FLGS-04. Fluorescence lifetime imaging (FLIm) is a dye-free, high sensitivity approach for fluorescence guided surgery in high-grade and low-grade gliomas

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi226-vi226
Author(s):  
Orin Bloch ◽  
Alba Alfonso Garcia ◽  
Silvia Noble Anbunesan ◽  
Roberto Frusciante ◽  
Julien Bec ◽  
...  
Keyword(s):  
Fluorescence Lifetime ◽  
Tumor Resection ◽  
Low Grade ◽  
Glioma Tissue ◽  
Low Grade Gliomas ◽  
Lifetime Imaging ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Tumor Identification ◽  
Idh Mutations

Abstract INTRODUCTION Fluorescence-guided surgery can improve tumor identification and extent of surgical resection. 5-ALA is the standard for GBM, but is limited by lack of quantitative fluorescence, a need to work in the dark, and a lack of sensitivity for low grade tumors. We have developed a novel instrument for dye-free tissue autofluorescence lifetime imaging (FLIm) to identify glioma tissue during resection. This approach utilizes time-resolved autofluorescence measurements in narrow-band channels to assess markers of tissue metabolism. Compared to intensity-based imaging of exogenous fluorophores, FLIm has greater sensitivity without dependence on background lighting. The advantages of FLIm include quantitative tissue analysis, the ability to work under full light conditions, sensitivity for high and low grade gliomas, and the potential ability to identify IDH mutational status. In this study, we validated the use of FLIm for identification of glioma tissue at tumor resection margins. METHODS FLIm was used to image tissue margins during glioma resections and compared to microbiopsies from imaged regions to correlate fluorescence with histopathology. RESULTS FLIm was applied intraoperatively to 11 GBM and 5 LGG patients (7 imaged biopsies per patient). In GBM, tumor infiltration of cortex was associated with significantly decreased fluorescence lifetime (FL) in channels 2 (470/28nm;p<0.05) and 3 (542/50nm;p<0.002). In subcortical margins, FL was inversely proportional to the density of tumor in channels 2,3 (p<0.05). When IDH wild-type GBMs were compared to IDH1-mutant tumors, FL was noted to be significantly longer in channel 1 (390/40nm;p<0.05), and trended towards longer FL in channel 2, shorter FL in channel 3. In LGG, FL was significantly correlated with tumor density in channel 2 (p<0.01). CONCLUSIONS FLIm is a dye-free, quantitative alternative to 5-ALA for fluorescence guided glioma resections with sensitivity to high and low-grade tumors, and the ability to predict IDH mutations in GBM. Further validation studies are on-going.

scholarly journals Pharmacoresistant seizures and IDH mutation in low grade gliomas

2021 ◽  
Author(s):  
Carlos Eduardo Correia ◽  
Yoshie Umemura ◽  
Jessica R Flynn ◽  
Anne S Reiner ◽  
Edward K Avila
Keyword(s):  
Tumor Resection ◽  
Incidence Rates ◽  
P Value ◽  
Low Grade ◽  
Idh Mutation ◽  
Wild Type ◽  
Mutation Status ◽  
Low Grade Gliomas ◽  
Idh1 R132h ◽  
Idh Mutations

Abstract Purpose Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. Methods Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥ 2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥ 2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. Results Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only six were IDH2 R172K. 120 patients (89%) had tumor resection and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray’s P-value= 0.26). Conclusions 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors.The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

Influence of dexamethasone on visible 5-ALA fluorescence and quantitative protoporphyrin IX accumulation measured by fluorescence lifetime imaging in glioblastomas: is pretreatment obligatory before fluorescence-guided surgery?

2021 ◽  
pp. 1-9
Author(s):  
Lisa I. Wadiura ◽  
David Reichert ◽  
Veronika Sperl ◽  
Alexandra Lang ◽  
Barbara Kiesel ◽  
...  
Keyword(s):  
Fluorescence Lifetime ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Protoporphyrin Ix ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Significant Difference ◽  
The Mean

OBJECTIVE Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is nowadays widely applied for improved resection of glioblastomas (GBMs). Initially, pretreatment with dexamethasone was considered to be essential for optimal fluorescence effect. However, recent studies reported comparably high rates of visible fluorescence in GBMs despite absence of dexamethasone pretreatment. Recently, the authors proposed fluorescence lifetime imaging (FLIM) for the quantitative analysis of 5-ALA–induced protoporphyrin IX (PpIX) accumulation. The aim of this study was thus to investigate the influence of dexamethasone on visible fluorescence and quantitative PpIX accumulation. METHODS The authors prospectively analyzed the presence of visible fluorescence during surgery in a cohort of patients with GBMs. In this study, patients received dexamethasone preoperatively only if clinically indicated. One representative tumor sample was collected from each GBM, and PpIX accumulation was analyzed ex vivo by FLIM. The visible fluorescence status and mean FLIM values were correlated with preoperative intake of dexamethasone. RESULTS In total, two subgroups with (n = 27) and without (n = 20) pretreatment with dexamethasone were analyzed. All patients showed visible fluorescence independent from preoperative dexamethasone intake. Furthermore, the authors did not find a statistically significant difference in the mean FLIM values between patients with and without dexamethasone pretreatment (p = 0.097). CONCLUSIONS In this first study to date, the authors found no significant influence of dexamethasone pretreatment on either visible 5-ALA fluorescence during GBM surgery or PpIX accumulation based on FLIM. According to these preliminary data, the authors recommend administering dexamethasone prior to fluorescence-guided surgery of GBMs only when clinically indicated.

