Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

Clinical utility and safety of a trapezoid-shaped electrode placement for evaluating the mesio-basal temporal lobe during epilepsy surgery.

A trapezoid-shaped electrode (TSE) is used for detecting epileptogenicity in patients with temporal lobe epilepsy (TLE). However, the utility and safety associated with TSE placement have not been reported. In this study, we evaluated the safety and usefulness of TSE by analyzing the seizure detection, surgical outcomes and complications in patients with TLE who underwent intracranial electrodes (ICE) placement. Between April 2000 and August 2019, 50 patients with TLE who underwent 51 ICE placement procedures were examined. A TSE with eight contacts covering the parahippocampal gyrus and basal temporal lobe was used. Among the 37 patients who underwent TSE placement, 26 and 11 patients were diagnosed with mesial TLE (mTLE) and extra-mTLE, respectively. The 14 remaining patients without TSE placement were diagnosed with extra-mTLE. Seizure freedom was achieved in 73% (19/26) of mTLE patients detected by TSE and 50% (14/24) of extra-mTLE patients.Good seizure outcomes (Engel class I and II) were observed in 81% (21/26) patients with mTLE and 67% (16/24) patients with extra-mTLE. Radiographic complications were observed in 20% (10/50) patients who underwent ICE placement. Although 6% (3/50) patients showed transient neurological deficits, none were permanent. The electrodes responsible for the occurrence of complications included nine grid electrodes and one TSE. The complication rate after TSE placement was 3% (1/37). More than 64 electrode contacts and male sex, not TSE placement, were identified as significant risk factors for developing complications. This study demonstrated the usefulness and safety of TSE for evaluating mTLE in patients undergoing ICE placement.

Long-term efficacy and safety of perampanel as an add-on therapy in patients with epilepsy.

BACKGROUND: Perampanel (PER) is a newly developed amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist that has been globally approved for the treatment of both focal and generalized seizures. The efficacy and safety of PER have only been reported over short periods of treatment so far. This study aims to clarify the long-term efficacy and safety of PER as an add-on therapy. METHOD: This retrospective observational study investigated 176 epilepsy patients who received PER as add-on medical therapy in two Japanese epilepsy centers between June 2016 and July 2022. The adherence, seizure frequency, and plasma concentration of PER were evaluated at three time points: 6 months, 12 months, and 24 months or longer after the start of adjunctive PER treatment. RESULTS: 112 patients undergoing PER treatment were evaluated at 6 months, 86 were evaluated at 12 months, and 52 were evaluated at 24 months or longer. Overall, 42.9 % (48/112), 45.4 % (40/86), and 44.2 % (23/52) of the patients were seizure-free at 6, 12, and 24 months or longer, respectively. The rate of PER tolerance was 78.3 %, 69.9 %, and 54.7 % at 6, 12, and 24 months or longer, respectively. At the latest timepoint, the seizure-free group was taking a significantly lower dose of PER than the seizure-remnant group, and the number of anti-seizure medications (ASMs) was associated with seizure outcomes. In addition, the seizure-free rate was significantly higher in patients who received PER as a first add-on than in those who received it as a late add-on. No significant difference was found in the plasma concentration of PER between the seizure-free and seizure-remnant groups at 24 months or longer. Among the patients receiving PER at dose of 2 mg, however, the plasma concentrations were significantly higher in the seizure-free group than in the seizure-remnant group (282.7 ± 109.8 µg/ml vs 94.7 ± 54.9 µg/ml, p = 0.0024). CONCLUSION: This long-term retrospective observational study provides evidence of the efficacy and safety of PER over 2 years treatment period in Japan. Notably, patients who started on PER as the first add-on showed a better seizure outcome than those who received it as a late add-on over the long term. Measured plasma concentrations may provide valuable guidance for the management of patients. Higher plasma concentration at low dose PER may suggest the better seizure control.

Photodynamic augmentation of oncolytic virus therapy for central nervous system malignancies.

Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies, allowing for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination (peak wavelength: 585-595 nm) were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested photodynamic-oncolytic virus (PD-OV) therapy employing intratumoral injection of G47Δ-KR followed by laser light tumor irradiation (wavelength: 585 nm) in GBM and MM xenografts. PD-OV therapy was feasible in these models and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser light) or laser light alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.

Exomap1 mouse: a transgenic model for in vivo studies of exosome biology.

Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the exomap1 transgenic mouse model. In response to Cre recombinase, exomap1 mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen. As expected, cell type-specific expression of Cre induced the cell type-specific expression of HsCD81mNG in diverse cell types, correctly localized HsCD81mNG to the plasma membrane, and selectively loaded HsCD81mNG into secreted vesicles that have the size (~80 nm), topology (outside out), and content (presence of mouse exosome markers) of exosomes. Furthermore, mouse cells expressing HsCD81mNG released HsCD81mNG-marked exosomes into blood and other biofluids. Using high-resolution, single-exosome analysis by quantitative single molecule localization microscopy, we show here that that hepatocytes contribute ~15% of the blood exosome population whereas neurons contribute <1% of blood exosomes. These estimates of cell type-specific contributions to blood EV population are consistent with the porosity of liver sinusoidal endothelial cells to particles of ~50-300 nm in diameter, as well as with the impermeability of blood-brain and blood-neuron barriers to particles >5 nm in size. Taken together, these results establish the exomap1 mouse as a useful tool for in vivo studies of exosome biology, and for mapping cell type-specific contributions to biofluid exosome populations. In addition, our data confirm that CD81 is a highly-specific marker for exosomes and is not enriched in the larger microvesicle class of EVs.

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. RESULTS: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

Correlation of Intraoperative 5-ALA-Induced Fluorescence Intensity and Preoperative 11C-Methionine PET Uptake in Glioma Surgery.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) is widely employed to assist fluorescence-guided surgery for malignant brain tumors. Positron emission tomography with 11C-methionine (MET-PET) represents the activity of brain tumors with precise boundaries but is not readily available. We hypothesized that quantitative 5-ALA-induced fluorescence intensity might correlate with MET-PET uptake in gliomas. METHODS: Adult patients with supratentorial astrocytic gliomas who underwent preoperative MET-PET and surgical tumor resection using 5-ALA were enrolled in this prospective study. The regional tumor uptake of MET-PET was expressed as the ratio of standardized uptake volume max to that of the normal contralateral frontal lobe. A spectrometric fluorescence detection system measured tumor specimens' ex vivo fluorescence intensity at 635 nm. Ki-67 index and IDH mutation status were assessed by histopathological analysis. Use of an antiepileptic drug (AED) and contrast enhancement pattern on MRI were also investigated. RESULTS: Thirty-two patients, mostly with Glioblastoma IDH wild type (46.9%) and anaplastic astrocytoma IDH mutant (21.9%), were analyzed. When the fluorescence intensity was ranked into four groups, the strongest fluorescence group exhibited the highest mean MET-PET uptake and Ki-67 index values. When rearranged into fluorescence Visible or Non-visible groups, the Visible group had significantly higher MET-PET uptake and Ki-67 index compared to the Non-visible group. Contrast enhancement on MRI and IDH wild type tumors were more frequent among the Visible group. AED use did not correlate with 5-ALA-induced fluorescence intensity. CONCLUSIONS: In astrocytic glioma surgery, visible 5-ALA-induced fluorescence correlated with high MET-PET uptake, along with a high Ki-67 index.

Therapeutic Options for Recurrent Glioblastoma-Efficacy of Talaporfin Sodium Mediated Photodynamic Therapy.

Recurrent glioblastoma (GBM) remains one of the most challenging clinical issues, with no standard treatment and effective treatment options. To evaluate the efficacy of talaporfin sodium (TS) mediated photodynamic therapy (PDT) as a new treatment for this condition, we retrospectively analyzed 70 patients who underwent surgery with PDT (PDT group) for recurrent GBM and 38 patients who underwent surgery alone (control group). The median progression-free survival (PFS) in the PDT and control groups after second surgery was 5.7 and 2.2 months, respectively (p = 0.0043). The median overall survival (OS) after the second surgery was 16.0 and 12.8 months, respectively (p = 0.031). Both univariate and multivariate analyses indicated that surgery with PDT and a preoperative Karnofsky Performance Scale were significant independent prognostic factors for PFS and OS. In the PDT group, there was no significant difference regarding PFS and OS between patients whose previous pathology before recurrence was already GBM and those who had malignant transformation to GBM from lower grade glioma. There was also no significant difference in TS accumulation in the tumor between these two groups. According to these results, additional PDT treatment for recurrent GBM could have potential survival benefits and its efficacy is independent of the pre-recurrence pathology.

Anatomy-oriented stereotactic approach to cerebrospinal fluid collection in mice.

