_:b8011735 "We used the imaging change score as a marker for drug distribution based on a study that showed that new FLAIR/T2 signal changes are correlated with drug distribution [>>11<<]. We were unable to identify any correlation between the imaging change score, local tumor control or clinical outcome. The numbers of catheters associated with more extensive imaging changes were relatively low and therefore we might" . _:b8011703 "introduction" . _:b8011729 . . . . _:b8011728 "Recently, gadoteridol-loaded liposomes were shown to be successfully delivered in a canine model via CED and this technology also allows for monitoring of the distribution of these particles by real time imaging [>>20<<]. Using this technique, a recent study from Varenika et al. [21] showed that leakage occurred in 20% of infusions in monkeys. The clinical development of such a technique would identify patients in whom leakage occurred during the" . . . . . . _:b8011722 . _:b436041375 . _:b436041311 "7"^^ . _:b436041356 . _:b436041368 . _:b8011734 . _:b8011733 "has been demonstrated in tumor samples as well as variation in the expression from various sites of tumor, however the use of different antibodies used in these studies makes it difficult to assess the real impact of these findings [>>6<<, 22\u201325]. Given that most patients will undergo surgery at recurrence, the expression of the target gene at the tumor margins is much more crucial than the expression in the core of the tumor." . _:b8011706 "CB, a recombinant cytotoxin composed of the human interleukin -13 (IL-13) and a truncated form of the Pseudomonas aeruginosa Exotoxin A, has been shown to be highly toxic to cells expressing the IL-13 receptor [>>4<<, 5]. Pseudomonas Exotoxin A kills mammalian cells by catalyzing irreversible ADP-ribosylation and inactivation of the elongation factor 2 necessary for protein synthesis. Human GBMs express high levels of the IL-13 receptor in comparison" . _:b8011703 . _:b436041355 . _:b8011724 _:b8011732 . _:b8011713 . _:b8011724 _:b8011733 . . _:b8011724 _:b8011734 . . _:b8011724 _:b8011735 . _:b436041317 "3"^^ . _:b8011724 _:b8011728 . _:b436041313 . _:b8011724 _:b8011729 . _:b8011724 _:b8011730 . _:b8011724 _:b8011731 . _:b436041316 "3"^^ . _:b436041319 . _:b436041319 "3"^^ . . _:b8011710 "if CED can successfully distribute IL13-PE38QQR demonstrated that co-infusion of IL13-PE38QQR with 123I-labeled human serum albumin (HAS) in patients with GBM led under ideal circumstances to adequate tissue distribution of the drug [>>8<<]. The authors also identified that proximity to subarachnoid space and placement close to an ependymal surface has a significant detrimental influence on the drug delivery." . _:b436041318 "3"^^ . _:b8011708 . . _:b436041313 "4"^^ . _:b8011709 . . _:b436041312 "4"^^ . _:b8011724 _:b8011725 . _:b8011710 . _:b8011724 _:b8011726 . _:b436041315 "3"^^ . _:b436041351 . _:b8011724 _:b8011727 . _:b8011711 . . _:b436041314 "4"^^ . _:b436041315 . _:b8011704 . _:b436041336 . _:b436041325 "3"^^ . _:b8011705 . _:b436041324 "3"^^ . _:b8011714 _:b8011716 . _:b8011714 _:b8011717 . _:b8011706 . _:b436041327 "2"^^ . _:b436041361 . _:b8011714 _:b8011718 . . _:b436041352 . _:b436041379 . _:b8011707 . _:b436041326 "2"^^ . _:b8011714 _:b8011715 . _:b8011719 _:b8011720 . _:b8011719 _:b8011721 . _:b8011718 . _:b8011716 . _:b8011706 . _:b8011719 _:b8011722 . _:b436041321 "3"^^ . _:b8011719 _:b8011723 . _:b8011720 "Imaging change score due to CB via CED was graded according to guidelines outlined in Table\u00A05 [>>10<<]. Imaging change scores on both day 43 and day 71 were evaluated for 271 catheters, among which 80% had the same imaging change scores on both days (one-sided 95% lower confidence limit\u00A0=\u00A076%). The majority of catheters had low to" . . _:b8011725 . _:b8011717 . _:b436041345 . _:b436041320 "3"^^ . _:b8011735 . _:b8011718 . _:b436041323 "3"^^ . _:b436041353 . _:b8011719 . _:b436041322 "3"^^ . _:b436041382 . _:b8011712 . _:b436041333 "2"^^ . _:b8011704 . . . _:b8011713 . _:b8011719 "results" . _:b436041332 "2"^^ . . _:b8011712 . _:b436041335 "2"^^ . . _:b8011714 . _:b436041312 . _:b436041385 . _:b436041367 . _:b8011715 . _:b436041334 "2"^^ . . . _:b436041329 "2"^^ . _:b8011724 . _:b436041342 . _:b8011731 "With respect to target expression, several studies have shown that the target of CB, the IL-13R, is over-expressed in a large number of high grade glioma explants [6, >>22<<]. A recent study using a commercially available tissue array and IL-13R antibody showed that up to 75% of patients with GBM over-express the IL-13R. This will allow upfront testing for future trials and should be included in the" . _:b436041378 . . _:b8011725 . . _:b436041328 "2"^^ . . _:b8011726 . _:b436041331 "2"^^ . _:b436041338 . _:b8011727 . _:b436041330 "2"^^ . . _:b436041371 . . _:b8011720 . _:b436041341 "2"^^ . _:b436041387 . _:b436041324 . _:b8011721 . _:b436041340 "2"^^ . . _:b436041383 . _:b8011720 . _:b8011722 . _:b436041343 "2"^^ . _:b8011723 . _:b436041342 "2"^^ . _:b436041344 . . _:b8011732 . _:b436041366 . _:b436041337 "2"^^ . _:b8011714 "materials and methods" . _:b8011733 . _:b436041336 "2"^^ . . _:b436041370 . _:b8011726 . _:b8011734 . _:b436041339 "2"^^ . _:b436041329 . _:b436041323 . _:b8011735 . _:b436041338 "2"^^ . _:b8011728 . _:b436041349 "2"^^ . _:b8011722 "A prior study of patients treated with CB via CED suggested that the development of new T2/FLAIR signal abnormality is associated with drug distribution [>>11<<]. We therefore used the imaging change score as a surrogate for drug distribution in this imaging analysis." . . _:b8011729 . _:b436041348 "2"^^ . _:b8011732 . . _:b8011730 . . _:b436041351 "2"^^ . _:b8011731 . _:b436041350 "2"^^ . _:b8011734 . _:b8011708 . _:b436041345 "2"^^ . . . . _:b436041344 "2"^^ . _:b8011717 . . _:b436041347 "2"^^ . . _:b436041346 "2"^^ . _:b436041320 . _:b436041358 . _:b436041357 "2"^^ . . _:b436041365 . _:b436041327 . _:b436041356 "2"^^ . . _:b436041359 "2"^^ . . _:b436041358 "2"^^ . _:b436041362 . _:b436041353 "2"^^ . _:b436041332 . . _:b436041352 "2"^^ . _:b436041317 . _:b436041311 . _:b436041355 "2"^^ . _:b436041369 . _:b436041354 "2"^^ . _:b8011721 "The distribution of imaging change score found in our study resembles that previously reported by Kunwar et al. [>>9<<] based on earlier phase I studies using CB at a similar concentration." . _:b436041365 "2"^^ . _:b436041376 . _:b8011710 . _:b436041364 "2"^^ . . . _:b8011708 "Human GBMs express high levels of the IL-13 receptor in comparison to normal brain and therefore this genetically engineered drug should be highly specific to tumor cells [>>6<<, 7]. Investigations to assess if CED can successfully distribute IL13-PE38QQR demonstrated that co-infusion of IL13-PE38QQR with 123I-labeled human serum albumin (HAS) in patients with GBM led under ideal circumstances to adequate tissue" . _:b436041367 "2"^^ . _:b436041318 . . _:b436041366 "2"^^ . . _:b436041317 . _:b436041361 "2"^^ . _:b436041316 . _:b436041360 "2"^^ . _:b436041349 . _:b436041319 . . "10.1007%2Fs11060-010-0255-0" . _:b436041363 "2"^^ . . _:b436041390 . _:b436041318 . . _:b8011713 "have shown that the development of new T2/FLAIR signal abnormalities after delivery of CB via CED is an indication of successful drug delivery using concurrent infusion of CB and 123I-labeled HSA in combination with SPECT analysis [>>11<<]. The encouraging results from prior phase I studies led to the design of the multicenter phase III trial." . _:b436041362 "2"^^ . . _:b8011723 "The composite analysis of prior phase I trials by Kunwar et al. [>>9<<] demonstrated that patients with two or more catheters positioned per guidelines (n\u00A0=\u00A024) had an improved median survival of 55.6\u00A0weeks (95% CI, 21.0\u201345.9) compared to 37.4\u00A0weeks (95% CI, 21.0\u201345.9) for patients with fewer than two" . _:b436041313 . . _:b436041373 "2"^^ . _:b436041312 . . _:b8011715 . _:b436041372 "2"^^ . _:b436041315 . _:b436041375 "2"^^ . _:b8011727 "The median survival in the PRECISE study for patients treated with CB was reported to be 45.3\u00A0weeks, which is in concordance with prior studies [>>9<<]. Conversely, the median survival for patients with good catheter scores in the PRECISE trial was significantly lower (39.9\u00A0weeks with 95% CI, 32.6\u201352.4) compared to prior phase I trials (55.6\u00A0weeks with 95% CI, 21.0\u201345.9). In this" . _:b436041347 . _:b436041314 . _:b436041374 "2"^^ . _:b8011729 "Using this technique, a recent study from Varenika et al. [>>21<<] showed that leakage occurred in 20% of infusions in monkeys." . _:b436041386 . _:b436041325 . _:b436041369 "2"^^ . _:b436041331 . _:b436041324 . _:b436041326 . . _:b436041368 "2"^^ . _:b436041388 . _:b436041324 . . _:b436041325 . _:b436041327 . _:b436041326 . _:b436041327 . _:b436041371 "2"^^ . _:b436041320 . _:b436041321 . _:b436041326 . _:b436041322 . _:b436041323 . _:b436041370 "2"^^ . _:b436041316 . _:b436041321 . _:b436041317 . _:b436041318 . _:b436041316 . _:b436041319 . _:b436041381 "2"^^ . _:b436041312 . . _:b436041320 . _:b436041313 . _:b436041314 . _:b436041359 . _:b436041315 . _:b436041380 "2"^^ . _:b436041340 . _:b436041323 . . _:b436041341 . _:b436041342 . _:b8011704 "The introduction of temozolamide led to prolonged survival of newly diagnosed patients with GBM after radiation and surgical resection to 15\u00A0months [>>1<<] but therapeutic options for recurrent GBM are limited." . _:b436041343 . _:b436041383 "2"^^ . . _:b436041336 . _:b436041322 . _:b436041337 . _:b436041338 . _:b436041339 . _:b436041382 "2"^^ . . _:b436041332 . _:b436041333 . _:b436041333 . _:b436041334 . _:b436041335 . _:b436041377 "2"^^ . _:b436041343 . _:b436041348 . _:b436041328 . _:b436041332 . _:b436041384 . _:b436041329 . _:b436041330 . _:b8011711 . _:b436041331 . _:b436041376 "2"^^ . _:b436041335 . . _:b436041379 "2"^^ . _:b436041334 . _:b8011732 "This will allow upfront testing for future trials and should be included in the eligibility criteria [>>23<<]. The percentage of IL13R positive samples within the PRECISE cohort is currently not known and might have influenced the outcome. Heterogeneous expression of the IL-13R has been demonstrated in tumor samples as well as variation in the" . _:b436041378 "2"^^ . . _:b8011734 "has been demonstrated in tumor samples as