Fluorescence-guided Resection Research Articles

Intraoperative fluorescence-guided resection of high-grade glioma: A systematic review

High-grade glioma (HGG) is a devastating disease with very poor prognosis. Maximal resection of HGG improves survival and maximal visualization of the tumor, if reliable, improves the resection. Fluorescence is widely used as guidance mechanism and has demonstrated potential in maximizing the extent of HGG resection. Our goal is to summarize the current techniques using fluorescence during the resection of HGG and demonstrate how its use increases gross total resection rates, overall survival (OS), and progression-free survival (PFS). However, further prospective, multicenter, randomized controlled trials are still in need to prove the advantage of fluorescence-guided surgery on patients' OS/PFS.

Fluorescence-Guided Resection of Glial Brain Tumors with Fotoditazin

Objective: the purpose of this study was to assess the usefulness and accuracy of visualization of glial brain tumors of varying degrees of malignancy when surgically removed with fluorescent control of fotoditazine. Evaluation of the edges of tumor tissue was also carried out in order to increase the degree gross total resection (GTR), and to evaluate the specificity and sensitivity of the fluorescence method. Design and methods: thirty one glial tumor patients, with varying degrees of malignancy, underwent controlled fluorescence-guided resection in the presence of the indicator molecule fotoditazine. To detect fluorescence, a OHS-1 operating microscope Leica with a special fluorescence module was used. Evaluation of the efficacy, sensitivity and specificity of the method was assessed using various histo-morphological studies. GTR was assessed using postoperative MRI. Results: for grade I and II gliomas, the sensitivity of the surgical tumor removal method was 68.3%, and the specificity was 60.1%. For grade III and IV gliomas, the sensitivity of the surgical tumor removal method was 85.4%, and the specificity was 76.2%. The extent to which total surgical resection was achieved was 79.3% in grade I-II and 95.6% in grade III-IV. Conclusions: intraoperative fluorescent imaging with fotoditazine is a highly effective, sensitive, and specific method which permits glial tumors of various histologic types to be resected more completely and effectively.

Extent of Resection in Newly Diagnosed Glioblastoma: Impact of a Specialized Neuro-Oncology Care Center

Treatment of glioblastoma (GBM) consists of microsurgical resection followed by concomitant radiochemotherapy and adjuvant chemotherapy. The best outcome regarding progression free (PFS) and overall survival (OS) is achieved by maximal resection. The foundation of a specialized neuro-oncology care center (NOC) has enabled the implementation of a large technical portfolio including functional imaging, awake craniotomy, PET scanning, fluorescence-guided resection, and integrated postsurgical therapy. This study analyzed whether the technically improved neurosurgical treatment structure yields a higher rate of complete resection, thus ultimately improving patient outcome. Patients and methods: The study included 149 patients treated surgically for newly diagnosed GBM. The neurological performance score (NPS) and the Karnofsky performance score (KPS) were measured before and after resection. The extent of resection (EOR) was volumetrically quantified. Patients were stratified into two subcohorts: treated before (A) and after (B) the foundation of the Regensburg NOC. The EOR and the PFS and OS were evaluated. Results: Prognostic factors for PFS and OS were age, preoperative KPS, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status and EOR. Patients with volumetrically defined complete resection had significantly better PFS (9.4 vs. 7.8 months; p = 0.042) and OS (18.4 vs. 14.5 months; p = 0.005) than patients with incomplete resection. The frequency of transient or permanent postoperative neurological deficits was not higher after complete resection in both subcohorts. The frequency of complete resection was significantly higher in subcohort B than in subcohort A (68.2% vs. 34.8%; p = 0.007). Accordingly, subcohort B showed significantly longer PFS (8.6 vs. 7.5 months; p = 0.010) and OS (18.7 vs. 12.4 months; p = 0.001). Multivariate Cox regression analysis showed complete resection, age, preoperative KPS, and MGMT promoter status as independent prognostic factors for PFS and OS. Our data show a higher frequency of complete resection in patients with GBM after the establishment of a series of technical developments that resulted in significantly better PFS and OS without increasing surgery-related morbidity.

