Objective: The complexity, heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merit...Objective: The complexity, heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merited. Testing this hypothesis, the tumor marker, metabolic activity, and overall survival(OS) responses, to the use of one such system, implantable macrobeads [RENCA macrobeads(RMBs)], in phase I and IIa clinical trials in advanced,treatment-resistant metastatic colorectal cancer(m CRC) are described here.Methods: Forty-eight m CRC patients(30 females; 18 males), who had failed all available, approved treatments,underwent RMB implantation(8 RMB/kg body weight) up to 4 times in phase I and phase IIa open-label trials.Physicals, labs [tumor and inflammation markers, lactate dehydrogenase(LDH)] and positron emission tomography-computed tomography(PET-CT) imaging to measure number/volume and metabolic activity of the tumors were performed pre-and 3-month-post-implantation to evaluate safety and initial efficacy(as defined by biological responses). PET-CT maximum standard uptake value(SUVmax)(baseline and d 90; SUVmax ≥2.5), LDH,and carcinoembryonic antigen(CEA) and/or cancer antigen 19-9(CA 19-9) response(baseline, d 30 and/or d 60)were assessed and compared to OS.Results: Responses after implantation were characterized by an at least 20% decrease in CEA and/or CA 19-9 in75% of patients. Fluorodeoxyglucose(FDG)-positive lesions(phase I, 39; 2 a, 82) were detected in 37/48 evaluable patients, with 35% stable volume and stable or decreased SUV(10) plus four with necrosis; 10, increased tumor volume, SUV. LDH levels remained stable and low in Responders(R)(d 0–60, 290.4–333.9), but increased steadily in Non-responders(NR)(d 0–60, 382.8–1,278.5)(d 60, P=0.050). Responders to RMBs, indicated by the changes in the above markers, correlated with OS(R mean OS=10.76 months; NR mean OS=4.9 months; P=0.0006).Conclusions: The correlations of the tumor marker, tumor volume and SUV changes on PET-CT, and LDH levels themselves, and with OS, support the concept of a biological response to RMB implantation and the validity of the biological-systems approach to m CRC. A phase III clinical trial is planned.展开更多
Juvenile idiopathic arthritis(JIA)is the most common rheumatic disease of childhood,and juvenile idiopathic associated uveitis(JIA-U)is the most frequently noted extra-articular manifestation.JIA-U can present asympto...Juvenile idiopathic arthritis(JIA)is the most common rheumatic disease of childhood,and juvenile idiopathic associated uveitis(JIA-U)is the most frequently noted extra-articular manifestation.JIA-U can present asymptomatically and lead to ocular complications,so regular screening and monitoring are needed to prevent potentially sight-threatening sequelae.Topical glucocorticoids such as prednisolone acetate are usually the first line of treatment for anterior uveitis associated with JIA-U,but long-term use may be associated with cataract,ocular hypertension and glaucoma.Disease modifying anti-rheumatic drugs(DMARDs)such as methotrexate allow tapering of the corticosteroids to prevent long-term complications.Biologic therapies have been increasingly used as targeted therapies for JIA-U,particularly monoclonal antibodies targeting the proinflammatory cytokine TNF-αsuch as adalimumab and infliximab.One recent,multicenter,prospective,randomized clinical trial provided evidence of the efficacy of adalimumab with methotrexate for JIA-U compared to methotrexate alone.Another clinical trial studying the interleukin-6 inhibitor tocilizumab for JIA-U showed promise in tapering topical corticosteroids.Additionally,JAK inhibitors are emerging biologic therapies for JIA-U in patients refractory to TNF-αinhibitors,with a clinical trial assessing the efficacy of baricitinib for JIA-U underway.While clinical trials on these novel biologics are limited,further investigation of these agents may provide additional therapeutic options for JIA-U.展开更多
Uveitis,or inflammation of the uveal tissues(iris,ciliary body and the choroid),and its contiguous structures,can lead to severe visual impairment and is among the leading causes of vision impairment worldwide(1).In c...Uveitis,or inflammation of the uveal tissues(iris,ciliary body and the choroid),and its contiguous structures,can lead to severe visual impairment and is among the leading causes of vision impairment worldwide(1).In clinical practice,specialists in uveitis and ocular immunology are called upon to manage a range of uveitis syndromes-infectious disease,noninfectious autoimmune conditions,and masquerade syndromes such as lymphoma.Moreover,ophthalmologists of all subspecialties(i.e.,medical and surgical retina,corneal surgeons,orbital/oculoplastic surgeons,and comprehensive ophthalmologists)are called upon to manage uveitis syndromes,emphasizing clear importance to understanding common uveitis syndromes,diagnostic workups,and the state-of-the-art in uveitis and ocular inflammation care.展开更多
基金financial support of this project received from Metromedia Bio-Science, LLC