well as variation in the expression from various sites of tumor, however the use of different antibodies used in these studies makes it difficult to assess the real impact of these findings [6, >>22<<\u201325]. Given that most patients will undergo surgery at recurrence, the expression of the target gene at the tumor margins is much more crucial than the expression in the core of the tumor." . _:b436041329 . _:b436041389 "2"^^ . _:b436041328 . _:b436041388 "2"^^ . _:b436041335 . _:b436041331 . . _:b436041334 . _:b8011730 . _:b436041311 . . _:b436041330 . . _:b8011733 . . _:b436041390 "2"^^ . . . _:b436041341 . _:b436041337 . . . _:b436041385 "2"^^ . _:b436041340 . . _:b436041384 "2"^^ . _:b436041343 . _:b436041387 "2"^^ . . _:b436041380 . _:b436041342 . _:b436041354 . _:b436041325 . _:b8011721 . . _:b436041386 "2"^^ . _:b436041337 . _:b436041374 . _:b436041336 . . _:b436041333 . _:b8011723 . _:b436041350 . _:b436041339 . _:b436041311 . _:b436041338 . _:b8011707 "CB, a recombinant cytotoxin composed of the human interleukin -13 (IL-13) and a truncated form of the Pseudomonas aeruginosa Exotoxin A, has been shown to be highly toxic to cells expressing the IL-13 receptor [4, >>5<<]. Pseudomonas Exotoxin A kills mammalian cells by catalyzing irreversible ADP-ribosylation and inactivation of the elongation factor 2 necessary for protein synthesis. Human GBMs express high levels of the IL-13 receptor in comparison to" . _:b436041322 . _:b436041341 . . _:b436041349 . . _:b436041372 . . _:b436041348 . _:b8011727 . _:b436041351 . _:b436041363 . . . _:b436041373 . _:b436041314 . _:b436041350 . _:b8011703 . _:b436041345 . _:b8011705 . . _:b8011707 . . _:b436041344 . _:b436041377 . _:b436041347 . . _:b436041346 . _:b436041339 . _:b436041357 . "PMC0" . _:b436041360 . . _:b436041356 . _:b8011731 . . _:b436041359 . _:b436041358 . _:b8011725 "As such, the degree of variations in extent of resection may have influenced the study outcome negatively [>>18<<]." . _:b436041330 . _:b8011703 _:b8011704 . _:b8011734 . _:b436041353 . _:b8011703 _:b8011705 . _:b8011703 _:b8011706 . _:b8011703 _:b8011707 . _:b8011703 _:b8011708 . _:b436041352 . _:b8011703 _:b8011709 . _:b8011703 _:b8011710 . _:b8011703 _:b8011711 . _:b436041355 . _:b8011728 . . . _:b8011705 "regional delivery systems for these patients including convection enhanced delivery (CED) combined with targeted therapy such as cintredekin-besudotox (CB) and TP-38, a recombinant protein targeting the epidermal growth factor receptor [>>2<<, 3]. CB, also referred to as IL13-PE38QQR, has been tested in prior phase I studies using CED as delivery methodology." . _:b436041354 . . _:b436041365 . _:b436041364 . _:b436041364 . _:b436041367 . . . _:b436041366 . _:b436041340 . _:b436041361 . . . _:b8011712 "The imaging changes seen on MRIs of patients treated with CB via CED are summarized by Parney et al. [>>10<<] and a specific scoring system has been established." . . _:b436041360 . . _:b8011709 . _:b436041363 . . _:b436041362 . _:b8011734 . _:b436041321 . _:b436041373 . _:b436041372 . _:b436041388 . _:b436041389 . _:b436041375 . _:b436041346 . _:b436041390 . . _:b436041389 . _:b8011730 "With respect to target expression, several studies have shown that the target of CB, the IL-13R, is over-expressed in a large number of high grade glioma explants [>>6<<, 22]. A recent study using a commercially available tissue array and IL-13R antibody showed that up to 75% of