Fluorescence-guided resection of glioma using «photoditazin»

OBJECTIVE. The aim of this research was to improve results of gloss total resections of glial tumors of the brain. MATERIAL AND METHODS. Fluorescence-guided resection was performed in 31 patients with glial tumors of different degree of malignancy. «Photoditazin» was applied during operation. The authors assessed the efficacy, sensitivity and specificity of the method and degree of radical nature of resection in relation to surgery of gliomas. RESULTS. Sensitivity of the method numbered 68,3 % and specificity was 60,1 % in cases of gliomas of grade I-II. It was 85,4 % and 76,2 %, respectively in cases of gliomas of grade III-IV. The degree of achievement of gloss total resection (GTR) was 79,3 % (gliomas of grade III-IV) and 95,6 % (gliomas of grade III-IV). CONCLUSIONS. Intraoperative fluorescent diagnostics using «Photoditazin» was highly effective, sensitive and very specific method in surgery of glial tumors of different degree of malignancy. The method allowed doctors to develop the radical nature of surgery in cases of glial tumors removal.

Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas.

OBJECTIVE Glioblastoma (GBM) is characterized by distinct intratumoral histopathological heterogeneity with regard to variable tumor morphology, cell proliferation, and microvascularity. Maximum resection of a GBM results in an improved prognosis and thus represents the aim of surgery in the majority of cases. Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is currently widely applied for improved intraoperative tumor visualization in patients with a GBM. Three intratumoral fluorescence levels (i.e., strong, vague, or no fluorescence) can usually be distinguished during surgery. So far, however, their exact histopathological correlates and their surgical relevance have not been clarified sufficiently. Thus, the aim of this study was to systematically analyze tissue samples from newly diagnosed GBMs with different fluorescence levels according to relevant histopathological parameters. METHODS This prospective study recruited patients who underwent 5-ALA fluorescence-guided resection of a newly diagnosed radiologically suspected GBM. Each patient received 5-ALA approximately 3 hours before surgery, and a modified neurosurgical microscope was applied for intraoperative visualization of 5-ALA-induced fluorescence. During surgery, tissue samples with strong, vague, or no fluorescence were collected. For each sample, the presence of tumor tissue, quality of tissue (compact, infiltrative, or no tumor), histopathological criteria of malignancy (cell density, nuclear pleomorphism, mitotic activity, and presence of microvascular proliferation/necrosis), proliferation rate (MIB-1 labeling index [LI]), and microvessel density (using CD34 staining) were investigated. RESULTS Altogether, 77 patients with a newly diagnosed, histopathologically confirmed GBM were included, and 131 samples with strong fluorescence, 69 samples with vague fluorescence, and 67 samples with no fluorescence were collected. Tumor tissue was detected in all 131 (100%) of the samples with strong fluorescence and in 65 (94%) of the 69 samples with vague fluorescence. However, mostly infiltrative tumor tissue was still found in 33 (49%) of 67 samples despite their lack of fluorescence. Strong fluorescence corresponded to compact tumors in 109 (83%) of 131 samples, whereas vague fluorescence was consistent with infiltrative tumors in 44 (64%) of 69 samples. In terms of the histopathological criteria of malignancy, a significant positive correlation of all analyzed parameters comprising cell density, nuclear pleomorphism, mitotic activity, microvascular proliferation, and necrosis with the 3 fluorescence levels was observed (p < 0.001). Furthermore, the proliferation rate significantly and positively correlated with strong (MIB-1 LI 28.3%), vague (MIB-1 LI 16.7%), and no (MIB-1 LI 8.8%) fluorescence (p < 0.001). Last, a significantly higher microvessel density was detected in samples with strong fluorescence (CD34 125.5 vessels/0.25 mm2) than in those with vague (CD34 82.8 vessels/0.25 mm2) or no (CD34 68.6 vessels/0.25 mm2) fluorescence (p < 0.001). CONCLUSIONS Strong and vague 5-ALA-induced fluorescence enables visualization of intratumoral areas with specific histopathological features and thus supports neurosurgeons in improving the extent of resection in patients with a newly diagnosed GBM. Despite the lack of fluorescence, tumor tissue was still observed in approximately half of the cases. To overcome this current limitation, the promising approach of complementary spectroscopic measurement of fluorescence should be investigated further.

Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis

BackgroundFluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a promising real-time navigation method in the surgical resection of malignant gliomas. In order to determine whether this method is applicable to metastatic brain tumors, we evaluated the usefulness of intraoperative fluorescence patterns and histopathological features in patients with metastatic brain tumors.MethodsWe retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue.ResultsTumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2–6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2–3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004).ConclusionPeritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection.Trial registrationInstitutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas.

BACKGROUND: Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy. OBJECTIVE: To perform a double-blinded randomized study comparing 3 different doses of 5-ALA. METHODS: Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet–blue illumination, the surgeon's impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content. RESULTS: The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. tmax for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]). CONCLUSION: The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.

Preclinical evaluation of spatial frequency domain-enabled wide-field quantitative imaging for enhanced glioma resection.

5-Aminolevelunic acid-induced protoporphyrin IX (PpIX) fluorescence-guided resection (FGR) enables maximum safe resection of glioma by providing real-time tumor contrast. However, the subjective visual assessment and the variable intrinsic optical attenuation of tissue limit this technique to reliably delineating only high-grade tumors that display strong fluorescence. We have previously shown, using a fiber-optic probe, that quantitative assessment using noninvasive point spectroscopic measurements of the absolute PpIX concentration in tissue further improves the accuracy of FGR, extending it to surgically curable low-grade glioma. More recently, we have shown that implementing spatial frequency domain imaging with a fluorescent-light transport model enables recovery of two-dimensional images of [PpIX], alleviating the need for time-consuming point sampling of the brain surface. We present first results of this technique modified for <italic<in vivo</italic< imaging on an RG2 rat brain tumor model. Despite the moderate errors in retrieving the absorption and reduced scattering coefficients in the subdiffusive regime of 14% and 19%, respectively, the recovered [PpIX] maps agree within 10% of the point [PpIX] values measured by the fiber-optic probe, validating its potential as an extension or an alternative to point sampling during glioma resection.

Abstract 1870: Fluorescence-guided soft tissue sarcoma surgery using a cetuximab-imaging probe conjugate

Abstract BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of solid malignancies whose treatment includes margin-negative resection. Large tumor size and anatomic constraints make margin assessment challenging. Fluorescence-guided surgical resection can help delineate intraoperative margins; preclinical studies demonstrate improved oncologic outcomes in other malignancies using cancer-specific imaging probes. Recent literature describes cathepsin activated probes selective for STS, but no studies using disease-specific chemotherapeutic agents conjugated to imaging probes. This novel strategy has potential to decrease unnecessary healthy tissue resection and improve oncologic outcomes by reducing margin-positive resections. Epidermal growth factor receptor (EGFR) is overexpressed in multiple subtypes of STS and is a potential target for fluorescence-guided surgery. Recent studies show fluorescently labeled cetuximab, an FDA-approved, anti-EGFR antibody, to be safe and useful for margin assessment in other malignancies. Our aim was to evaluate its potential for STS, examining tumor-targeting specificity of two drug-probe conjugates, and comparing them to the described cathepsin-activated probes. We hypothesize the drug-probe conjugates would successfully target STS, with superior tumor specificity. We also aimed to determine the smallest tumor detectable by our conjugate. METHODS: Athymic nude mice with subcutaneous HT1080 fibrosarcoma tumors were injected with one of five probes: IRDye800CW fluorescent probe conjugated to either cetuximab (anti-EGFR) or DC101 (anti-VEGFR2), IRDye800CW conjugated to an isotype control (IgG), or a cathepsin-activated probe (IntegriSense 750 and Prosense 750). Fluorescence imaging was performed daily with open- and closed-field systems. Tumor-to-background ratios (TBR), signal washout times and normalized signal averages were evaluated. On day 9, smallest resectable game evaluation was performed to assess sensitivity for detecting residual post-resection tumor RESULTS: At day 9 post-injection, the TBR of the cetuximab-IRDye800CW group (11.1) was significantly greater than Integrisense750 (6.88, p=0.005), the IgG-IRDye800CW control (4.44, p=0.00005), Prosense750 (2.35, p=0.00009), and DC101-IRDye800CW (1.87, p=0.00003). During in vivo imaging, cetuximab-IRDye800CW outperformed all other agents by several folds of contrast enhancement. The smallest resectable game evaluation demonstrated 1mm3 fragment detection using the cetuximab-IRDye800CW probe. CONCLUSIONS: This study demonstrates superiority of cetuximab-IRDye800CW for disease-specific imaging in a subcutaneous animal model of STS. The novel strategy of coupling improved margin-negative surgical resection with established chemotherapy has considerable translational significance and is an avenue for exploration with other drugs used to treat STS. Citation Format: Nicole K. Behnke, Jason M. Warram, Andrew C. Prince. Fluorescence-guided soft tissue sarcoma surgery using a cetuximab-imaging probe conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1870. doi:10.1158/1538-7445.AM2017-1870

Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: A retrospective multicenter analysis

BackgroundSeveral studies demonstrated that intraoperative near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) identifies (sub)capsular colorectal liver metastases (CRLM) missed by other techniques. It is unclear if this results in any survival benefit. This study evaluates long-term follow-up after NIRF-guided resection of CRLM using ICG. MethodsFirst, patients undergoing resection of CRLM with or without NIRF imaging were analyzed retrospectively. Perioperative details, liver-specific recurrence-free interval and overall survival were compared. Second, the prognosis of patients in whom additional metastases were identified solely by NIRF was studied. ResultsEighty-six patients underwent resection with NIRF imaging and 87 without. In significantly more patients of the NIRF imaging cohort additional metastases were identified during surgery (25% vs. 13%, p = 0.04). Tumors identified solely by NIRF imaging were significantly smaller compared to additional metastases identified also by inspection, palpation or intraoperative ultrasound (3.2 ± 1.8 mm vs. 7.4 ± 2.6 mm, p < 0.001). Liver-specific recurrence-free survival at 4 years was 47% with NIRF imaging and 39% without (hazard ratio at multivariate analysis 0.73, 95% CI 0.42–1.28, p = 0.28). Overall survival at 4 years was 62% and 59%, respectively (p = 0.79). No liver recurrences occurred within 3 years follow-up in 52% of patients in whom additional metastases were resected based on only NIRF imaging. ConclusionsThis study suggests that NIRF imaging identifies significantly more and smaller tumors during resection of CRLM, preventing recurrences in a subset of patients. Given its safety profile and low expense, routine use can be considered until tumor targeting fluorescent tracers are clinically available.

Fluorescence in a cryptococcoma following administration of 5-aminolevulinic acid hydrochloride (Gliolan)

A 54-year-old man presented with two episodes of dysarthria and left facial droop. Both episodes resolved by the time of examination. MRI of the brain revealed a right frontotemporal, heterogeneously...

P09.34 Limitations of visualized fluorescence in malignant gliomas: an objective quantification of protoporphyrin levels and correlation with histopathology: Implications on fluorescence-guided resections

P09.34 Limitations of visualized fluorescence in malignant gliomas: an objective quantification of protoporphyrin levels and correlation with histopathology: Implications on fluorescence-guided resections

Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note.

