In-patient neurosurgical tumor treatments for malignant glioma patients in Germany.

OBJECTIVE: Treatment for malignant gliomas involves multiple disciplines, including neurosurgery, radiation therapy, medical and neuro-oncology, and palliative medicine, with function-preserving neurosurgical tumor removal being crucial. However, real-world data on hospital cases, treatment types, especially regarding surgical approaches, and the associated complication and mortality rates in Germany are lacking. METHODS: We analyzed data on hospital cases involving malignant gliomas (ICD-10-GM code C71) from the German §21 Hospital Remuneration Act, provided by the Institute for the Hospital Remuneration System (InEK GmbH), from 2019 to 2022. Our focus was on neuro-oncological operations defined by the German Cancer Society (DKG) and included specific operation and procedure (OPS) codes. RESULTS: From 2019 to 2022, there were 101,192 hospital cases involving malignant gliomas in Germany. Neurosurgical tumor removal was performed in 27,193 cases (26.9%). Microsurgical techniques were used in 95% of surgeries, intraoperative navigation systems in 84%, fluorescence-guided surgeries in 45.6%, and intraoperative neurophysiological monitoring (IONM) in 46.4%. Surgical or medical complications occurred in 2903 cases (10.7%). The hospital mortality rate was 2.7%. Mortality was significantly higher in patients aged 65 and older (Odds ratio 2.9, p < 0.0001), and lower in cases using fluorescence-guided procedures (Odds ratio 0.8, p = 0.015) and IONM (Odds ratio 0.5, p < 0.0001). CONCLUSIONS: Over the course of 4 years, over 100,000 hospital cases involving adult patients diagnosed with malignant gliomas were treated in Germany, with 27,193 cases undergoing tumor removal using various modern surgical techniques. The hospital mortality rate was 2.7%.

Pharmaceutical equivalent 5-aminolevulinic acid fluorescence guided resection of central nervous system tumors: feasibility, safeness and cost-benefit considerations.

PURPOSE: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) has been an essential tool in the 'standard of care' of malignant gliomas. Over the last two decades, its indications have been extended to other neoplasms, such as metastases and meningiomas. However, its availability and cost-benefit still pose a challenge for widespread use. The present article reports a retrospective series of 707 cases of central nervous system (CNS) tumors submitted to FGR with pharmacological equivalent 5-ALA and discusses financial implications, feasibility and safeness. METHODS: From December 2015 to February 2024, a retrospective single institution series of 707 cases of 5-ALA FGR were analyzed. Age, gender, 5-ALA dosage, intraoperative fluorescence finding, diagnosis and adverse effects were recorded. Financial impact in the surgical treatment cost were also reported. RESULTS: there was an additional cost estimated in $300 dollars for each case, increasing from 2,37 to 3,28% of the total hospitalization cost. There were 19 (2,69%) cases of asymptomatic photosensitive reaction and 2 (0,28%) cases of photosensitive reaction requiring symptomatic treatment. 1 (0,14%) patient had a cutaneous rash sustained for up to 10 days. No other complications related to the method were evident. In 3 (0,42%) cases of patients with intracranial hypertension, there was vomiting after administration. CONCLUSION: FGR with pharmacological equivalent 5-ALA can be considered safe and efficient and incorporates a small increase in hospital expenses. It constitutes a reliable solution in avoiding prohibitive costs worldwide, especially in countries where commercial 5-ALA is unavailable.

Association of 5-aminolevulinic acid fluorescence guided resection with photodynamic therapy in recurrent glioblastoma: a matched cohort study.