patients with GBM over-express the IL-13R. This will allow upfront testing for future trials and should be included in the" . _:b436041384 . _:b436041385 . _:b436041374 . . _:b436041386 . _:b436041387 . _:b436041380 . _:b436041381 . _:b436041369 . _:b436041382 . . _:b8011724 . _:b436041383 . _:b436041376 . _:b436041377 . _:b436041368 . _:b436041378 . _:b436041379 . . . _:b436041371 . _:b436041357 . . _:b436041370 . _:b8011719 . _:b8011714 . _:b436041381 . _:b436041380 . . _:b436041356 . _:b436041357 . _:b436041383 . _:b436041358 . _:b8011711 "These studies also proved that CB could be infused safely via CED in patients after tumor resection [>>9<<]. The imaging changes seen on MRIs of patients treated with CB via CED are summarized by Parney et al. [10] and a specific scoring system has been established. It is thought that higher grades of imaging changes are due to a necrotic and" . _:b436041359 . _:b436041352 . _:b436041353 . _:b436041382 . _:b436041354 . _:b436041355 . _:b436041348 . _:b436041349 . _:b8011709 "Human GBMs express high levels of the IL-13 receptor in comparison to normal brain and therefore this genetically engineered drug should be highly specific to tumor cells [6, >>7<<]. Investigations to assess if CED can successfully distribute IL13-PE38QQR demonstrated that co-infusion of IL13-PE38QQR with 123I-labeled human serum albumin (HAS) in patients with GBM led under ideal circumstances to adequate tissue" . _:b436041377 . _:b436041350 . _:b8011726 "In fact, a recent study based on the experience of the North American Brain Tumor Consortium (NABTC) demonstrates a strong correlation between progression status at 6\u00A0months and OS among adult patients with recurrent high grade glioma [>>19<<]." . _:b436041351 . _:b436041381 . _:b436041344 . _:b436041345 . _:b436041376 . _:b436041346 . _:b436041347 . . _:b436041372 . _:b436041373 . _:b8011717 "To visualize these trajectories on all available images, CT and MRI data were overlaid using the image fusion functionality in the iPlan\u00AE Flow planning and simulation software, which is described in more detail elsewhere [8, >>13<<, 14]." . _:b436041379 . _:b436041374 . _:b436041375 . _:b436041368 . _:b436041369 . _:b436041378 . _:b436041370 . _:b436041371 . _:b436041364 . _:b436041365 . _:b436041389 . _:b436041366 . . _:b436041367 . _:b436041360 . _:b436041361 . _:b436041388 . _:b436041362 . _:b436041363 . _:b8011703 _:b8011712 . _:b8011716 . _:b8011703 _:b8011713 . _:b8011716 "To visualize these trajectories on all available images, CT and MRI data were overlaid using the image fusion functionality in the iPlan\u00AE Flow planning and simulation software, which is described in more detail elsewhere [>>8<<, 13, 14]." . _:b436041390 . _:b436041328 . . _:b8011724 "discussion" . _:b436041385 . . _:b436041384 . _:b436041387 . . _:b8011718 "Imaging change scores were assessed for each catheter as outlined in Table\u00A05 [>>10<<]. Local tumor control was defined as absence of tumor recurrence or progression within 1\u00A0cm radius of the trajectory length of the catheter. Local tumor control was assessed for each catheter. Progression was defined as existing tumor" . . _:b436041386 . . _:b8011715 "CB was purified as described prior under current good manufacturing practices [>>6<<]. CB was infused at a concentration of 0.5\u00A0\u03BCg/ml at a total rate of 0.750\u00A0ml/h for 96\u00A0h after catheter placement was confirmed." .