouk, Nacer, Caroen, Scott, and Cabrales, Pedro
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Digestive Diseases ,Vaccine Related ,Colo-Rectal Cancer ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Chemotherapy ,tyrosine kinase inhibitor ,regorafenib ,RRx-001 ,colorectal cancer ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
The multi-kinase inhibitor Regorafenib, approved for the treatment of metastatic colorectal cancer, is poorly tolerated with a Grade 3/4 drug related adverse event rate of 54% resulting in frequent dose reductions and discontinuations. RRx-001 is a minimally toxic NLRP3 inhibitor small molecule with macrophage-repolarizing properties in Phase 3 clinical trials. Studies have demonstrated the inhibitory impact of M2 macrophages on the activity of tyrosine kinases, suggesting that the repolarization of macrophages by RRx-001 may enhance the activity of TKIs. The purpose of these experiments was to determine whether RRx-001 demonstrated in vitro and in vivo synergy with regorafenib in colorectal cancer and whether RRx-001 attenuated the toxicity of regorafenib. Tumor-bearing mice were randomized into four cohorts: RRx-001 alone, regorafenib alone, RRx-001 + regorafenib and control. RRx-001 demonstrated in vitro and in vivo synergy with regorafenib with attenuation of toxicity in colorectal cancer cell lines. These results provide a rationale to treat colorectal cancer with RRx-001 plus another tyrosine kinase inhibitor like regorafenib.
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- 2022
11. A Review of Persistent Post-COVID Syndrome (PPCS)
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Oronsky, Bryan, Larson, Christopher, Hammond, Terese C., Oronsky, Arnold, Kesari, Santosh, Lybeck, Michelle, and Reid, Tony R.
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- 2023
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12. Low referral completion of rapid diagnostic test-negative patients in community-based treatment of malaria in Sierra Leone
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Reid Tony, de Smet Martin, Khogali Mohammed, Thomson Anna, Mukhtar Ahmed, Peterson Stefan, and von Schreeb Johan
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Malaria is hyper-endemic and a major public health problem in Sierra Leone. To provide malaria treatment closer to the community, Médecins Sans Frontières (MSF) launched a community-based project where Community Malaria Volunteers (CMVs) tested and treated febrile children and pregnant women for malaria using rapid diagnostic tests (RDTs). RDT-negative patients and severely ill patients were referred to health facilities. This study sought to determine the referral rate and compliance of patients referred by the CMVs. Methods In MSF's operational area in Bo and Pujehun districts, Sierra Leone, a retrospective analysis of referral records was carried out for a period of three months. All referral records from CMVs and referral health structures were reviewed, compared and matched for personal data. The eligible study population included febrile children between three and 59 months and pregnant women in their second or third trimester with fever who were noted as having received a referral advice in the CMV recording form. Results The study results showed a total referral rate of almost 15%. During the study period 36 out of 2,459 (1.5%) referred patients completed their referral. There was a significant difference in referral compliance between patients with fever but a negative RDT and patients with signs of severe malaria. Less than 1% (21/2,442) of the RDT-negative patients with fever completed their referral compared to 88.2% (15/17) of the patients with severe malaria (RR = 0.010 95% CI 0.006 - 0.015). Conclusions In this community-based malaria programme, RDT-negative patients with fever were referred to a health structure for further diagnosis and care with a disappointingly low rate of referral completion. This raises concerns whether use of CMVs, with referral as backup in RDT-negative cases, provides adequate care for febrile children and pregnant women. To improve the referral completion in MSF's community-based malaria programme in Sierra Leone, and in similar community-based programmes, a suitable strategy needs to be defined.
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- 2011
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13. A Patient-Derived Orthotopic Xenograft Model of Gastroesophageal-Junction Adenocarcinoma Translated to the Clinic by Tumor-Targeting Fluorescent Antibodies to Carcinoembryonic-Antigen-Related Cell-Adhesion Molecules
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Turner, Michael A, Amirfakhri, Siamak, Nishino, Hiroto, Lwin, Thinzar M, Savides, Thomas J, Reid, Tony R, Singer, Bernhard B, Hoffman, Robert M, and Bouvet, Michael
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Cancer ,Rare Diseases ,Digestive Diseases ,Adenocarcinoma ,Animals ,Esophageal Neoplasms ,Heterografts ,Humans ,Mice ,Mice ,Nude ,Xenograft Model Antitumor Assays ,PDOX ,patient-derived orthotopic xenograft ,gastro-esophageal junction ,adenocarcinoma ,carcinoembryonic-antigen-related cell adhesion ,fluorescent antibodies ,gastro – esophageal junction ,Clinical Sciences ,Oncology & Carcinogenesis - Abstract
Background/aimDuring surgical resection of gastroesophageal-junction (GEJ) adenocarcinoma, the margin status is often difficult to visualize resulting in high recurrence rates. The aim of the present study was to develop a labelling technique that would allow improved visualization of GEJ tumor margins for surgeons to reduce recurrence rates in a patient-like model.Materials and methodsA patient GEJ tumor was obtained from an endoscopic biopsy and implanted subcutaneously in a nude mouse. A patient-derived orthotopic xenograft (PDOX) model was established by implanting tumor fragments grown from a subcutaneous model to the cardia of the stomach of nude mice. CC1/3/5-SAB, an antibody to carcinoembryonic-antigen-related cell-adhesion molecules, was conjugated with infrared dye IRDye800 to create SAB-IR800. Forty-eight hours after i.v. injection of SAB-IR800, GEJ-PDOX mice were imaged.ResultsFluorescence imaging with SAB-IR800 brightly visualized the GEJ adenocarcinoma demonstrating specific targeting. In the PDOX model, injection of SAB-IR800 (50 μg) resulted in a tumor to background ratio of 1.78 at 48 hours and 1.86 at 72 hours.ConclusionPDOX models of GEJ tumors can be established from patients by endoscopic biopsy without undergoing surgical resection. GEJ PDOX models should be useful for developing novel diagnostics and therapeutics for this recalcitrant disease.