PURPOSE: Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding the best standard of care (SOC) upon its inevitable recurrence. There are novel adjuvant therapies that aim to improve local disease control. Nowadays, the association of intraoperative photodynamic therapy (PDT) immediately after a 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) in malignant gliomas surgery has emerged as a potential and feasible strategy to increase the extent of safe resection and destroy residual tumour in the surgical cavity borders, respectively. OBJECTIVES: To assess the survival rates and safety of the association of intraoperative PDT with 5-ALA FGR, in comparison with a 5-ALA FGR alone, in patients with recurrent glioblastoma. METHODS: This article describes a matched-pair cohort study with two groups of patients submitted to 5-ALA FGR for recurrent glioblastoma. Group 1 was a prospective series of 11 consecutive cases submitted to 5-ALA FGR plus intraoperative PDT; group 2 was a historical series of 11 consecutive cases submitted to 5-ALA FGR alone. Age, sex, Karnofsky performance scale (KPS), 5-ALA post-resection status, T1-contrast-enhanced extent of resection (EOR), previous and post pathology, IDH (Isocitrate dehydrogenase), Ki67, previous and post treatment, brain magnetic resonance imaging (MRI) controls and surgical complications were documented. RESULTS: The Mantel-Cox test showed a significant difference between the survival rates (p = 0.008) of both groups. 4 postoperative complications occurred (36.6%) in each group. As of the last follow-up (January 2024), 7/11 patients in group 1, and 0/11 patients in group 2 were still alive. 6- and 12-months post-treatment, a survival proportion of 71,59% and 57,27% is expected in group 1, versus 45,45% and 9,09% in group 2, respectively. 6 months post-treatment, a progression free survival (PFS) of 61,36% and 18,18% is expected in group 1 and group 2, respectively. CONCLUSION: The association of PDT immediately after 5-ALA FGR for recurrent malignant glioma seems to be associated with better survival without additional or severe morbidity. Despite the need for larger, randomized series, the proposed treatment is a feasible and safe addition to the reoperation.

The usefulness of intraoperative sodium fluorescein in the surgical treatment of relapsed high-grade brain tumors in pediatric patients.

PURPOSE: We report the usefulness of intraoperative sodium fluorescein (SF) in the surgical treatment of relapsed high-grade brain tumors in pediatric neurosurgery. METHODS: We describe our protocol for intraoperative SF and three cases of patients between 5 and 11 years diagnosed and surgically treated for relapsed high-grade brain tumors using SF. RESULTS: The 560-nm microscope filter enables the use of low doses of this fluorochrome. A dose of 3 mg/kg of patient weight of 10% SF, administered intravenously, is safe and effective in children. The effect of SF was immediate, providing a clear margin between the tumor and healthy tissue, which enabled good tumor resection. We observed no adverse effects in the postoperative period, and the patients evolved satisfactorily. CONCLUSIONS: To the best of our knowledge, we describe for the first time the use of fluorescein in reoperations of relapsed high-grade brain tumors in childhood with promising results. Using SF in children is a safe, affordable, and effective technique that offers an excellent intraoperative image, being a feasible option to improve oncological resection. This study is one of the few that uses SF in pediatric neurosurgery, where it could be very beneficial.

Resection of Intramedullary Hemangioblastoma: Timing of Surgery and Its Impact on Neurological Outcome and Quality of Life.

Background and Objectives: Spinal intramedullary hemangioblastomas (SIMH) are benign vascular lesions that are pathological hallmarks of von Hippel-Lindau disease (vHL) and constitute the third most common intramedullary neoplasm in adults. So far, maximal and safe resection is the first choice of treatment. However, as SIMH show no malignant transformation, it remains unclear whether surgical resection is beneficial for all patients. Materials and Methods: We retrospectively analyzed the surgical outcomes of 27 patients who were treated between 2014 and 2022 at our neurosurgical department and investigated potential risk factors that influence the surgical outcome. Pre- and postoperative neurological status were classified according to the McCormick scale. Furthermore, surgical quality indicators, such as length of hospital stay (LOS; days), 90-day readmissions, nosocomial infections, and potential risk factors that might influence the surgical outcome, such as tumor size and surgical approach, have been analyzed. In addition to that, patients were asked to fill out the EQ-5D-3L questionnaire to assess their quality of life after surgery. Results: Surgery on SIMH patients that display no or minor neurological deficits (McCormick scale I or II) is associated with a favorable postoperative outcome and overall higher quality of life compared to those patients that already suffer from severe neurological deficits (McCormick scale III or IV). Conclusion: Early surgical intervention prior to the development of severe neurological deficits may offer a better neurological outcome and quality of life.

The utilization of sodium fluorescein in pediatric brain stem gliomas: a case report and review of the literature.