OBJECTIVE Fluorescence guidance with 5-aminolevulinic acid (5-ALA) helps improve resections of malignant gliomas. However, one limitation is the low intensity of blue light for background illumination. Fluorescein has recently been reintroduced into neurosurgery, and novel microscope systems are available for visualizing this fluorochrome, which highlights all perfused tissues but has limited selectivity for tumor detection. Here, the authors investigate a combination of both fluorochromes: 5-ALA for distinguishing tumor and fluorescein for providing tissue fluorescence of adjacent brain tissue. METHODS The authors evaluated 6 patients who harbored cerebral lesions suggestive of high-grade glioma. Patients received 5-ALA (20 mg/kg) orally 4 hours before induction of anesthesia. Low-dose fluorescein (3 mg/kg intravenous) was injected immediately after anesthesia induction. Pentero microscopes (equipped either with Yellow 560 or Blue 400 filters) were used to visualize fluorescence. To simultaneously visualize both fluorochromes, the Yellow 560 module was combined with external blue light illumination (D-light C System). RESULTS Fluorescein-induced fluorescence created a useful background for protoporphyrin IX (PPIX) fluorescence, which appeared orange to red, surrounded by greenly fluorescent normal brain and edematous tissue. Green brain-tissue fluorescence was helpful in augmenting background. Levels of blue illumination that were too strong obscured PPIX fluorescence. Unspecific extravasation of fluorescein was noted at resection margins, which did not interfere with PPIX fluorescence detection. CONCLUSIONS Dual labeling with both PPIX and fluorescein fluorescence is feasible and gives superior background information during fluorescence-guided resections. The authors believe that this technique carries potential as a next step in fluorescence-guided resections if it is completely integrated into the surgical microscope.

INTRAOPERATIVE FLUORESCENCE-GUIDED RESECTION OF HIGH-GRADE GLYOBLASTOMA USING 5-AMINOLEVULINIC ACID: A META-ANALYSIS

Background. Glioblastoma (GBM) is a high-grade primary brain tumor characterized by resistance to modern treatment modalities. Intraoperative fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) is one of the most innovative techniques to improve the local control rate in GBM surgery. Objective: to assess the diagnostic accuracy, sensitivity and specificity of 5-ALA fluorescence- guided resection (5-ALA-FGR) in patients with GBM. Material and methods. Surgical outcomes of 5-ALA-FGR in patients with GBM were studied in a meta-analysis of clinical series published from 2000 to 2017. Results. The meta-analysis included 26 studies. Gross total tumor resection was achieved in 74.8 % of patients (95 % CI: 67.4–83.5 %). The use of 5-ALA-FGR increased the disease-free survival time in patients with GBM by an average of 8.14 months (95 % CI: 4.36–12.02). The difference in the overall survival of GBM patients in favor of 5-ALA-FGR was 4.35–6.17 months (95 % CI: 0.9–13.23). The specificity and sensitivity of 5-ALA-FGR was high, being 86.6–87.5 % (95 % CI: 81.6–91.7) and 79.8–82.2 % (95 % CI: 73.5–91.07), respectively. Conclusion. The meta-analysis of 26 clinical series showed the high sensitivity and specificity of 5-ALA-FGR. Moreover, the use of 5-ALA-FGR in GBM was reported to increase the disease-free survival and the extent of surgical resection in patients with GBM.

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells

5-Aminolevulinic acid (5-ALA) can accumulate protoporphyrinIX (PpIX) in tumour cell mitochondria and is well known for its utility in fluorescence-guided resection of malignant gliomas as a live molecular marker. Previously, we and other authors demonstrated that 5-ALA has a radiosensitizing effect for tumours. In the present study, we aimed to investigate the mechanism underlying the radiosensitizing effect of 5-ALA by focusing on glioma cell mitochondria. Using an enhancer (ciprofloxacin) of 5-ALA-induced PpIX accumulation, we evaluated the influence of ionizing irradiation(IR) and delayed reactive oxygen species(ROS) production 12h after IR by colony-forming assay and flow cytometry(FCM) with different amounts of PpIX accumulation. The mitochondrial mass and mitochondrial electron transport chain(mtETC) activity were evaluated by FCM and western blot analysis. Cell death and delayed ROS production after IR in glioma cells were increased in proportion to 5-ALA-induced PpIX accumulation. Delayed ROS production enhanced by 5-ALA localized to the glioma cell mitochondria. Mitochondrial mass and mitochondrial complexIII activity, among mtETC factors, were also increased 12h after IR in glioma cells in proportion to 5-ALA-induced PpIX accumulation with some variation. These results suggest that 5-ALA enhances IR-induced mitochondrial oxidative stress and leads to increased cell death with mitochondrial changes, thereby acting as a targeting mitochondrial drug, and so‑called radiosensitizer in glioma cells.