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- 2021
14. In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit
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Tomita, Yusuke, Oronsky, Bryan, Abrouk, Nacer, Cabrales, Pedro, Reid, Tony R, Lee, Min-Jung, Yuno, Akira, Baker, Jonathan, Lee, Sunmin, and Trepel, Jane B
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Lung ,Clinical Research ,Cancer ,Lung Cancer ,Circulating tumor cell ,small cell lung cancer ,RRx-001 ,Myc ,CD47 ,programmed death-ligand-1 ,Clinical Sciences ,Oncology and carcinogenesis - Abstract
BackgroundSmall cell lung cancer (SCLC) is the most aggressive lung tumor, characterized by a rapid doubling time and the development of widespread metastases, for which immune checkpoint inhibitors have been approved to overcome T cell anergy. In light of its dismal prognosis, and lack of curative options, new therapies for extensive-disease SCLC are desperately needed.MethodsRRx-001 is a small molecule Myc inhibitor and down-regulates CD47 expression on tumor cells. We evaluated the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) pre and post RRx-001 treatment in a phase 2 clinical trial, called QUADRUPLE THREAT, where patients with previously treated SCLC received RRx-001 in combination with a platinum doublet. The trial was registered with ClinicalTrials.gov, number NCT02489903. Fourteen patients with SCLC were analyzed to investigate the association between clinical outcome and PD-L1 expression on CTCs pre and post RRx-001. The correlation between the binary clinical outcome (clinical benefit vs. progressive disease) and the change of PD-L1 expression on CTCs after RRx-001 was analyzed using a logistic regression adjusting for baseline PD-L1 expression.ResultsThe logistic model McFadden goodness of fit score was 0.477. The logistic model analyzing the association between decreased PD-L1 expression on CTCs after RRx-001 and response to reintroduced platinum doublet had an approximate 92.8% accuracy in its prediction of clinical benefit. The estimated receiver operating characteristic (ROC) displayed a ROC area under the curve (AUC) of 0.93 (95% confidence interval, 0.78-0.99).ConclusionsThese results suggest that PD-L1 expression on CTCs decreased after RRx-001 was significantly correlated with response to reintroduced platinum-based doublet therapy. Monitoring PD-L1 expression on CTCs during RRx-001 treatment may serve as a biomarker to predict response to RRx-001-based cancer therapy.
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- 2021
15. Financial access to health care in Karuzi, Burundi: a household-survey based performance evaluation
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Van Herp Michel, Bachy Catherine, Reid Tony, Ponsar Frederique, Lambert-Evans Sophie, and Philips Mit
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Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background In 2003, Médecins Sans Frontières, the provincial government, and the provincial health authority began a community project to guarantee financial access to primary health care in Karuzi province, Burundi. The project used a community-based assessment to provide exemption cards for indigent households and a reduced flat fee for consultations for all other households. Methods An evaluation was carried out in 2005 to assess the impact of this project. Primary data collection was through a cross-sectional household survey of the catchment areas of 10 public health centres. A questionnaire was used to determine the accuracy of the community-identification method, households' access to health care, and costs of care. Household socioeconomic status was determined by reported expenditures and access to land. Results Financial access to care at the nearest health centre was ensured for 70% of the population. Of the remaining 30%, half experienced financial barriers to access and the other half chose alternative sites of care. The community-based assessment increased the number of people of the population who qualified for fee exemptions to 8.6% but many people who met the indigent criteria did not receive a card. Eighty-eight percent of the population lived under the poverty threshold. Referring to the last sickness episode, 87% of households reported having no money available and 25% risked further impoverishment because of healthcare costs even with the financial support system in place. Conclusion The flat fee policy was found to reduce cost barriers for some households but, given the generalized poverty in the area, the fee still posed a significant financial burden. This report showed the limits of a programme of fee exemption for indigent households and a flat fee for others in a context of widespread poverty.
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- 2009
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16. Treating 4,000 diabetic patients in Cambodia, a high-prevalence but resource-limited setting: a 5-year study
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Keuky Lim, Chy Say, Reid Tony, Isaakidis Petros, Raguenaud Marie-Eve, Arellano Gemma, and Van Damme Wim
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Medicine - Abstract
Abstract Background Despite the worldwide increasing burden of diabetes, there has been no corresponding scale-up of treatment in developing countries and limited evidence of program effectiveness. In 2002, in collaboration with the Ministry of Health of Cambodia, Médecins Sans Frontières initiated an outpatient program of subsidized diabetic care in two hospital-based chronic disease clinics in rural settings. We aimed to describe the outcomes of newly and previously diagnosed diabetic patients enrolled from 2002 to 2008. Methods We calculated the mean and proportion of patients who met the recommended treatment targets, and the drop from baseline values for random blood glucose (RBG), hemoglobin A1c (HbA1c), blood pressure (BP), and body mass index (BMI) at regular intervals. Analysis was restricted to patients not lost to follow-up. We used the t test to compare baseline and subsequent paired values. Results Of 4404 patients enrolled, 2,872 (65%) were still in care at the time of the study, 24 (0.5%) had died, and 1,508 (34%) were lost tofollow-up. Median age was 53 years, 2,905 (66%) were female and 4,350 (99%) had type 2 diabetes. Median (interquartile range (IQR)) follow-up was 20 months (5 to 39.5 months). A total of 24% (51/210) of patients had a HbA1c concentration of P < 0.001) and a drop of 2.7% (95% CI 2.3 to 3.0) in mean HbA1c (P < 0.001) between baseline and month 6. In all, 45% (327/723) and 62% (373/605) of patients with systolic or diastolic hypertension at baseline, respectively, reached = 130/80 mm Hg within 1 year. There was a drop of 13.5 mm Hg (95% CI 12.1 to 14.9) in mean systolic blood pressure (SBP) (P < 0.001), and a drop of 11.7 mm Hg (95% CI 10.8 to 12.6) in mean diastolic blood pressure (DBP) (P < 0.001) between baseline and month 6. Only 22% (90/401) patients with obesity at baseline lowered their BMI 2 after 1 year. Factors associated with loss to follow-up were male sex, age >60 years, living outside the province, normal BMI on admission, high RBG on last visit, and coming late for the last consultation. Conclusion Significant and clinically important improvements in glycemia and BP were observed, but a relatively low proportion of diabetic patients reached treatment targets. These results and the high loss to follow-up rate highlight the challenges of delivering diabetic care in rural, resource-limited settings.