INTRODUCTION: A major challenge in the surgical resection of brainstem tumors is distinguishing tumor from normal tissue. One approach for addressing this problem is the use of fluorescent tracers such as sodium fluorescein (NaFl). NaFl disseminates through a disruption in the blood-brain barrier (BBB) and accumulates in the extracellular space of brain tumors. Intraoperative fluorescence microscopy can be performed to identify tumor tissue and avoid damage to adjacent, normal tissue. Here, we present the case of a 16-year-old male who underwent a left retrosigmoid craniotomy with splitting of the tentorium to remove a large exophytic brainstem tumor involving the cerebellar peduncle and with superior extension into the midbrain and thalamus. OBJECTIVES: The primary objective of this study was to investigate the effectiveness of sodium fluorescein as an intraoperative technique and evaluate its potential benefit for resection of tumors in eloquent regions in the pediatric population. To do so, we focused on a case study approach; however, we also performed a literature review and evaluated different intraoperative fluorescent techniques and their benefits for tumor resection. METHODS: We performed a literature search using PubMed and Google Scholar by the key words "sodium fluorescein," "brain stem tumor," and "central nervous system neoplasms." Twenty-nine articles including both pediatric and adult populations were selected for analysis and qualitative review. RESULTS: In this case study, sodium fluorescein helped the surgeons to identify and obtain a gross total resection of a large brainstem tumor. The marker was especially helpful for discerning the inferior pole of the tumor buried inconspicuously in cerebellar tissue. We evaluate different fluorescent tracers, 5-ALA and ICG, and discuss their application and benefits in tumor resection surgery. We present different cases that found sodium fluorescein to be helpful in achieving a gross total resection. CONCLUSION: The application of sodium fluorescein proved to be a safe and effective technique for the resection of brain stem tumors as shown in this case study. It helped to expose concealed areas and illuminate the tumor capsule. Further studies should test the clinical use of sodium fluorescein on brain stem tumor resection.

Fluorescence-guided resection in bone and soft tissue infiltrating meningiomas.

BACKGROUND: Bone infiltration of the tumour is common in meningioma surgery. This may also affect patients without indicative signs of bone infiltration on preoperative imaging. Unrecognized bone invasion may lead to higher recurrence rates. 5-ALA fluorescence-guided resection (5-ALA-fg) could be a promising tool to help recognize possible bone invasion and/or tumour remnants. However, there is still little data about 5-ALA-fg resection in bone and soft tissue infiltrating meningiomas. METHODS: We performed a retrospective study of 11 patients who were operated with the aid of 5-ALA due to bone and soft tissue infiltrating meningiomas at the University Hospital of St. Poelten between 2013 and 2019. RESULTS: Strong and homogeneous fluorescence of the meningioma was observed in 9 cases (81.8%) and vague and heterogeneous fluorescence in 2 cases (18.2%). Hyperostosis on computerized tomography was evident in 3 of 6 cases (50%) and bone infiltration was visible in preoperative magnetic resonance imaging in 7 of 11 patients (63.6%). All eleven patients showed positive fluorescence of the bone infiltrating part. In all 7 cases where tissue could be collected, histopathological testing verified tumour infiltration (100%). There was also fluorescence of the periosteum in 3 cases and histopathological testing verified tumour infiltration in 100%. CONCLUSION: There is growing evidence that 5-ALA-fg resection can help to identify bone infiltration in meningioma surgery. Therefore, it may help to improve extent of resection. However, further studies are necessary to investigate the rate of false-negative fluorescence and its effect on progression free survival. If 5-ALA-fg resection of meningioma is performed, the attending surgeon should also consider investigating the adjacent periosteum under blue light for detection of possible fluorescence.

The role of 5-aminolevulinic acid in spinal tumor surgery: a review.

PURPOSE: Primary intradural spinal neoplasms account for a small proportion of central nervous system tumors. The primary treatment for these tumors consists of maximal safe resection and preservation of neurologic function. Gross total resection, which is associated with the lowest rate of tumor recurrence and longer progression-free survival for most histologies, can be difficult to achieve. Currently, the use of 5-aminolevulinc acid (5-ALA) which takes advantage of Protoporphyrin IX (PpIX) fluorescence, is a well-established technique for improving resection of malignant cerebral gliomas. This technique is being increasingly applied to other cerebral neoplasms, and multiple studies have attempted to evaluate the utility of 5-ALA-aided resection of spinal neoplasms. METHODS: The authors reviewed the existing literature on the use of 5-ALA and PpIX fluorescence as an aid to resection of primary and secondary spinal neoplasms by searching the PUBMED and EMBASE database for records up to March 2018. Data was abstracted from all studies describing spinal neurosurgical uses in the English language. RESULTS: In the reviewed studies, the most useful fluorescence was observed in meningiomas, ependymomas, drop metastases from cerebral gliomas, and hemangiopericytomas of the spine, which is consistent with applications in cerebral neoplasms. CONCLUSIONS: The available literature is significantly limited by a lack of standardized methods for measurement and quantification of 5-ALA fluorescence. The results of the reviewed studies should guide future development of rational trial protocols for the use of 5-ALA guided resection in spinal neoplasms.

