Role of urothelial cells in BCG immunotherapy for superficial bladder cancer

Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been directed to decipher the exact mechanism of action of the BCG-associated antitumour effect. Bacillus Calmette-Guérin causes an extensive local inflammatory reaction in the bladder wall. Of this, the massive appearance of cytokines in the urine of BCG-treated patients stands out. Activated lymphocytes and macrophages are the most likely sources of these cytokines, but at present other cellular sources such as urothelial tumour cells cannot be ruled out. Bacillus Calmette-Guérin is internalised and processed both by professional antigen-presenting cells and urothelial tumour cells, resulting in an altered gene expression of these cells that accumulates in the presentation of BCG antigens and secretion of particular cytokine

Biocompatibility and degradation mechanisms of predegraded and non-predegraded poly(lactide) implants:An animal study

In all patients treated with as-polymerized poly( L-lactide) (PLLA), a swelling at the site of implantation was observed after three years of implantation. These swellings seem to be related with degrading PLLA and the formation of particles of high crystallinity. To avoid these complications, poly(96%L-, 4%D-lactide) (PLA96) was developed that possesses lower crystallinity that probably results in a faster and more complete degradation. To study the cause of the swelling of PLLA implants and to study the degradation of PLA96 long-term implantation studies are required. Considering the very slow degradation rate of as-polymerized PLLA, in vitro predegradation was performed at elevated temperatures (90 degrees C) to simulate long-term physiological degradation. In this study a comparison was made between the histopathological reaction to non-degraded and predegraded PLLA, PLA96 and polyethylene (PE) discs implanted subcutaneously in rats. Animals were sacrificed after a postoperative period varying from 4 to 52 weeks. Chemical, light- and electron microscopical analysis and semi-quantitative measurements were performed. Based on the chemical analysis, the degradation rate of PLA96 was higher compared with PLLA. The histological reaction to non-degraded PLLA and PLA96 discs was very mild. The histological reaction to the predegraded implants was qualitatively similar to the reaction to the non-degraded implants, however, quantitatively an increase was noted. A number of predegraded PLLA and PLA96 discs showed an increase of volume with implantation time caused by the formation of fields of polymer debris accompanied by a granulomatous inflammatory reaction. The debris zone was found to consist of both polylactide polymer fragments and small remnants of degenerated cells. From our results it can be concluded that, when compared to PLLA, the degradation of PLA96 is enhanced. Subcutaneously implanted predegraded PLLA a nd PLA96 discs can induce a swelling similar to th at observed with PLLA implants in patients. So, in vitro predegradation followed by in vivo implantation might be used as a model to predict late complications during clinical use.</p

Biocompatibility and degradation mechanisms of predegraded and non-predegraded poly(lactide) implants: An animal study

In all patients treated with as-polymerized poly( L-lactide) (PLLA), a swelling at the site of implantation was observed after three years of implantation. These swellings seem to be related with degrading PLLA and the formation of particles of high crystallinity. To avoid these complications, poly(96%L-, 4%D-lactide) (PLA96) was developed that possesses lower crystallinity that probably results in a faster and more complete degradation. To study the cause of the swelling of PLLA implants and to study the degradation of PLA96 long-term implantation studies are required. Considering the very slow degradation rate of as-polymerized PLLA, in vitro predegradation was performed at elevated temperatures (90 degrees C) to simulate long-term physiological degradation. In this study a comparison was made between the histopathological reaction to non-degraded and predegraded PLLA, PLA96 and polyethylene (PE) discs implanted subcutaneously in rats. Animals were sacrificed after a postoperative period varying from 4 to 52 weeks. Chemical, light- and electron microscopical analysis and semi-quantitative measurements were performed. Based on the chemical analysis, the degradation rate of PLA96 was higher compared with PLLA. The histological reaction to non-degraded PLLA and PLA96 discs was very mild. The histological reaction to the predegraded implants was qualitatively similar to the reaction to the non-degraded implants, however, quantitatively an increase was noted. A number of predegraded PLLA and PLA96 discs showed an increase of volume with implantation time caused by the formation of fields of polymer debris accompanied by a granulomatous inflammatory reaction. The debris zone was found to consist of both polylactide polymer fragments and small remnants of degenerated cells. From our results it can be concluded that, when compared to PLLA, the degradation of PLA96 is enhanced. Subcutaneously implanted predegraded PLLA a nd PLA96 discs can induce a swelling similar to th at observed with PLLA implants in patients. So, in vitro predegradation followed by in vivo implantation might be used as a model to predict late complications during clinical use

Laat optredende weefselreacties en degradatie van afbreekbare polylactide implantaten. Een experimenteel onderzoek in de rat