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- 2009
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17. Providing HIV care in the aftermath of Kenya's post-election violence Medecins Sans Frontieres' lessons learned January – March 2008
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Telfer Barbara, van Engelgem Ian, Reid Tony, and Manzi Marcel
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Special situations and conditions ,RC952-1245 ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Abstract Kenya's post-election violence in early 2008 created considerable problems for health services, and in particular, those providing HIV care. It was feared that the disruptions in services would lead to widespread treatment interruption. MSF had been working in the Kibera slum for 10 years and was providing antiretroviral therapy to 1800 patients when the violence broke out. MSF responded to the crisis in a number of ways and managed to keep HIV services going. Treatment interruption was less than expected, and MSF profited from a number of "lessons learned" that could be applied to similar contexts where a stable situation suddenly deteriorates.
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- 2008
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18. Implementation of a comprehensive program including psycho-social and treatment literacy activities to improve adherence to HIV care and treatment for a pediatric population in Kenya
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Mutunga Angela, Ouko Judith, Reid Tony, Telfer Barbara, Van Winghem Joelle, Jama Zaina, and Vakil Shobha
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Pediatrics ,RJ1-570 - Abstract
Abstract Background To achieve good clinical outcomes with HAART, patient adherence to treatment and care is a key factor. Since the literature on how to care for pediatric HIV patients is limited, we describe here adherence interventions implemented in our comprehensive care program in a resource-limited setting in Kenya. Methods We based our program on factors reported to influence adherence to HIV care and treatment. We describe, in detail, our program with respect to how we adapted our clinical settings, implemented psycho-social support activities for children and their caregivers and developed treatment literacy for children and teenagers living with HIV/AIDS. Results This paper focused on the details of the program, with the treatment outcomes as secondary. However, our program appeared to have been effective; for 648 children under 15 years of age who were started on HAART, the Kaplan-Meier mortality survival estimate was 95.27% (95%CI 93.16–96.74) at 12 months after the time of initiation of HAART. Conclusion Our model of pediatric HIV/AIDS care, focused on a child-centered approach with inclusion of caregivers and extended family, addressed the main factors influencing treatment adherence. It appeared to produce good results and is replicable in resource-limited settings.
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- 2008
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19. Success with antiretroviral treatment for children in Kigali, Rwanda: Experience with health center/nurse-based care
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Gazille Claire, Asiimwe Anita, Uwera Jeanine, De Naeyer Ludwig, van Griensven Johan, and Reid Tony
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Pediatrics ,RJ1-570 - Abstract
Abstract Background Although a number of studies have shown good results in treating children with antiretroviral drugs (ARVs) in hospital settings, there is limited published information on results in pediatric programs that are nurse-centered and based in health centers, in particular on the psychosocial aspects of care. Methods Program treatment and outcome data were reported from two government-run health centers that were supported by Médecins Sans Frontières (MSF) in Kigali, Rwanda between October 2003 and June 2007. Interviews were held with health center staff and MSF program records were reviewed to describe the organization of the program. Important aspects included adequate training and supervision of nurses to manage ARV treatment. The program also emphasized family-centered care addressing the psychosocial needs of both caregivers and children to encourage early diagnosis, good adherence and follow-up. Results A total of 315 children (< 15 years) were started on ARVs, at a median age of 7.2 years (range: 0.7–14.9). Sixty percent were in WHO clinical stage I/II, with a median CD4% of 14%. Eighty-nine percent (n = 281) started a stavudine-containing regimen, mainly using the adult fixed-dose combination. The median follow-up time after ARV initiation was 2 years (interquartile range 1.2–2.6). Eighty-four percent (n = 265) of children were still on treatment in the program. Thirty (9.5%) were transferred out, eight (2.6%) died and 12 (3.8%) were lost to follow-up. An important feature of the study was that viral loads were done at a median time period of 18 months after starting ARVs and were available for 87% of the children. Of the 174 samples, VL was < 400 copies/ml in 82.8% (n = 144). Two children were started on second-line ARVs. Treatment was changed due to toxicity for 26 children (8.3%), mainly related to nevirapine. Conclusion This report suggests that providing ARVs to children in a health center/nurse-based program is both feasible and very effective. Adequate numbers and training of nursing staff and an emphasis on the psychosocial needs of caregivers and children have been key elements for the successful scaling-up of ARVs at this level of the health system.