Extraction of cerebrospinal fluid (CSF) in small animal models is an indispensable technique used in neuroscience and neuro-oncology research but can be technically challenging due to the small size of the brain. Here we describe a simple, reliable, and highly reproducible method for collecting CSF from anesthetized laboratory mice based on anatomical foundation, with no requirement of introducing any custom-made types of equipment. The mouse's head is fixed to a stereotaxic frame in the position that allows the maximum opening of the cisterna magna. A Hamilton syringe attached with a 26 gauge needle is inserted stereotactically in parallel to the brain axis to reach the cistern. The clear CSF (approximately 10 µl) can then be drawn slowly in approximately 5 min. Our modified approach minimizes technical variations that can result from customized equipment, and is applicable in broad research settings.

Effects of sevoflurane anesthesia on intraoperative high-frequency oscillations in patients with temporal lobe epilepsy.

PURPOSE: This is a cross-sectional study without an unexposed group. We elucidated the effects of sevoflurane anesthesia on high-frequency oscillations (HFOs) to examine the usefulness of assessing intraoperative HFOs. METHODS: We recorded electrocorticography in seven patients with medication-resistant temporal lobe epilepsy (TLE) caused by unilateral hippocampal sclerosis who were seizure-free after temporal lobectomy. We analyzed the number of intraoperative spikes and HFOs on spikes in the epileptogenic parahippocampal gyrus and nonepileptogenic superior temporal gyrus with sevoflurane concentrations of 1.5%, 2.0%, 2.5%, and 3.0%. RESULTS: The number of spikes and HFOs in the epileptogenic area significantly increased with an increase in the sevoflurane concentration. In the nonepileptogenic area, spikes and HFOs did not significantly increase with increases in the sevoflurane concentration. However, 2.5% sevoflurane markedly induced spikes and ripples but no fast ripples (FRs) in one patient, and 3.0% sevoflurane induced marked increases in both ripples and FRs in two patients. CONCLUSIONS: The proconvulsant effect of sevoflurane on intraoperative HFOs in patients with TLE depends on the concentration. While HFOs induced by higher sevoflurane concentrations may be a useful biomarker for epileptogenic areas, careful interpretation is also needed because a higher sevoflurane concentration can also induce false-positive HFOs in nonepileptogenic areas.

Transient Global Amnesia: A Diffusion and Perfusion MRI study.

BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is a rare clinical entity with a sudden onset of anterograde amnesia that recovers within 24 hours. The underlying pathophysiology is uncertain. Imaging studies are controversial, but diffusion-weighted images often show small diffusion-restricted lesions in the hippocampus, which may suggest ischemic damage. Thus, we conducted the first clinical study using neurite orientation dispersion and density imaging (NODDI) and arterial spin labeling (ASL) to examine whether the microstructure and perfusion status of the hippocampus are influenced by the presence of diffusion-restricted lesions. METHODS: Ten patients with a clinical diagnosis of TGA were evaluated by conventional MRI, NODDI, and ASL. The intracellular volume fraction (ICVF) and orientation dispersion index (ODI) on NODDI and cerebral blood flow (CBF) determined by ASL in the hippocampus were calculated and compared by diffusion-weighted imaging (DWI) positivity. Correlations among ICVF, ODI, and CBF were also analyzed. RESULTS: Three patients had typical unilateral DWI-positive lesions. No significant differences in any of the three parameters were detected between DWI-positive and DWI-negative hippocampi. A statistically significant correlation was detected between the ODI and CBF (R = .51, P = .021). CONCLUSIONS: The first NODDI and ASL study in patients after TGA demonstrated no obvious microstructural or perfusion abnormalities in the hippocampus with typical DWI-positive lesions, which may indicate that TGA does not cause destructive damage or involve baseline microstructure or perfusion abnormalities in the hippocampus in relation to diffusion-restricted lesions.

De Novo Renal Artery Stenosis Developed in Initially Normal Renal Arteries during the Long-Term Follow-Up of Patients with Moyamoya Disease.