Intraoperative imaging techniques for glioma surgery.

Gliomas are CNS neoplasms that infiltrate the surrounding brain parenchyma, complicating their treatment. Tools that increase extent of resection while preventing neurological deficit are essential to improve prognosis of patients diagnosed with gliomas. Tools such as intraoperative MRI, ultrasound and fluorescence-guided microsurgery have been used in the surgical resection of CNS gliomas with the goal of maximizing extent of resection to improve patient outcomes. In addition, emerging experimental techniques, for example, optical coherence tomography and Raman spectroscopy are promising techniques which could 1 day add to the increasing armamentarium used in the surgical resection of CNS gliomas. Here, we present the potential advantages and limitations of these imaging techniques for the purposes of identifying gliomas in the operating room.

Fluorescence-guided resection of extracranial soft tissue tumour infiltration in atypical meningioma.

The exact role of 5-aminolevulinic acid (5-ALA) fluorescence-guided meningioma resection is as yet unclear. Although most of the meningiomas show positive fluorescence, the influence on outcome, fluorescence heterogeneity within the tumour, the correlation between fluorescence and the proliferation rate, as well as different quantitative measurements are a matter of debate. Positive fluorescence in bone infiltrative meningiomas is well described, whereas little data exist about 5-ALA fluorescence within soft tissue infiltration. We add a case of histologically confirmed fluorescent tumour infiltration into soft tissue. A 78-year-old woman underwent resection of an atypical meningioma at the University Hospital of St. Poelten. Preoperative imaging showed tumour infiltration throughout the calvaria. 5-ALA fluorescence of the tumour as well as bone, periost and temporal muscle helped to perform a gross total resection. Histological examination showed an atypical meningioma (WHO Grade II) and gave proof of tumour infiltration of the bone and temporal muscle. With the aid of 5-ALA fluorescence, a gross total resection could be performed.

Periventricular glioblastomas and ependymal involvement interrogated using intraoperative fluorescence - a pathological correlative study.

RATIONALE: Subventricular zone (SVZ) involvement has been proposed as an adverse prognostic factor in glioblastomas (GBM). The true extent of ventricular involvement at surgery is often difficult to establish and is poorly studied. Tumour fluorescence provides us with an exciting opportunity to interrogate tumour extent intraoperatively. METHODS: We conducted a retrospective analysis of all cases of GBMs operated using aminolevulinic acid-induced fluorescence and analyzed radiological SVZ involvement alongwith the incidence of ventricular entry at surgery, ependymal fluorescence and histological correlation of the ependymal involvement. RESULTS: Of 30 GBMs, radiological SVZ involvement was seen in 26 of which ventricles were opened at surgery in 19. Diffuse ependymal fluorescence was seen in 10 of the 19 cases (51%) and histology revealed tumour infiltration in only one of the five cases where ependymal tissue was sampled. Focal ependymal fluorescence seen in two of the 19 cases was always pathological. Diffuse ependymal fluorescence did not always correlate with gross appearance of the ventricular lining at surgery. Nor did it correlate with SVZ involvement. CONCLUSIONS: Pathological significance of diffusely fluorescing ependymal lining seen during surgery is questionable and need not represent tumour extension. Ependymal fluorescence may sometimes not be visualized even when the tumour appears to involve the SVZ. These results highlight the potential limitations of fluorescence especially in the bordering infiltrating zone where its predictive value is diminished.

Fluorescence guided resection with 5-aminolevulinic acid of a pilomyxoid astrocytoma of the third ventricle.

Fluorescence-guided resection with 5-aminolevulinic acid has been shown to be useful in the resection of certain brain tumors other than high grade gliomas, facilitating the intraoperative differentiation of neoplastic tissue. The technique enables the surgeon to ensure that no tumor fragments remain, thereby achieving higher rates of complete resection. Tihan first described pilomyxoid astrocytomas in 1999. They are currently classified as grade II astrocytoma according to the WHO classification system and, because of their tendency to recur and their dissemination through the cerebrospinal fluid pathways, they are considered to be more aggressive than pilocytic astrocytoma. As a result, management of these tumors must be more aggressive, always aiming for complete macroscopic resection whenever possible. In this article, we present a case of pilomyxoid astrocytoma of the third ventricle in which the use of fluorescence-guided resection with 5-ALA facilitated complete resection. Imaging tests performed after five years revealed no signs of recurrence and no adjuvant radiotherapy or chemotherapy was required. This article also comprises a review of the literature concerning the characteristics and management of this tumor, which was recently considered to be a different histopathological entity.