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- 2008
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20. Desperate Times, Desperate Measures: The Case for RRx-001 in the Treatment of COVID-19
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Oronsky, Bryan, Knox, Susan, Cabrales, Pedro, Oronsky, Arnold, and Reid, Tony R
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Rare Diseases ,Pneumonia & Influenza ,Clinical Research ,Cancer ,Clinical Trials and Supportive Activities ,Prevention ,Lung ,Pneumonia ,Infectious Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Respiratory ,Good Health and Well Being ,Antihypertensive Agents ,Azetidines ,Bosentan ,COVID-19 ,Drug Repositioning ,Humans ,Nitric Oxide Donors ,Nitro Compounds ,Pandemics ,SARS-CoV-2 ,COVID-19 Drug Treatment ,RRx-001 ,Nitric oxide ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
This article summarizes the likely attenuation properties of RRx-001 in COVID-19 based on its mechanism of action and the putative pathogenesis of the disease, which appears to activate inflammatory, oxidative, and immune cascades with the potential to culminate in acute respiratory distress syndrome, cytokine storm and death. An ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 appears to present with 3 major patterns of clinical symptomatology: (1) mild upper respiratory tract infection, (2) non-life-threatening pneumonia, and (3) severe pneumonia and acute respiratory distress syndrome that initially manifest as a mild prodrome lasting for 7-8 days before rapid clinical and radiological deterioration requiring ICU transfer. RRx-001 is a targeted nitric oxide donor. This small molecule, which has been evaluated in multiple Phase 1-2 clinical trials for cancer as well as a Phase 3 clinical trial for the treatment of small cell lung cancer called REPLATINUM (NCT03699956), is minimally toxic and demonstrates clear evidence of antitumor activity. During the course of these clinical trials it was noted that the rate of chronic obstructive pulmonary disease exacerbation and pneumonia in actively smoking small cell lung cancer patients treated with RRx-001 is less than 1%. Due to extensive history of tobacco use, 40%-70% of patients with lung cancer have chronic obstructive pulmonary disease and the expected rate of pulmonary infection in this population is 50%-70%, which was not observed in RRx-001 clinical trials. Moreover, in preclinical studies of pulmonary hypertension, RRx-001 was found to be comparable with or more effective than the FDA approved agent, Bosentan. The potential pulmonary protective effects of RRx-001 in patients with recurrent lung infections coupled with preclinical models demonstrating RRx-001-mediated reversal of pulmonary hypertension suggests RRx-001 may have therapeutic activity in patients with acute respiratory symptoms due to COVID 19. Clinical trials have been initiated to confirm the hypothesis that RRx-001 may be repurposed to treat SARS-CoV-2 infection.
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- 2020
21. Vector control in a malaria epidemic occurring within a complex emergency situation in Burundi: a case study
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D'Alessandro Umberto, Baza Dismas, Reid Tony, Maes Peter, Van Herp Michel, Protopopoff Natacha, Van Bortel Wim, and Coosemans Marc
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background African highlands often suffer of devastating malaria epidemics, sometimes in conjunction with complex emergencies, making their control even more difficult. In 2000, Burundian highlands experienced a large malaria outbreak at a time of civil unrest, constant insecurity and nutritional emergency. Because of suspected high resistance to the first and second line treatments, the provincial health authority and Médecins Sans Frontières (Belgium) decided to implement vector control activities in an attempt to curtail the epidemic. There are few reported interventions of this type to control malaria epidemics in complex emergency contexts. Here, decisions and actions taken to control this epidemic, their impact and the lessons learned from this experience are reported. Case description Twenty nine hills (administrative areas) were selected in collaboration with the provincial health authorities for the vector control interventions combining indoor residual spraying with deltamethrin and insecticide-treated nets. Impact was evaluated by entomological and parasitological surveys. Almost all houses (99%) were sprayed and nets use varied between 48% and 63%. Anopheles indoor resting density was significantly lower in treated as compared to untreated hills, the latter taken as controls. Despite this impact on the vector, malaria prevalence was not significantly lower in treated hills except for people sleeping under a net. Discussion Indoor spraying was feasible and resulted in high coverage despite being a logistically complex intervention in the Burundian context (scattered houses and emergency situation). However, it had little impact on the prevalence of malaria infection, possibly because it was implemented after the epidemic's peak. Nevertheless, after this outbreak the Ministry of Health improved the surveillance system, changed its policy with introduction of effective drugs and implementation of vector control to prevent new malaria epidemics. Conclusion In the absence of effective drugs and sufficient preparedness, present study failed to demonstrate any impact of vector control activities upon the course of a short-duration malaria epidemic. However, the experience gained lead to increased preparedness and demonstrated the feasibility of vector control measures in this specific context.
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- 2007
- Full Text
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22. Extended treatment with MY-NEOVAX, personalized neoantigen-enhanced oncolytic viruses, for two end-stage cancer patients
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Bouvet, Michael, Reid, Tony R, Larson, Chris, Oronsky, Bryan, Carter, Corey, and Morris, John C
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Genetics ,Vaccine Related ,Prevention ,Gene Therapy ,Digestive Diseases ,Cancer ,Immunization ,Good Health and Well Being ,Biomedical and clinical sciences - Abstract
Neoantigen vaccines involving multi-peptides and poly-epitope-encoding RNA or DNA have undergone early phase clinical testing with modest reported antitumor effects [ 1]. The less-than-expected activity of these neoantigenic vaccines may correspond with the development of immune escape mechanisms. One permutation on neoantigen vaccines, which may counter or prevent these adaptive immune escape mechanisms, are 'personalized' oncolytic viruses that encode one or more tumor-specific transgenes. Herein, positive therapeutic effects for MY-NEOVAX™, personalized neoantigen-enhanced oncolytic adenoviruses, are described for two heavily pretreated end-stage patients, one with high-grade metastatic neuroendocrine carcinoma of the pancreas and the other with colorectal cancer metastatic to the brain, liver and lungs. To date, treatment benefit has exceeded 12 months without dose-limiting toxicities or related serious adverse events and with documented radiologic stabilization and improved performance status.