Fluorescence-guided surgery with aminolevulinic acid for low-grade gliomas

2018 ◽  
Vol 141 (1) ◽  
pp. 13-18 ◽  
Author(s):  
Benjamin K. Hendricks ◽  
Nader Sanai ◽  
Walter Stummer
Keyword(s):  
Aminolevulinic Acid ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery

scholarly journals Fluorescence Lifetime Imaging and Spectroscopic Co-Validation for Protoporphyrin IX-Guided Tumor Visualization in Neurosurgery

2021 ◽  
Vol 11 ◽  
Author(s):  
David Reichert ◽  
Mikael T. Erkkilae ◽  
Johanna Gesperger ◽  
Lisa I. Wadiura ◽  
Alexandra Lang ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Fluorescence Lifetime ◽  
Protoporphyrin Ix ◽  
Low Grade ◽  
Light Illumination ◽  
Fluorescence Lifetime Imaging ◽  
High Grade ◽  
Low Grade Gliomas ◽  
Lifetime Imaging ◽  
High Grade Gliomas

Maximal safe resection is a key strategy for improving patient prognosis in the management of brain tumors. Intraoperative fluorescence guidance has emerged as a standard in the surgery of high-grade gliomas. The administration of 5-aminolevulinic acid prior to surgery induces tumor-specific accumulation of protoporphyrin IX, which emits red fluorescence under blue-light illumination. The technology, however, is substantially limited for low-grade gliomas and weakly tumor-infiltrated brain, where low protoporphyrin IX concentrations are outweighed by tissue autofluorescence. In this context, fluorescence lifetime imaging has shown promise to distinguish spectrally overlapping fluorophores. We integrated frequency-domain fluorescence lifetime imaging in a surgical microscope and combined it with spatially registered fluorescence spectroscopy, which can be considered a research benchmark for sensitive protoporphyrin IX detection. Fluorescence lifetime maps and spectra were acquired for a representative set of fresh ex-vivo brain tumor specimens (low-grade gliomas n = 15, high-grade gliomas n = 80, meningiomas n = 41, and metastases n = 35). Combining the fluorescence lifetime with fluorescence spectra unveiled how weak protoporphyrin IX accumulations increased the lifetime respective to tissue autofluorescence. Infiltration zones (4.1ns ± 1.8ns, p = 0.017) and core tumor areas (4.8ns ± 1.3ns, p = 0.040) of low-grade gliomas were significantly distinguishable from non-pathologic tissue (1.6ns ± 0.5ns). Similarly, fluorescence lifetimes for infiltrated and reactive tissue as well as necrotic and core tumor areas were increased for high-grade gliomas and metastasis. Meningioma tumor specimens showed strongly increased lifetimes (12.2ns ± 2.5ns, p = 0.005). Our results emphasize the potential of fluorescence lifetime imaging to optimize maximal safe resection in brain tumors in future and highlight its potential toward clinical translation.

scholarly journals Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2674
Author(s):  
Tessa Buckle ◽  
Maarten van Alphen ◽  
Matthias N. van Oosterom ◽  
Florian van Beurden ◽  
Nina Heimburger ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Oral Cavity Cancer ◽  
Ex Vivo ◽  
Intermediate Step ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Tumor Identification ◽  
Imaging Results ◽  
Pathological Evaluation ◽  
Fluorescence Camera

Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8–3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.

scholarly journals Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mikael T. Erkkilä ◽  
David Reichert ◽  
Johanna Gesperger ◽  
Barbara Kiesel ◽  
Thomas Roetzer ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Fluorescence Lifetime ◽  
Tumor Tissue ◽  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Low Grade ◽  
Wide Field ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging

AbstractMaximal safe tumor resection remains the key prognostic factor for improved prognosis in brain tumor patients. Despite 5-aminolevulinic acid-based fluorescence guidance the neurosurgeon is, however, not able to visualize most low-grade gliomas (LGG) and infiltration zone of high-grade gliomas (HGG). To overcome the need for a more sensitive visualization, we investigated the potential of macroscopic, wide-field fluorescence lifetime imaging of nicotinamide adenine dinucleotide (NADH) and protoporphyrin IX (PPIX) in selected human brain tumors. For future intraoperative use, the imaging system offered a square field of view of 11 mm at 250 mm free working distance. We performed imaging of tumor tissue ex vivo, including LGG and HGG as well as brain metastases obtained from 21 patients undergoing fluorescence-guided surgery. Half of all samples showed visible fluorescence during surgery, which was associated with significant increase in PPIX fluorescence lifetime. While the PPIX lifetime was significantly different between specific tumor tissue types, the NADH lifetimes did not differ significantly among them. However, mainly necrotic areas exhibited significantly lower NADH lifetimes compared to compact tumor in HGG. Our pilot study indicates that combined fluorescence lifetime imaging of NADH/PPIX represents a sensitive tool to visualize brain tumor tissue not detectable with conventional 5-ALA fluorescence.