Fluorescence guided resection and glioblastoma in 2015: A review.

High-grade gliomas represent a widely heterogeneous group of tumors, the most frequent of which is glioblastoma multiforme. Its annual incidence has risen over the last decades, particularly amongst elderly people. The actual standards of care allow for a 15-month median survival rate for WHO grade IV gliomas. As recurrence occurs in more than 85% of patients at the surgical margins, the initial resection extent is a cornerstone of disease control. Fluorescence guided resection (FGR) aims at increasing complete resections and, thus, local control. This technique uses 5-aminolevulinic acid (5-ALA), a natural intermediate substance in the heme-porphyrin biosynthesis pathway, and a protoporphyrin IX (PpIX) precursor. PpIX is fluorescent under blue light exposure. Recent studies reported a significant increase in complete resections using FGR, which were associated with prolonged progression free survival, fewer reinterventions, and delayed neurological deterioration. Here, we depict the principles of this surgical technique, its actual outcomes, and future developments.

Achieving Gross Total Resection in Neurosurgery: A Review of Intraoperative Techniques and Their Influence on Surgical Goals.

The definition of complete resection in neurosurgery depends on tumor type, surgical aims, and postoperative investigations, directly guiding the choice of intraoperative tools. Most common tumor types present challenges in achieving complete resection due to their infiltrative nature and anatomical constraints. The development of adjuvant treatments has altered the balance between oncological aims and surgical risks. We review local recurrence associated with incomplete resection based on different definitions and emphasize the importance of achieving maximal safe resection in all tumor types. Intraoperative techniques that aid surgeons in identifying tumor boundaries are used in practice and in preclinical or clinical research settings. They encompass both conservative and invasive techniques. Among them, morphological tools include imaging modalities such as intraoperative magnetic resonance imaging, ultrasound, and optical coherence tomography. Fluorescence-guided surgery, mainly using 5-aminolevulinic acid, enhances gross total resection in glioblastomas. Nuclear methods, including positron emission tomography probes, provide tumor detection based on beta or gamma emission after a radiotracer injection. Mass spectrometry- and spectroscopy-based methods offer molecular insights. The adoption of these techniques depends on their relevance, effectiveness, and feasibility. With the emergence of positron emission tomography imaging for use in recurrence benchmarking, positron emission tomography probes raise particular interest among those tools. While all such tools provide valuable insights, their clinical benefits need further evaluation.

Fluorescence-Guided Surgical Techniques in Adult Diffuse Low-Grade Gliomas: State-of-the-Art and Emerging Techniques: A Systematic Review.

Diffuse low-grade gliomas are infiltrative tumors whose margins are not distinguishable from the adjacent healthy brain parenchyma. The aim was to precisely examine the results provided by the intraoperative use of macroscopic fluorescence in diffuse low-grade gliomas and to describe the new fluorescence-based techniques capable of guiding the resection of low-grade gliomas. Only about 20% and 50% of low-grade gliomas are macroscopically fluorescent after 5-amino-levulinic acid (5-ALA) or fluorescein sodium intake, respectively. However, 5-ALA is helpful for detecting anaplastic foci, and thus choosing the best biopsy targets in diffuse gliomas. Spectroscopic detection of 5-ALA-induced fluorescence can detect very low and non-macroscopically visible concentrations of protoporphyrin IX, a 5-ALA metabolite, and, consequently, has excellent performances for the detection of low-grade gliomas. Moreover, these tumors have a specific spectroscopic signature with two fluorescence emission peaks, which is useful for distinguishing them not only from healthy brain but also from high-grade gliomas. Confocal laser endomicroscopy can generate intraoperative optic biopsies, but its sensitivity remains limited. In the future, the coupled measurement of autofluorescence and induced fluorescence, and the introduction of fluorescence detection technologies providing a wider field of view could result in the development of operator-friendly tools implementable in the operative routine.

Fluorescence guidance in skull base surgery: Applications and limitations - A systematic review.