- Published
- 2019
23. ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer
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Reid, Tony R., Abrouk, Nacer, Caroen, Scott, Oronsky, Bryan, Stirn, Meaghan, Larson, Christopher, Beale, Keola, Knox, Susan J., and Fisher, George
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- 2023
- Full Text
- View/download PDF
24. PREVLAR: Phase 2a randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy
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Bonomi, Marcelo, Blakaj, Dukagjin M, Kabarriti, Rafi, Colvett, Kyle, Takiar, Vinita, Biagioli, Matthew, Bar-Ad, Voichita, Goyal, Sharad, Muzyka, Brian, Niermann, Kenneth, Abrouk, Nacer, Oronsky, Bryan, Reid, Tony, Caroen, Scott, Sonis, Stephen, and Sher, David J.
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- 2023
- Full Text
- View/download PDF
25. RRx-001 and the “Right stuff”: Protection and treatment in outer space
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Oronsky, Bryan, Caroen, Scott, Abrouk, Nacer, and Reid, Tony R.
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- 2022
- Full Text
- View/download PDF
26. Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study)
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Le, Dung T, Picozzi, Vincent J, Ko, Andrew H, Wainberg, Zev A, Kindler, Hedy, Wang-Gillam, Andrea, Oberstein, Paul, Morse, Michael A, Zeh, Herbert J, Weekes, Colin, Reid, Tony, Borazanci, Erkut, Crocenzi, Todd, LoConte, Noelle K, Musher, Benjamin, Laheru, Dan, Murphy, Aimee, Whiting, Chan, Nair, Nitya, Enstrom, Amanda, Ferber, Sandy, Brockstedt, Dirk G, and Jaffee, Elizabeth M
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Digestive Diseases ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research ,Orphan Drug ,Pancreatic Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adenocarcinoma ,Adult ,Antineoplastic Combined Chemotherapy Protocols ,Cyclophosphamide ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Pancreatic Neoplasms ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeLimited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial.Patients and methodsPatients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.ResultsThe study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred.ConclusionsThe combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435.
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- 2019
27. Pancreas Cancer‐Associated Weight Loss
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Hendifar, Andrew E, Petzel, Maria QB, Zimmers, Teresa A, Denlinger, Crystal S, Matrisian, Lynn M, Picozzi, Vincent J, Rahib, Lola, Hendifar, Andrew, Tuli, Richard, Wolpin, Brian, Hidalgo, Manuel, Ryan, David, Hingorani, Sunil, Chiorean, Elena Gabriela, Coveler, Andrew, O'Reilly, Eileen, Balachandran, Vinod, Simeone, Diane, Lowy, Andrew, Fanta, Paul, Kurzrock, Razelle, Reid, Tony, Ko, Andrew, Collisson, Eric, Tempero, Margaret, Kindler, Hedy, George, Thomas, Trevino, Jose, Vonderheide, Robert, Beatty, Gregory, Picozzi, Vincent, Mandelson, Margaret, Wang‐Gillam, Andrea, Hawkins, William, Fleshman, Julie, Maitra, Anirban, Manax, Victoria, and Matrisian, Lynn
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Pancreatic Cancer ,Cancer ,Clinical Research ,Digestive Diseases ,Rare Diseases ,Prevention ,Nutrition ,Clinical Trials and Supportive Activities ,Cachexia ,Humans ,Pancreatic Neoplasms ,Prevalence ,Quality of Life ,Weight Loss ,Pancreatic cancer ,Weight loss ,Anorexia ,Malabsorption ,Supportive care ,Precision Promise Consortium ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.
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- 2019
28. Brief report: RRx-001 is a c-Myc inhibitor that targets cancer stem cells.
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Oronsky, Bryan, Reid, Tony R, Oronsky, Arnold, Caroen, Scott, Carter, Corey A, and Cabrales, Pedro
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RRx-001 ,Wnt pathway ,c-Myc ,cancer stem cell ,resistance reversal ,Oncology and Carcinogenesis - Abstract
The goal of anticancer therapy is to selectively eradicate all malignant cells. Unfortunately for the majority of patients with metastatic disease, this goal is consistently thwarted by the nearly inevitable development of therapeutic resistance; the main driver of therapeutic resistance is a minority subpopulation of cancer cells called cancer stem cells (CSCs) whose mitotic quiescence essentially renders them non-eradicable. The Wnt signaling pathway has been widely implicated as a regulator of CSCs and, therefore, its inhibition is thought to result in a reversal of therapeutic resistance via loss of stem cell properties. RRx-001 is a minimally toxic redox-active epi-immunotherapeutic anticancer agent in Phase III clinical trials that sensitizes tumors to radiation and cytotoxic chemotherapies. In this article, as a potential mechanism for its radio- and chemosensitizing activity, we report that RRx-001 targets CD133 + /CD44 + cancer stem cells from three colon cancer cell-lines, HT-29, Caco-2, and HCT116, and inhibits Wnt pathway signalling with downregulation of c-Myc.