5-Aminolaevulinic Acid–Induced Fluorescence in Primary Central Nervous System Lymphoma

Diagnosis of primary central nervous system lymphoma (PCNSL) is usually confirmed by brain biopsy and subsequent neuropathologic workup. 5-Aminolevulinic acid (5-ALA)-induced fluorescence has been established for diagnostic and therapeutic purposes in glioma treatment during the last few years and is discussed for use in other cranial tumors. Its role in diagnosis and treatment of PCNSL is still elusive. This retrospective study includes clinical, magnetic resonance imaging, pathologic and surgical data of selected 11 patients with PCNSL at two university hospitals within the last 4 years undergoing surgical treatment for resection because of imminent mass effect or suspected cerebral glioma. Patients received 5-ALA for fluorescence-guided resection preoperatively. The 11 subjects age ranged from 59 to 81 years. Postsurgical pathologic workup revealed malignant B cell lymphoma with morphologic features of diffuse large B cell lymphoma. Eight of these 11 patients with PCNSL showed a clear fluorescence induced by 5-ALA. After surgical resection, patients were treated with combination chemotherapy regimens. In patients with glioma, the use of 5-ALA is known to be associated with increased extent of resection and survival benefit. Our data and retrospective analysis of a larger patient cohort suggest that the use of 5-ALA in PCNSL should be included in a surgical approach, if this is reconsidered for select patients within a clinical study. In addition, even photodynamic therapy in combination with 5-ALA might be studied.

ACTR-49. PHASE 1 SAFETY STUDY OF BLZ-100 FOR FLUORESCENCE-GUIDED RESECTION OF GLIOMA IN ADULT SUBJECTS

Real time, fluorescence-guided resection (FGS) of brain cancer may improve extent of resection while minimizing brain injury. BLZ-100 is a near-infrared (NIR) imaging agent composed of the tumor-targeting peptide, chlorotoxin and the NIR fluorescent dye, indocyanine green. It has the potential to selectively label brain and other tumors. This Phase 1 dose escalation study characterized the safety and fluorescence imaging of BLZ-100 in adults with newly diagnosed or recurrent glioma. An IV injection was given before surgery (range 3 -29 hours). Dose escalation utilized a “3+3” design with 5 pre-specified dose levels. Dose limiting toxicity (DLT) was defined as any ≥ Grade 3 BLZ-100 related adverse event (AE) within 7 days of dosing. Safety measures included AEs, laboratory measures, vital signs, and electrocardiograms. Fluorescent images were taken before and after resection (in situ) and of excised tissue (ex vivo) using a NIR camera system suitable for surgery. A total of 17 subjects were enrolled and received doses from 3 to 30 mg. No DLT was observed and none of the treatment-emergent AEs were associated with BLZ-100 dosing. There were 9 cases with WHO Grade III and IV disease and 8 with WHO grade I and II. Fluorescent signal in excised tumor samples increased with increasing dose, with robust fluorescence noted consistently at doses ≥18 mg. Fluorescence was noted in both early (day of) and late (next day) interval (time between imaging and excision) cases, however, the earlier time interval appeared better. Cases with high grade disease had more subjects positive (7/9) and more intense signal compared to those with low grade disease (3/8) based on both in situ and ex vivo imaging. The location of fluorescent signal in excised specimen was concordant with pathology confirmed tumor. These data support the potential use of BLZ-100 for FGS of gliomas.