Introduction: Intraoperative fluorescence guidance is a well-established surgical adjunct in high-grade glioma surgery. In contrast, the clinical use of such dyes and technology has been scarcely reported in skull base surgery. Research question: We aimed to systematically review the clinical applications of different fluorophores in both open and endonasal skull base surgery. Material and methods: We performed a systematic review and discussed the current literature on fluorescence guidance in skull base surgery. Results: After a comprehensive literature search, 77 articles on skull base fluorescence guidance were evaluated. A qualitative analysis of the articles is presented, discussing clinical indications and current controversies. The use of intrathecal fluorescein was the most frequently reported in the literature. Beyond that, 5-ALA and ICG were two other fluorescent dyes most extensively discussed, with some experimental fluorophore applications in skull base surgery. Discussion and conclusion: Intraoperative fluorescence imaging can serve as an adjunct technology in skull base surgery. The scope of initial indications of these fluorophores has expanded beyond malignant glioma resection alone. We discuss current use and controversies and present an extensive overview of additional indications for fluorescence imaging in skull base pathologies. Further quantitative studies will be needed in the future, focusing on tissue selectivity and time-dependency of the different fluorophores currently commercially available, as well as the development of new compounds to expand applications and facilitate skull base surgeries.

Unraveling the blue shift in porphyrin fluorescence in glioma: The 620 nm peak and its potential significance in tumor biology.

In glioma surgery, the low-density infiltration zone of tumors is difficult to detect by any means. While, for instance, 5-aminolevulinic acid (5-ALA)-induced fluorescence is a well-established surgical procedure for maximizing resection of malignant gliomas, a cell density in tumor tissue of 20-30% is needed to observe visual fluorescence. Hyperspectral imaging is a powerful technique for the optical characterization of brain tissue, which accommodates the complex spectral properties of gliomas. Thereby, knowledge about the signal source is essential to generate specific separation (unmixing) procedures for the different spectral characteristics of analytes and estimate compound abundances. It was stated that protoporphyrin IX (PpIX) fluorescence consists mainly of emission peaks at 634 nm (PpIX634) and 620 nm (PpIX620). However, other members of the substance group of porphyrins fluoresce similarly to PpIX due to their common tetrapyrrole core structure. While the PpIX634 signal has reliably been assigned to PpIX, it has not yet been analyzed if PpIX620 might result from a different porphyrin rather than being a second photo state of PpIX. We thus reviewed more than 200,000 spectra from various tumors measured in almost 600 biopsies of 130 patients. Insufficient consideration of autofluorescence led to artificial inflation of the PpIX620 peak in the past. Recently, five basis spectra (PpIX634, PpIX620, flavin, lipofuscin, and NADH) were described and incorporated into the analysis algorithm, which allowed more accurate unmixing of spectral abundances. We used the improved algorithm to investigate the PpIX620 signal more precisely and investigated coproporphyrin III (CpIII) fluorescence phantoms for spectral unmixing. Our findings show that the PpIX634 peak was the primary source of the 5-ALA-induced fluorescence. CpIII had a similar spectral characteristic to PpIX620. The supplementation of 5-ALA may trigger the increased production of porphyrins other than PpIX within the heme biosynthesis pathway, including that of CpIII. It is essential to correctly separate autofluorescence from the main PpIX634 peak to analyze the fluorescence signal. This article highlights the need for a comprehensive understanding of the spectral complexity in gliomas and suggests less significance of the 620 nm fluorescence peak for PpIX analysis and visualization.

Combined indocyanine green and medical glue enables stable and precise position in animal studies: promising for fluorescence-guided pulmonary ground glass nodule resection.