- Published
- 2018
29. Navigating the “No Man's Land” of TKI-Failed EGFR-Mutated Non–Small Cell Lung Cancer (NSCLC): A Review
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Oronsky, Bryan, Ma, Patrick, Reid, Tony R, Cabrales, Pedro, Lybeck, Michelle, Oronsky, Arnold, Oronsky, Neil, and Carter, Corey A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Cancer ,Clinical Research ,Lung Cancer ,Lung ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Brain Neoplasms ,Carcinoma ,Non-Small-Cell Lung ,Combined Modality Therapy ,Disease Progression ,ErbB Receptors ,Humans ,Immunotherapy ,Lung Neoplasms ,Mutation ,Protein Kinase Inhibitors ,Recurrence ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
As the leading cause of cancer-related mortality, lung cancer is a worldwide health issue that is overwhelmingly caused by smoking. However, a substantial minority (~25%) of patients with non-small cell lung cancer (NSCLC) has never smoked. In these patients, activating mutations of the epidermal growth factor receptor (EGFR) are more likely, which render their tumors susceptible for a finite period to treatment with EGFR tyrosine kinase inhibitors (TKIs) and confer a better prognosis than EGFR wild-type NSCLC. On progression, due to the inevitable insurgence of resistance, TKIs are generally followed by second- or third-line salvage chemotherapy until treatment failure, after which no standard treatment options are available, resulting in a poor prognosis and a high risk of death. With the focus of clinical attention on treatment with TKIs, few studies on optimal salvage therapies, including cytotoxic chemotherapy, after failure of EGFR TKIs have been reported. Despite a paucity of available data, the aim of this review is to summarize the "no-man's land" of TKI-failed EGFR-mutated NSCLC and expand on alternative strategies as well as potential future directions.
- Published
- 2018
30. Predicting the Abscopal Phenomenon—Letter to the Editor
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Conley, Anthony P., primary, Oronsky, Bryan, additional, Caroen, Scott, additional, Larson, Chris, additional, and Reid, Tony, additional
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- 2024
- Full Text
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31. Abstract 10336: Phase 3 Anticancer Agent, RRx-001, Ameliorates Hypoxia-Induced Pulmonary Hypertension
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Cabrales, Pedro, Reid, Tony, Caroen, Scott, and Oronsky, Bryan
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- 2022
- Full Text
- View/download PDF
32. RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials
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Oronsky, Bryan, Paulmurugan, Ramasamy, Foygel, Kira, Scicinski, Jan, Knox, Susan J, Peehl, Donna, Zhao, Hongjuan, Ning, Shoucheng, Cabrales, Pedro, Summers, Thomas A, Reid, Tony R, Fitch, William L, Kim, Michelle M, Trepel, Jane B, Lee, Min-Jung, Kesari, Santosh, Abrouk, Nacer D, Day, Regina M, Oronsky, Arnold, Ray, Carolyn M, and Carterg, Corey A
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Animals ,Antineoplastic Agents ,Azetidines ,Cell Death ,Drug Resistance ,Neoplasm ,Humans ,Macrophages ,Neoplasms ,Nitro Compounds ,Tumor associated macrophages ,cancer therapy ,RRx-001 ,cancer stem cells ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
IntroductionAccording to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future.
- Published
- 2017
33. RRx-001 Priming of PD-1 Inhibition in the Treatment of Small Cell Carcinoma of the Vagina: A Rare Gynecological Tumor
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Brzezniak, Christina, Oronsky, Bryan, Trepel, Jane, Summers, Thomas A, Cabrales, Pedro, Lee, Min-Jung, Day, Regina, Jha, Saheli, Caroen, Scott, Zeman, Karen, Ferry, Lindsey, Harmer, Cindy, Oronsky, Neil, Lybeck, Michelle, Lybeck, Harry E, Brown, James F, Reid, Tony R, and Carter, Corey A
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Lung ,Lung Cancer ,Orphan Drug ,Cancer ,Small cell carcinoma ,Vagina ,Tumor-associated macrophage stimulation ,Immunotherapy ,Chemotherapy ,Pseudoprogression ,RRx-001 ,Oncology and carcinogenesis - Abstract
Small cell carcinoma of the vagina is rare, so rare in fact that the total number reported in English-language journals is less than 30. Due to this extremely low incidence, no specific treatment guidelines have been established, and most of what is clinically known is derived from a handful of single case reports. However, as befitting its highly aggressive histologic features, which are reminiscent of small cell lung cancer (SCLC), first-line treatment is modeled after SCLC. Herein is reported the case of a 51-year-old African-American patient with metastatic biopsy-proven small cell carcinoma of the vagina that progressed through multiple therapies: first-line cisplatin and etoposide (making it platinum-resistant) and radiotherapy, followed by the tumor macrophage-stimulating agent RRx-001 in a clinical trial called QUADRUPLE THREAT, which per protocol preceded a mandated rechallenge with cisplatin and etoposide. RECIST v.1.1 tumor progression on both RRx-001 and cisplatin/etoposide was accompanied by central necrosis in several of the enlarged lymph nodes and hepatic metastases, which may have been evidence of pseudoprogression, accounting for her ongoing longer-than-expected survival, since the necrotic tissue may have primed the activity of the PD-1 inhibitor. The lack of response to RRx-001 is hypothesized to have correlated with sparse tumor macrophage infiltration, seen on pre- and post-treatment biopsies, since the mechanism of action of RRx-001 relates to stimulation of tumor-associated macrophages.