SURG-39. SURGICAL RESECTION OF GLIOBLASTOMA IN ELDERLY PATIENTS: THE POTENTIAL ROLE OF 5-ALA FLUORESCENCE GUIDANCE

Glioblastoma (GBM) is the most common primary brain tumor in adults and commonly occurs in individuals aged 65 years or older. The prognosis of elderly patients with GBM is universally poor: their median survival ranges from 4 to 9 months. The main reason is that older patients are often treated more conservatively than younger; this is a result of reluctance to offer aggressive treatment for fear of postoperative complications. Several series report that the 5-ALA fluorescence-guided resection increases the extension of tumor removal, improving survival. The aim of this study is to evaluate the impact of 5-ALA on outcomes in elderly GBM. The present experience is related to 36 patients (32 newly diagnosed and 4 recurrent GBM). At diagnosis the age ranged from 65 to 79 years. Co-morbidities (CM) were identified with CIRS scale. All the patients have been submitted to radiotherapy and/or chemotherapy; second and in some cases third line treatments were utilized in recurrent cases. Follow-up ranged from 1 year to 2 years. In more than 90 % of patients tumour tissue showed intraoperative red fluorescence; mainly in recurrent GBM, when MRI documented heterogeneous lesions with enhancing areas mixed with gliotic scars, fluorescence-guided surgery allowed a better definition of active tumor, with net margins from perilesional “healthy” brain. Early postoperative MRI confirmed gross total resection without contrast enhancement in 80 % of patients. In the present experience the procedure did not determine any relevant additional deficit. The median OS was 18 months with a rate of survival at 2 years of 35%. 5-ALA fluorescence-guided surgery improves tumor detection and allows extended resection of GBM in elderly. Postoperatively, there is no impact on neurological status or CM, with a consistent effect on overall survival. The evaluation of CM should drive the therapeutic decisions in elderly patients affected with GBM.

P08.64 5-ALA fluorescence-guided surgical resection of glioblastoma in the elderly

P08.64 5-ALA fluorescence-guided surgical resection of glioblastoma in the elderly

Insular gliomas and the role of intraoperative assistive technologies: Results from a volumetry-based retrospective cohort

IntroductionIn the field of Glioma surgery, there has been an increasing interest in the use of assistive technologies to overcome the difficulty of preserving brain function while improving surgical radicality. In most reports, tumor localization has seldom been considered a variable and the role of intraoperative adjuncts is yet to be determined for gliomas of the insula. ObjectivesTo evaluate the efficacy of fluorescence-guided resection with 5-ALA, intraoperative neurophysiological monitoring (IOM), neuronavigation, and tractography in the Extent of Resection (EOR), functionality scores, overall survival (OS) and progression-free survival (PFS) in a retrospective cohort of insular gliomas. MethodsWe reviewed all cases of insular tumors operated on at the Department of Neurosurgery, University Hospital of Tübingen − Germany, between May 2008 and November 2013. EOR was determined by volumetric analysis. Mann Whitney, Chi-square and Kaplan Meier functions were used for assessment of each technology’s effect on primary and secondary outcomes. Results28 cases (18 men (64%) and 10 women (36%); median age at diagnosis: 52.5 years, range 12 − 59) were considered eligible for analysis. High grade and low grade gliomas accounted for 20 (71%) and 8 (29%) cases, respectively. The most used technologies were IOM (64%) and Neuronavigation (68%). 5-ALA was the only technique associated with EOR ≥90% (p=0.05). Tractography determined improvement in the Karnofsky Performance Scale (50% vs. 5% cases improved, p=0.02). There was a positive association between the use of neuronavigation and overall survival (23 vs. 27.4 months, p=0.03), but the use of 5-ALA was associated with shorter OS (34.8 vs. 21.1 months, p=0.01) and PFS (24.4 vs. 11.8, p=0.01). ConclusionsWe demonstrate for the first time that for insular gliomas 5-ALA plays a role in achieving higher EOR, although this technology was associated with poor OS and PFS; also tractography and neuronavigation can be of great importance in the treatment of insular gliomas as they determined better functionality and OS in this study, respectively. Prospective studies with a more prominent sample and proper multivariate analysis will help determine the real benefit of these adjuncts in the setting of insular gliomas.