BACKGROUND: The de novo occurrence of renal artery stenosis in renal arteries that were angiographically confirmed to be normal in the past has never been reported before in patients with moyamoya disease. CASE DESCRIPTION: During the long-term follow-up of pediatric patients with moyamoya disease, we observed 3 patients who developed de novo renal artery stenosis in arteries that had been angiographically confirmed to be normal 1 year after the surgery (7 years on average, ranging from 4 to 11 years). All of these patients were neurologically stable after successful indirect bypass surgery during childhood. However, more than 10 years after the surgery (15 years on average, ranging from 14 to 23 years), they developed hypertension and were found to have de novo renal artery stenosis, which was ameliorated by endovascular angioplasty. During the follow-up after angioplasty, 1 patient experienced a recurrence of hypertension and required a second and third angioplasty for restenosis. Another patient died of intracranial hemorrhage 2 years after angioplasty. In the 2 surviving patients, gene analysis of the ring finger protein 213 (RNF213; p.R4810K) point mutation, the susceptibility gene for moyamoya disease in the Asian population, was positive for the heterozygous variant. CONCLUSIONS: De novo renal artery stenosis might develop in initially normal arteries during long-term follow-up, particularly among pediatric patients with moyamoya disease. Considering the extracranial manifestations of moyamoya disease, clinicians should keep in mind that de novo renal artery stenosis could emerge later in their life. Thus, it is crucial to continue to follow these patients for decades, even if the patients are neurologically stable after bypass surgery. Monitoring for blood pressure and the de novo occurrence of renal artery stenosis is important to prevent hypertension-related morbidity and mortality, such as intracranial hemorrhage, in this disease population.

Video-assisted neck surgery (VANS) using a gasless lifting procedure for thyroid and parathyroid diseases: "The VANS method from A to Z".

PURPOSE: To describe and evaluate our video-assisted neck surgery (VANS) method for thyroid and parathyroid diseases. METHODS: We describe in detail the VANS method for enucleation, lobectomy, total (nearly total) thyroidectomy, and lymph node dissection for malignancy and Graves' disease. In collaboration with the Japan Society of Endoscopic Surgery (JSES), we evaluated several aspects of this method. The JSES evaluated the method for working-space formation and surgical complications, whereas we examined the learning curve of the surgeons, and the cosmetic satisfaction of the patients and the degree of numbness and pain they experienced. We also asked patients who underwent conventional surgery whether they would have selected VANS had it been available. RESULTS: The working space for 81.5% of the procedures in Japan was created using the gasless lifting method. The learning curve, considering both blood loss and operating time, decreased after 30 cases. Both factors improved for tumors smaller than 5 cm in diameter. Over 60% of the patients who underwent conventional surgery stated that they would have selected VANS, had it been available. Postoperative pain was worse after conventional surgery than after VANS, but neck numbness after VANS was more frequent than expected. CONCLUSIONS: The VANS method is a feasible, safe, and cost-effective procedure with clear cosmetic advantages over conventional surgery.

Effectiveness of perampanel as a first add-on antiepileptic drug for the treatment of partial epilepsy.

BACKGROUND: Perampanel (PER) is a newly introduced antiepileptic drug (AED) and is used in over 50 countries. In the current study, we analyzed the efficacy of PER for patients with partial epilepsy who were recruited from two hospitals that had both an epilepsy center and a general neurosurgical unit over a 1-year period. METHODS: The present study was a retrospective observational study that evaluated the effects of PER for the treatment of partial epilepsy in 51 patients. We analyzed the effects of PER at two checkpoints, i.e., 6 and 12 months after starting adjunctive PER treatment. Following this, we analyzed the effects of PER as a first add-on (only one prior AED) and late add-on (≥2 prior AEDs) therapy, and focused on the characteristics of the patients who achieved seizure freedom. RESULTS: Of the initial 51 patients, 45 and 39 patients were evaluated at the 6- and 12-month checkpoints, respectively. Overall, after starting treatment with PER, 29% (13/45) and 28% (11/39) of patients were seizure-free at 6 and 12 months, respectively. The tolerance rate of PER was 67% (30/45) at 6 months and 53.8% (21/39) at 12 months following treatment. The seizure-free rate of the 30 patients who were continuously treated with PER for 6 months was significantly higher in the patients who used PER as a first add-on treatment (75.0%, 6/8) than it was in the patients who used PER as a late add-on treatment (31.8%, 7/22) (p = 0.049). The seizure-free rate of the 21 patients who were continuously treated with PER for 12 months was significantly higher in the patients who used PER as a first add-on treatment (100%, 5/5) than it was in the patients who used PER as a late add-on treatment (37.5%, 6/16) (p = 0.035). Among the patients who achieved seizure freedom, the most frequently administered dose of PER was 2 mg at 6 (62%, 8/13) and 12 months (64%, 7/11). Levetiracetam was the most frequently administered concomitant AED at both 6 (92%, 12/13) and 12 months (91%, 10/11). CONCLUSION: This retrospective observational study provides evidence supporting the effectiveness of PER as a first add-on therapy in patients with partial epilepsy. Importantly, the seizure-free rate was better when PER was used as a first, rather than a second or later, add-on treatment.

