Stummer, W, Pichlmeier, U, Meinel, T, Wiestler, OD, Zanella, F and Reulen, HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7: 392-401
5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity.
322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.
Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.
Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.
"Under an external light source, photosensitizers could be excited to induce cytotoxic reactive oxygen species which would aggressively destroy cancer cells. However, single photosensitizers always had bad ability to locate tumors and could not remain in body for a long time, so the therapeutic exactitude and efficiency were limited to some extent  . In recent years, photosensitizers combined with nanomaterials as multifunctional PDT agents have attracted great attention for simultaneous imaging and therapy, such as Au nanorods@mSiO 2 -porphyrin for two-photon imaging and PDT , NaYF 4 :Yb/Er-ZnPc for fluorescence imaging and PDT , NaY- F 4 :Yb,Er/NaGdF 4 -Ce6 for dual-modal imaging and PDT , and so on [10e12]. "
[Show abstract][Hide abstract] ABSTRACT: Inorganic photosensitizer coupled Gd-based upconversion luminescent (UCL) nanocomposites have potential application for both magnetic resonance imaging (MRI) and photodynamic therapy (PDT) of cancers using the light stability and biocompatibility of TiO2 inorganic photosensitizer. However, TiO2 inorganic photosensitizer could only be excited by ultraviolet (UV) light, which was harmful and weakly penetrable in tissues. In this work, folic acid (FA)-targeted NaGdF4:Yb/Tm@SiO2@TiO2 nanocomposites (FA-Gd-Si-Ti NPs) were constructed and synthesized for both in vivo MRI and near infrared (NIR)-responsive inorganic PDT, in which TiO2 component could be excited by NIR light due to the UCL performance of NaGdF4:Yb/Tm component converting NIR to UV light. The results showed the as-prepared FA-Gd-Si-Ti NPs had good biocompatibility in vitro and in vivo. Moreover, MR study indicated that FA-Gd-Si-Ti NPs were good T1-weighted MRI contrast agents with high longitudinal relaxivity (r1) of 4.53 mm−1 s−1, also in vivo MRI of nude mice showed “bright” signal in MCF-7 tumor. Under the irradiation of 980 nm laser at the power density of 0.6 W/cm2 for 20 min, the viability of HeLa and MCF-7 cells incubated with FA-Gd-Si-Ti NPs could decrease from about 90 % to 35 % and 31%, respectively. Furthermore, in vivo PDT of MCF-7 tumor-bearing nude mice model showed that the inhibition ratio of tumors injected with FA-Gd-Si-Ti NPs reached up to 88.6% after 2-week treatment, compared with that of nude mice in control group. Based on the deep penetration of NIR light and the good biocompatibility of TiO2 inorganic photosensitizer, the as-prepared FA-Gd-Si-Ti NPs could have potential applications in both MRI and NIR-responsive PDT of cancers in deep tissues.
"Fluorescence-guided surgery results in increased resection of malignant gliomas [4,10,12,14,15,23,36,46]. In a large prospective multicenter randomized phase III trial Stummer et al.  showed that compared to conventional microsurgery use of neurochemical navigation with 5-ALA leads to significantly greater proportion of radiologically complete resections of glioblastomas (65% vs. 36%; P < 0.0001), smaller volume of the residual tumor (medians 0 cm 3 vs. 0.7 cm 3 ; P < 0.0001), and better progression-free survival at 6 months after intervention (41% vs. 21%: P = 0.0003). "
[Show abstract][Hide abstract] ABSTRACT: Objective:
To evaluate the role of the neurochemical navigation with 5-aminolevulinic acid (5-ALA) during intraoperative MRI (iMRI)-guided resection of the intracranial malignant gliomas.
The analysis included 99 consecutive surgical cases. Resection of the bulk of the neoplasm was mainly guided by the updated neuronavigation based on the low-field-strength (0.3T) iMRI, whereas at the periphery of the lesion neurochemical navigation with 5-ALA was additionally used.
In total, 286 tissue specimens were obtained during surgeries for histopathological examination. According to iMRI 98 samples with strong (91 cases), weak (6 cases), or absent (1 case) fluorescence corresponded to the bulk of the lesion and all of those ones contained tumor. Out of 188 tissue specimens obtained from the "peritumoral brain," the neoplastic elements were identified in 89%, 81% and 29% of samples with, respectively, strong (107 cases), weak (47 cases) and absent (34 cases) fluorescence. Positive predictive values of the tissue fluorescence for presence of neoplasm within and outside of its boundaries on iMRI were 100% and 86%, respectively.
Neurochemical navigation with 5-ALA is useful adjunct during iMRI-guided resection of intracranial malignant gliomas, which allows identification of the tumor extension beyond its radiological borders.
"Near-infrared (NIR) fluorescence imaging techniques have been developed for a number of clinical applications, ranging from improving tumor delineation, sentinel lymph node identification, and metastasis staging, to neuronal activity monitoring . Because the fluorescence imaging can provide high sensitive and real-time information of the surgical fields, it is a very promising technique for image guided surgery (IGS) [2–5]. The fluorescence signal either arises from endogenous fluorophores or exogenous fluorophores, for instance, indocyanine green (ICG) and methylene blue (MB) [6, 7]. "
[Show abstract][Hide abstract] ABSTRACT: Near-infrared (NIR) fluorescence imaging systems have been developed for image guided surgery in recent years. However, current systems are typically bulky and work only when surgical light in the operating room (OR) is off. We propose a single camera imaging system that is capable of capturing NIR fluorescence and color images under normal surgical lighting illumination. Using a new RGB-NIR sensor and synchronized NIR excitation illumination, we have demonstrated that the system can acquire both color information and fluorescence signal with high sensitivity under normal surgical lighting illumination. The experimental results show that ICG sample with concentration of 0.13 μM can be detected when the excitation irradiance is 3.92 mW/cm2 at an exposure time of 10 ms.
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