Biodegradable poly(L-lactide) (PLLA) plates and screws are currently being used as an alternative for metal plates and screws for the fixation of bone fractures. However, in patients treated with as-polymerized poly(L-lactide) (PLLA), a swelling at the site of implantation was observed after three and more years following the implantation. In this study a comparison was made between the histopathological reaction to non-degraded and predegraded as-polymerized PLLA, and as a control, polyethylene (PE) disks implanted subcutaneously in rats. In addition, another recently developed poly(96%L,4%D-lactide) (PLA96) was tested that possesses lower crystallinity that probably results in a faster and more complete degradation. The histological reaction to the predegraded implants was qualitatively similar to the reaction to the non-degraded implants, however, quantitatively an increase was noted. The local swelling observed in vivo with the predegraded PLLA and PLA96 showed histologically similar characteristics as material explanted from patients. The results of this study indicate that in vitro predegradation followed by in vivo implantation might be used as a model to predict late complications of biodegradable implants. At the moment biodegradable materials are not included in the ISO/CEN 10993-6 guidelines: Biological evaluation of medical devices. Part 6 Tests for local effects after implantation. The described model, in vitro predegradation followed by in vivo implantation, might be suited as an implantation assay for biodegradable materials.Biologisch afbreekbare implantaten van poly-L-lactide (PLLA) worden thans gebruikt als alternatief voor metalen platen en schroeven voor de fixatie van botbreuken. Tijdens het gebruik van deze afbreekbare implantaten zijn er echter locale complicaties waargenomen in de vorm van zwellingen vanaf ongeveer drie tot vier jaar na implantatie. In deze studie werd de histopathologische reactie van ongedegradeerd en pre-gedegradeerd 'as-polymerized' PLLA, en als controle van polyethyleen (PE) onderzocht door middel van de subcutane implantatie van schijfjes materiaal in ratten. Tevens werd in deze studie een recent ontwikkeld copolymeer van D- en L-lactide onderzocht, poly(96%L,4%D-lactide) (PLA96), een polymeer met een lagere kristalliniteit wat resulteert in een snellere en meer complete degradatie. De histologische reactie op de pre-gedegradeerde implantaten was kwalitatief gelijk, maar kwantitatief veel sterker dan de reactie op de ongedegradeerde implantaten. De zwelling die in vivo waargenomen werd na in vitro predegradatie van de PLLA en PLA96 polymeren vertoont histologisch dezelfde karakteristieken als de zwelling zoals deze bij patienten na enkele jaren werd waargenomen. De resultaten van deze studie geven aan dat in vitro predegradatie gevolgd door in vivo implantatie als een model gebruikt kan worden om laat optredende reacties van afbreekbare implantaten te voorspellen. Afbreekbare materialen zijn tot op heden nog niet opgenomen in de ISO/CEN richtlijnen voor wat betreft de locale effecten na implantatie (ISO/CEN 10993-6, Biological evaluation of medical devices. Part 6 Tests for local effects after implantation). Het in dit rapport beschreven model, in vitro predegradatie gevolgd door in vivo implantatie, is mogelijk geschikt om als implantatie model te dienen voor afbreekbare materialen

Laat optredende weefselreacties en degradatie van afbreekbare polylactide implantaten. Een experimenteel onderzoek in de rat

Biologisch afbreekbare implantaten van poly-L-lactide (PLLA) worden thans gebruikt als alternatief voor metalen platen en schroeven voor de fixatie van botbreuken. Tijdens het gebruik van deze afbreekbare implantaten zijn er echter locale complicaties waargenomen in de vorm van zwellingen vanaf ongeveer drie tot vier jaar na implantatie. In deze studie werd de histopathologische reactie van ongedegradeerd en pre-gedegradeerd 'as-polymerized' PLLA, en als controle van polyethyleen (PE) onderzocht door middel van de subcutane implantatie van schijfjes materiaal in ratten. Tevens werd in deze studie een recent ontwikkeld copolymeer van D- en L-lactide onderzocht, poly(96%L,4%D-lactide) (PLA96), een polymeer met een lagere kristalliniteit wat resulteert in een snellere en meer complete degradatie. De histologische reactie op de pre-gedegradeerde implantaten was kwalitatief gelijk, maar kwantitatief veel sterker dan de reactie op de ongedegradeerde implantaten. De zwelling die in vivo waargenomen werd na in vitro predegradatie van de PLLA en PLA96 polymeren vertoont histologisch dezelfde karakteristieken als de zwelling zoals deze bij patienten na enkele jaren werd waargenomen. De resultaten van deze studie geven aan dat in vitro predegradatie gevolgd door in vivo implantatie als een model gebruikt kan worden om laat optredende reacties van afbreekbare implantaten te voorspellen. Afbreekbare materialen zijn tot op heden nog niet opgenomen in de ISO/CEN richtlijnen voor wat betreft de locale effecten na implantatie (ISO/CEN 10993-6, Biological evaluation of medical devices. Part 6 Tests for local effects after implantation). Het in dit rapport beschreven model, in vitro predegradatie gevolgd door in vivo implantatie, is mogelijk geschikt om als implantatie model te dienen voor afbreekbare materialen.Biodegradable poly(L-lactide) (PLLA) plates and screws are currently being used as an alternative for metal plates and screws for the fixation of bone fractures. However, in patients treated with as-polymerized poly(L-lactide) (PLLA), a swelling at the site of implantation was observed after three and more years following the implantation. In this study a comparison was made between the histopathological reaction to non-degraded and predegraded as-polymerized PLLA, and as a control, polyethylene (PE) disks implanted subcutaneously in rats. In addition, another recently developed poly(96%L,4%D-lactide) (PLA96) was tested that possesses lower crystallinity that probably results in a faster and more complete degradation. The histological reaction to the predegraded implants was qualitatively similar to the reaction to the non-degraded implants, however, quantitatively an increase was noted. The local swelling observed in vivo with the predegraded PLLA and PLA96 showed histologically similar characteristics as material explanted from patients. The results of this study indicate that in vitro predegradation followed by in vivo implantation might be used as a model to predict late complications of biodegradable implants. At the moment biodegradable materials are not included in the ISO/CEN 10993-6 guidelines: Biological evaluation of medical devices. Part 6 Tests for local effects after implantation. The described model, in vitro predegradation followed by in vivo implantation, might be suited as an implantation assay for biodegradable materials.VWS/GMVIG