- Published
- 2017
34. THE NATIONAL EXPERIENCE: SCD contributor TONY REID made some BIG DEALS and fond memories on the show floor.
- Author
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REID, TONY
- Subjects
SPORTS halls of fame ,SPORTS cards ,SOCIAL media ,SPORTS collectibles ,BASEBALL cards ,RUMOR ,COPYING - Abstract
The article discusses the author's experience at The National Sports Collectors Convention in Cleveland. The author attended the convention on behalf of Greg Morris Cards and documented their consignments and purchases. They made several big deals, including the purchase of mid-1960s baseball sets and vintage hockey sets. The author's daughter also attended the convention and had a positive experience, adding to her card collection and winning prizes. The author also shares their personal experiences and highlights, such as finding a low-grade 1954 Topps Hank Aaron rookie card and meeting friends from the collecting community. The article concludes with the author's coverage of autograph signings by athletes such as Bo Jackson, Manny Ramirez, and Troy Polamalu. [Extracted from the article]
- Published
- 2024
35. COVID-19 and cancer: A guide with suggested COVID-19 rule-out criteria to support clinical decision-making
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Larson, Christopher, Oronsky, Bryan, Goyal, Sharad, Ray, Carolyn, Hedjran, Farah, Hammond, Terese C., Kesari, Santosh, Caroen, Scott, Lybeck, Michelle, Dobalian, Vaughn E., Oronsky, Arnold, and Reid, Tony
- Published
- 2020
- Full Text
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36. Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents.
- Author
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Oronsky, Bryan, Scicinski, Jan, Kim, Michelle M, Cabrales, Pedro, Salacz, Michael E, Carter, Corey A, Oronsky, Neil, Lybeck, Harry, Lybeck, Michelle, Larson, Christopher, Reid, Tony R, and Oronsky, Arnold
- Subjects
Humans ,Neoplasms ,Epigenesis ,Genetic ,Radiation Tolerance ,DNA methyltransferase inhibition ,epigenetic priming ,epigenetics ,histone deacetylase inhibition ,radiosensitization ,radiotherapy ,reactive oxygen species ,Epigenesis ,Genetic ,Biochemistry and Cell Biology - Abstract
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
- Published
- 2016
37. Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets.
- Author
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Carter, Corey A, Oronsky, Bryan, Caroen, Scott, Scicinski, Jan, Degesys, Aiste, Cabrales, Pedro, Reid, Tony R, and Brzezniak, Christina
- Subjects
Partial response ,Platinum doublets ,RRx-001 ,Refractory small-cell lung cancer - Abstract
Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.
- Published
- 2016
38. Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization.
- Author
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Carter, Corey A, Oronsky, Bryan T, Caroen, Scott Z, Scicinski, Jan J, Cabrales, Pedro, Reid, Tony, Degesys, Aiste, Jenkins, John, and Brzezniak, Christina
- Subjects
Non-small cell lung cancer ,Partial response ,Platinum doublets ,RRx-001 ,Refractory EGFR - Abstract
RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to 'episensitize' tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival.
- Published
- 2016
39. A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient after Priming with RRx-001
- Author
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Oronsky, Bryan, Caroen, Scott, Zeman, Karen, Quinn, Mary, Brzezniak, Christina, Scicinski, Jan, Cabrales, Pedro, Reid, Tony R, Trepel, Jane B, Abrouk, Nacer D, Larson, Christopher, Oronsky, Arnold, Lybeck, Harry E, Day, Regina M, and Carter, Corey A
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Lung Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Cancer ,Orphan Drug ,Clinical Research ,Lung ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,resistant SCLC ,RRx-001 ,resistance reversal ,resensitization ,platinum doublets ,epigenetic - Abstract
As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT; NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.
- Published
- 2016
40. RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets
- Author
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Carter, Corey A, Oronsky, Bryan T, Caroen, Scott Z, Scicinski, Jan J, Degesys, Aiste, Kim, Michelle M, Oronsky, Arnold L, Lybeck, Harry, Cabrales, Pedro, Oronsky, Neil, Reid, Tony, Roswarski, Joseph, and Brzezniak, Christina
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Lung ,Lung Cancer ,Clinical Trials and Supportive Activities ,Small-cell lung cancer ,Resistance ,Platinum doublets ,Epigenetic ,Resensitization ,Episensitization ,Oncology and carcinogenesis - Abstract
RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization.
- Published
- 2016
41. Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001
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Carter, Corey A, Schmitz, Bruno, Peterson, P Gabriel, Quinn, Mary, Degesys, Aiste, Jenkins, John, Oronsky, Bryan, Scicinski, Jan, Caroen, Scott, Reid, Tony R, Cabrales, Pedro, and Brzezniak, Christina
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Neurosciences ,Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,Neuroendocrine tumor ,Immune reactivity ,Pseudoprogression ,Tumor flare ,Serial biopsy ,RRx-001 ,Oncology and carcinogenesis - Abstract
Neuroendocrine tumors (NETs) are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not. In either case, the treatment strategy, apart from potentially curative surgical resection, is very poorly defined. This report describes the case of a 28-year-old white male with a diagnosis of high-grade NET of undetermined primary site metastatic to the lymph nodes, skin and paraspinal soft tissues, treated with the experimental anticancer agent RRx-001, in the context of a phase II clinical trial called TRIPLE THREAT (NCT02489903); serial sampling of tumor material through repeat biopsies demonstrated an intratumoral inflammatory response, including the amplification of infiltrating T cells, which correlated with clinical and symptomatic benefit. This case suggests that pseudoprogression or RRx-001-induced enlargement of tumor lesions, which has been previously described for several RRx-001-treated patients, is the result of tumoral lymphocyte infiltration.