文摘Objective: The complexity, heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merited. Testing this hypothesis, the tumor marker, metabolic activity, and overall survival(OS) responses, to the use of one such system, implantable macrobeads [RENCA macrobeads(RMBs)], in phase I and IIa clinical trials in advanced,treatment-resistant metastatic colorectal cancer(m CRC) are described here.Methods: Forty-eight m CRC patients(30 females; 18 males), who had failed all available, approved treatments,underwent RMB implantation(8 RMB/kg body weight) up to 4 times in phase I and phase IIa open-label trials.Physicals, labs [tumor and inflammation markers, lactate dehydrogenase(LDH)] and positron emission tomography-computed tomography(PET-CT) imaging to measure number/volume and metabolic activity of the tumors were performed pre-and 3-month-post-implantation to evaluate safety and initial efficacy(as defined by biological responses). PET-CT maximum standard uptake value(SUVmax)(baseline and d 90; SUVmax ≥2.5), LDH,and carcinoembryonic antigen(CEA) and/or cancer antigen 19-9(CA 19-9) response(baseline, d 30 and/or d 60)were assessed and compared to OS.Results: Responses after implantation were characterized by an at least 20% decrease in CEA and/or CA 19-9 in75% of patients. Fluorodeoxyglucose(FDG)-positive lesions(phase I, 39; 2 a, 82) were detected in 37/48 evaluable patients, with 35% stable volume and stable or decreased SUV(10) plus four with necrosis; 10, increased tumor volume, SUV. LDH levels remained stable and low in Responders(R)(d 0–60, 290.4–333.9), but increased steadily in Non-responders(NR)(d 0–60, 382.8–1,278.5)(d 60, P=0.050). Responders to RMBs, indicated by the changes in the above markers, correlated with OS(R mean OS=10.76 months; NR mean OS=4.9 months; P=0.0006).Conclusions: The correlations of the tumor marker, tumor volume and SUV changes on PET-CT, and LDH levels themselves, and with OS, support the concept of a biological response to RMB implantation and the validity of the biological-systems approach to m CRC. A phase III clinical trial is planned.
基金This project was supported by unrestricted departmental grant from Research to Prevent Blindness,Inc.to the Emory Eye Center,Emory University School of Medicine,National Eye Institute/National Institutes of Health core grant P30-EY06360(Department of Ophthalmology,Emory University School of Medicine)National Eye Institute of the National Institutes of Health under award number K23 EY030158(Shantha),R01EY030521(STAH),and R01 EY029594(SY)The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the views or policies of the Department of Health and Human Services,nor does mention of trade names,commercial products,or organizations imply endorsement by the U.S.Government.
文摘Juvenile idiopathic arthritis(JIA)is the most common rheumatic disease of childhood,and juvenile idiopathic associated uveitis(JIA-U)is the most frequently noted extra-articular manifestation.JIA-U can present asymptomatically and lead to ocular complications,so regular screening and monitoring are needed to prevent potentially sight-threatening sequelae.Topical glucocorticoids such as prednisolone acetate are usually the first line of treatment for anterior uveitis associated with JIA-U,but long-term use may be associated with cataract,ocular hypertension and glaucoma.Disease modifying anti-rheumatic drugs(DMARDs)such as methotrexate allow tapering of the corticosteroids to prevent long-term complications.Biologic therapies have been increasingly used as targeted therapies for JIA-U,particularly monoclonal antibodies targeting the proinflammatory cytokine TNF-αsuch as adalimumab and infliximab.One recent,multicenter,prospective,randomized clinical trial provided evidence of the efficacy of adalimumab with methotrexate for JIA-U compared to methotrexate alone.Another clinical trial studying the interleukin-6 inhibitor tocilizumab for JIA-U showed promise in tapering topical corticosteroids.Additionally,JAK inhibitors are emerging biologic therapies for JIA-U in patients refractory to TNF-αinhibitors,with a clinical trial assessing the efficacy of baricitinib for JIA-U underway.While clinical trials on these novel biologics are limited,further investigation of these agents may provide additional therapeutic options for JIA-U.
文摘Uveitis,or inflammation of the uveal tissues(iris,ciliary body and the choroid),and its contiguous structures,can lead to severe visual impairment and is among the leading causes of vision impairment worldwide(1).In clinical practice,specialists in uveitis and ocular immunology are called upon to manage a range of uveitis syndromes-infectious disease,noninfectious autoimmune conditions,and masquerade syndromes such as lymphoma.Moreover,ophthalmologists of all subspecialties(i.e.,medical and surgical retina,corneal surgeons,orbital/oculoplastic surgeons,and comprehensive ophthalmologists)are called upon to manage uveitis syndromes,emphasizing clear importance to understanding common uveitis syndromes,diagnostic workups,and the state-of-the-art in uveitis and ocular inflammation care.