Neurosurgical tools to extend tumor resection in hemispheric low-grade gliomas: conventional and contrast enhanced ultrasonography

2016 ◽  
Vol 32 (10) ◽  
pp. 1907-1914 ◽  
Author(s):  
Luca Mattei ◽  
Francesco Prada ◽  
Federico Giuseppe Legnani ◽  
Alessandro Perin ◽  
Alessandro Olivi ◽  
...  
Keyword(s):  
Tumor Resection ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Contrast Enhanced ◽  
Contrast Enhanced Ultrasonography

scholarly journals Brainstem Low-Grade Gliomas in Children—Excellent Outcomes With Multimodality Therapy

2016 ◽  
Vol 32 (2) ◽  
pp. 194-203 ◽  
Author(s):  
Santhosh A. Upadhyaya ◽  
Carl Koschmann ◽  
Karin Muraszko ◽  
Sriram Venneti ◽  
Hugh J. Garton ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Survival Rates ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Low Grade ◽  
University Of Michigan ◽  
Single Institution ◽  
Free Survival ◽  
Low Grade Gliomas ◽  
The University

Safe maximal surgical resection is the initial treatment of choice for pediatric brainstem low-grade gliomas. Optimal therapy for incompletely resected tumors or that progress after surgery is uncertain. We reviewed the clinical characteristics, therapy, and outcomes of all children with nontectal brainstem low-grade gliomas treated at the University of Michigan between 1993 and 2013. Median age at diagnosis was 6 years; histology was confirmed in 23 of 25 tumors, 64% were pilocytic astrocytoma. Nineteen patients underwent initial tumor resection; 14/19 received no upfront adjuvant therapy. Eight patients in the study had progressive disease; 5 initially resected tumors received chemotherapy at tumor relapse, all with partial or complete radiographic responses. Ten-year progression-free survival is 71% and overall survival, 100%. This single-institution retrospective study demonstrates excellent survival rates for children with brainstem low-grade gliomas. The efficacy of the well-tolerated chemotherapy in this series supports its role in the treatment of unresectable or progressive brainstem low-grade gliomas.

Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases

1995 ◽  
Vol 82 (4) ◽  
pp. 536-547 ◽  
Author(s):  
Ian F. Pollack ◽  
Diana Claassen ◽  
Qasim Al-Shboul ◽  
Janine E. Janosky ◽  
Melvin Deutsch
Keyword(s):  
Overall Survival ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Low Grade ◽  
Free Survival ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Fine Print

✓ Low-grade gliomas constitute the largest group of cerebral hemispheric tumors in the pediatric population. Although complete tumor resection is generally the goal in the management of these lesions, this can prove difficult to achieve because tumor margins may blend into the surrounding brain. This raises several important questions on the long-term behavior of the residual tumor and the role of adjuvant therapy in the management of these lesions. To examine these issues, the authors reviewed their experience in 71 children with low-grade cerebral hemispheric gliomas who were treated at their institution between 1956 and 1991 and assessed the relationship between clinical, radiographic, pathological, and treatment-related factors and outcome. Only seven patients in the series died, one from perioperative complications, five from progressive disease, and one (a child with neurofibromatosis) from a second neoplasm. For the 70 patients who survived the perioperative period, overall actuarial survivals at 5, 10, and 20 years were 95%, 93%, and 85%, respectively; progression-free status was maintained in 88%, 79%, and 76%, respectively. On univariate analysis, the factor that was most strongly associated with both overall and progression-free survival was the extent of tumor resection (p = 0.013 and p = 0.015, respectively). A relationship between extent of resection and progression-free survival was present both in patients with pilocytic astrocytomas (p = 0.041) and those with nonpilocytic tumors (p = 0.037). Histopathological diagnosis was also associated with overall survival on univariate analysis; poorer results were seen in the patients with nonpilocytic astrocytoma compared to those with other low-grade gliomas, such as pilocytic astrocytoma, mixed glioma, and oligodendroglioma (p = 0.021). The use of radiotherapy was not associated with a significant improvement in overall survival (p = 0.6). All three patients who ultimately developed histologically confirmed anaplastic changes in the vicinity of the original tumor had received prior radiotherapy, 20, 46, and 137 months, respectively, before the detection of malignant progression. In addition, children who received radiotherapy had a significantly higher incidence of late cognitive and endocrine dysfunction than the nonirradiated patients (p < 0.01 and 0.05, respectively). The authors conclude that children with low-grade gliomas of the cerebral hemispheres have an excellent overall prognosis. Complete tumor resection provides the best opportunity for long-term progression-free survival. However, even with incomplete tumor excision, long-term progression-free survival is common. The findings in this study do not support the routine use of postoperative radiotherapy after an initial incomplete tumor resection: although irradiation appears to increase the likelihood of long-term progression-free survival, overall survival is not improved significantly, and long-term morbidity may be increased.

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