- Published
- 2016
42. BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors
- Author
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Conley, Anthony P., primary, Roland, Christina L., additional, Bessudo, Alberto, additional, Gastman, Brian R., additional, Villaflor, Victoria M., additional, Larson, Christopher, additional, Reid, Tony R., additional, Caroen, Scott, additional, Oronsky, Bryan, additional, Stirn, Meaghan, additional, Williams, Jeannie, additional, Burbano, Erica, additional, Coyle, Angelique, additional, Barve, Minal A., additional, Wagle, Naveed, additional, Abrouk, Nacer, additional, and Kesari, Santosh, additional
- Published
- 2023
- Full Text
- View/download PDF
43. Commentary on oncolytic viruses: past, present, and future
- Author
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Larson, Christopher, primary, Oronsky, Bryan, additional, and Reid, Tony R, additional
- Published
- 2023
- Full Text
- View/download PDF
44. RRx-001 potentially reduces financial toxicity for patients and caregivers in head and neck cancer.
- Author
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Reid, Tony R., primary, Abrouk, Nacer A., additional, Oronsky, Bryan, additional, Caroen, Scott, additional, and Sonis, Stephen T., additional
- Published
- 2023
- Full Text
- View/download PDF
45. 1523 AdAPT-001 in advanced soft-tissue sarcoma (BETA PRIME): a multicenter, open-label, phase 1 clinical trial
- Author
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Conley, Anthony, primary, Williams, Jeannie, additional, Larson, Christopher, additional, Oronsky, Bryan, additional, Stirn, Meaghan, additional, Burbano, Erica, additional, Abrouk, Nacer, additional, Reid, Tony, additional, and Kesari, Santosh, additional
- Published
- 2023
- Full Text
- View/download PDF
46. Flushing Out Carcinoid Syndrome: Beneficial Effect of the Anticancer Epigenetic Agent RRx-001 in a Patient with a Treatment-Refractory Neuroendocrine Tumor.
- Author
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Carter, Corey A, Degesys, Aiste, Oronsky, Bryan, Scicinski, Jan, Caroen, Scott Z, Oronsky, Arnold L, Reid, Tony, Cabrales, Pedro, and Roswarski, Joe
- Subjects
Carcinoid syndrome ,Epigenetics ,Neuroendocrine tumor ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research - Abstract
Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms defined by the presence of cells with secretory granules and the potential to produce and release high levels of vasoactive peptides into the circulation, leading to severe flushing and diarrhea, which may adversely affect quality of life. This report presents the case of a 64-year-old man with chronic refractory diarrhea due to pulmonary NET treated with the experimental anticancer agent RRx-001 in a phase II trial called TRIPLE THREAT with subsequent resolution of his diarrhea.
- Published
- 2015
47. Encapsulation of adenovirus serotype 5 in anionic lecithin liposomes using a bead-based immunoprecipitation technique enhances transfection efficiency
- Author
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Mendez, Natalie, Herrera, Vanessa, Zhang, Lingzhi, Hedjran, Farah, Feuer, Ralph, Blair, Sarah L, Trogler, William C, Reid, Tony R, and Kummel, Andrew C
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Genetics ,Gene Therapy ,Cancer ,Adenoviridae ,Animals ,Cell Line ,Tumor ,Genetic Therapy ,HEK293 Cells ,Humans ,Immunoprecipitation ,Lecithins ,Liposomes ,Mice ,Mice ,129 Strain ,Oncolytic Virotherapy ,Transfection ,Adenovirus ,Drug delivery ,Gene therapy ,Liposome ,Nanoparticle ,Phospholipid ,Biomedical Engineering - Abstract
Oncolytic viruses (OVs) constitute a promising class of cancer therapeutics which exploit validated genetic pathways known to be deregulated in many cancers. To overcome an immune response and to enhance its potential use to treat primary and metastatic tumors, a method for liposomal encapsulation of adenovirus has been developed. The encapsulation of adenovirus in non-toxic anionic lecithin-cholesterol-PEG liposomes ranging from 140 to 180 nm in diameter have been prepared by self-assembly around the viral capsid. The encapsulated viruses retain their ability to infect cancer cells. Furthermore, an immunoprecipitation (IP) technique has shown to be a fast and effective method to extract non-encapsulated viruses and homogenize the liposomes remaining in solution. 78% of adenovirus plaque forming units were encapsulated and retained infectivity after IP processing. Additionally, encapsulated viruses have shown enhanced transfection efficiency up to 4 × higher compared to non-encapsulated Ads. Extracting non-encapsulated viruses from solution may prevent an adverse in vivo immune response and may enhance treatment for multiple administrations.
- Published
- 2014
48. Patent and Marketing Exclusivities 101 for Drug Developers
- Author
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Oronsky, Bryan, primary, Caroen, Scott, additional, Brinkhaus, Franck, additional, Reid, Tony, additional, Stirn, Meaghan, additional, and Kumar, Raj, additional
- Published
- 2023
- Full Text
- View/download PDF
49. Nucleocapsid as a next-generation COVID-19 vaccine candidate
- Author
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Oronsky, Bryan, Larson, Christopher, Caroen, Scott, Hedjran, Farah, Sanchez, Ana, Prokopenko, Elena, and Reid, Tony
- Published
- 2022
- Full Text
- View/download PDF
50. Looking at Beauty to Kalon in Western Greece: Selected Essays from the 2018 Symposium on the Heritage of Western Greece
- Author
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Reid, Heather L., Heather L. Reid, Tony Leyh, William Wians, Jessica Elbert Decker, Francesco Moles, Aura Picconi, Heather L. Reid, Mateo Duque, Nicola Galgano, Konstantinos Gkaleas, Marina Marren, Guilherme Domingues da Motta, Nickolas Pappas, Enrico Postiglione, Deborah De Chiara-Quenzer, Audrey L. Anton, Luca Torr and Reid, Heather L., Heather L. Reid, Tony Leyh, William Wians, Jessica Elbert Decker, Francesco Moles, Aura Picconi, Heather L. Reid, Mateo Duque, Nicola Galgano, Konstantinos Gkaleas, Marina Marren, Guilherme Domingues da Motta, Nickolas Pappas, Enrico Postiglione, Deborah De Chiara-Quenzer, Audrey L. Anton, Luca Torr
- Published
- 2019
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