Intraoperative Photodynamic Diagnosis Using Talaporfin Sodium Simultaneously Applied for Photodynamic Therapy against Malignant Glioma: A Prospective Clinical Study.

OBJECTIVE: The goal of this study was to demonstrate the feasibility of intraoperative photodynamic diagnosis (PDD) of malignant glioma using the fluorescence from talaporfin sodium (TS), which is used simultaneously for photodynamic therapy (PDT). METHODS: Patients with suspected primary malignant glioma who were eligible for surgical removal of the tumor and PDT with TS were enrolled in this prospective study. Tissue samples were obtained from the contrast-enhanced (CE) region and from the surrounding non-contrast-enhanced (NCE) marginal tissue at the boundary between the tumor and normal tissue. The excised samples were set into a fluorescence measurement system, which consisted of a semiconductor laser with a 400-nm wavelength for excitation, and a compact spectrometer for detection, which were applied and received through a custom-made probe consisting of coaxial optical fibers. The fluorescence spectrum was obtained, and peak intensity was calculated. Tumor cellularity was histopathologically analyzed and semi-quantitatively classified into four (0-3) categories. RESULTS: 86 samples from 17 surgical cases were available for fluorescence measurement and analysis. The fluorescence from TS had a single peak at 664 nm that was easily distinguished from the 400-nm excitation light. Samples from the CE regions showed higher fluorescence intensity than those from the NCE regions (P < 0.001). DAPI staining and fluorescence microscopy confirmed that cells in the CE regions showed red fluorescence in their cytoplasm. The fluorescence was notably strong along vascular endothelium. CE samples from newly diagnosed versus recurrent cases showed no difference in fluorescence intensity (P = 0.26). Among all samples (CE and NCE combined), the fluorescence intensity was very high in those of histopathological class 3, and a trend of increased fluorescence according to histopathological class (P < 0.001) was shown. Differences between class 0 and 3 (P < 0.001), class 1 and 3 (P < 0.001), and class 2 and 3 (P = 0.018) were significant. CONCLUSION: Intraoperative simultaneous PDD and PDT with TS can be performed for patients with malignant glioma. The blue excitation light that is used for 5-aminolevulinic acid PDD can be used for our technique (TS-PDD). The strong fluorescence from pathologically malignant tissues may be due at least in part to the involvement of microvascular structures.

Identification of pathological and normal parathyroid tissue by fluorescent labeling with 5-aminolevulinic acid during endocrine neck surgery.

BACKGROUND: When performing parathyroid or thyroid surgery, surgeons must distinguish parathyroid tissue from the surrounding thyroid tissue, to preserve healthy parathyroid tissue while excising diseased thyroid tissue or to completely remove pathological parathyroid lesions. Here, we explored the feasibility of labeling the parathyroid glands for easy identification by administering 5-aminolevulinic acid (5-ALA) orally to patients undergoing endocrine neck surgery, because 5-ALA accumulates in the parathyroid and has a fluorescent metabolite, protoporphyrin IX. METHODS: Twenty-nine patients about to undergo endocrine (parathyroid or thyroid gland) neck surgery were orally given 5-ALA, a nontoxic substance that occurs naturally in the human body and has no known major side effects. During surgery, we used blue light to excite protoporphyrin IX, the fluorescent metabolite of 5-ALA, and viewed the resulting bright red fluorescence through an optical filter. RESULTS: In the majority of the patients, the parathyroid glands were defined by a clear fluorescence. In 23 patients with pathological parathyroid tissue, the fluorescence enabled us to identify and completely remove diseased parathyroid tissue. In 3 patients with thyroid disease, we were able to easily remove diseased thyroid tissue, and an accidentally removed parathyroid gland was autotransplanted during surgery. CONCLUSIONS: In all but a few cases, 5-ALA clearly labeled parathyroid tissue, allowing for its clean removal or preservation according to the purpose of the surgery. This simple, benign technique is extremely useful for identifying parathyroid tissue, whether pathological or normal, during endocrine neck surgery.