Background: Accurate preoperative localization of pulmonary nodules is crucial for surgical treatment. The use of indocyanine green (ICG) for localization is prone to thoracic contamination and spread, resulting in the eventual failure of localization. By using medical glue combined with ICG, we can accurately and permanently locate various tissues in animal study, which can provide evidences for clinical translations. Methods: A series of medical glue and ICG volume ratios of 2:3, 3:3, 4:3, 6:3, and 9:3 were mixed and injected immediately into subcutaneous tissues of BALB/c nude mice; either medical glue or ICG was injected singly in the control group. Fluorescence intensity over time and boundary sharpness were investigated to determine the optimal ratio. Then, fluorescence guided resection of tissue was performed ex vivo on the pig intestine utilizing optimal ratio. Further, localization agents with the optimal ratio were injected into the organs of living mice, and fluorescence imaging for accurate positioning was performed 24 hours later. Results: The localization agents with a volume ratio of 4:3 showed the best boundary sharpness and the strongest photostability. With the guidance of fluorescence navigation, the marked tissues were accurately separated and removed from the surrounding tissue both on mice and on pig intestines. In the organs of living mice, the localization agents (ratio 4:3) realized accurate positioning of marked tissues. Additionally, the medical glue limited the diffusion of ICG, promising to enable more stable and precise positioning of the nodules during surgery. Conclusions: The combination of ICG and medical glue presents a superior approach when compared to the individual use of either ICG or medical glue. This technique offers enhanced precision and durability and sealed the wound, thereby mitigating the risk of pneumothorax following puncture procedures. This innovative technique optimizes the properties of medical adhesive to augment tissue density while harnessing the real-time fluorescent endoscopic marking capabilities of ICG during surgical interventions. By employing this innovative technique, it holds significant promise for augmenting the accuracy of pulmonary nodule localization in thoracoscopic surgery within future clinical applications.

Novel Iron-Chelating Prodrug Significantly Enhanced Fluorescence-Mediated Detection of Glioma Cells Experimentally In Vitro.

(1) Background: The protoporphyrin IX (PpIX)-mediated fluorescence-guided resection and interoperative photodynamic therapy (PDT) of remaining cells may be effective adjuvants to the resection of glioma. Both processes may be enhanced by increasing intracellular PpIX concentrations, which can be achieved through iron chelation. AP2-18 is a novel combinational drug, which ester-links a PpIX precursor (aminolaevulinic acid; ALA) to an iron-chelating agent (CP94). (2) Methods: Human glioma U-87 MG cells were cultured in 96-well plates for 24 h and incubated for 3 or 6 h with various test compound combinations: ALA (±) CP94, methyl aminolevulinate (MAL) (±) CP94 and AP2-18. PpIX fluorescence was measured at 0, 3 or 6 h with a Bio-tek Synergy HT plate reader, as well as immediately after irradiation with a 635 nm red light (Aktilite CL16 LED array), representing the PDT procedure. Cell viability post-irradiation was assessed using the neutral red assay. (3) Results: AP2-18 significantly increased PpIX fluorescence compared to all other test compounds. All treatment protocols effectively achieved PDT-induced cytotoxicity, with no significant difference between test compound combinations. (4) Conclusions: AP2-18 has potential to improve the efficacy of fluorescence-guided resection either with or without the subsequent intraoperative PDT of glioma. Future work should feature a more complex in vitro model of the glioma microenvironment.

Fluorescence real-time kinetics of protoporphyrin IX after 5-ALA administration in low-grade glioma.

OBJECTIVE: 5-Aminolevulinic acid (5-ALA) induces fluorescence in high-grade glioma (HGG), which is used for resection. However, the value of 5-ALA-induced fluorescence in low-grade glioma (LGG) is unclear. Time dependency and time kinetics have not yet been investigated. The purpose of this study was to investigate real-time kinetics of protoporphyrin IX (PpIX) in LGG based on hyperspectral fluorescence-based measurements and identify factors that predict fluorescence. METHODS: Patients with grade II gliomas and imaging from which HGGs could not be completely ruled out received 5-ALA at 20 mg/kg body weight 4 hours prior to surgery. Fluorescence intensity (FI) and PpIX concentration (CPpIX) were measured in tumor tissue utilizing a hyperspectral camera. Apparent diffusion coefficient (ADC)-based tumor cell density, Ki-67/MIB-1 index, chromosomal 1p/19q codeletion, and 18F-fluoroethyl-l-tyrosine (18F-FET) PET values and their role for predicting fluorescence were evaluated. RESULTS: Eighty-one biopsies from 25 patients were included. Tissues with fluorescence demonstrated FI and CPpIX maxima between 7 and 8 hours after administration. When visible fluorescence was observed, peaks of FI and CPpIX were observed within this 7- to 8-hour time frame, regardless of any MRI gadolinium contrast enhancement. Gadolinium enhancement (p = 0.008), Ki-67/MIB-1 index (p < 0.001), 18F-FET PET uptake ratio (p = 0.004), and ADC-based tumor cellularity (p = 0.017) significantly differed between fluorescing and nonfluorescing tissue, but not 1p/19q codeletions. Logistic regression demonstrated that 18F-FET PET uptake and Ki-67/MIB-1 index were independently related to fluorescence. CONCLUSIONS: This study reports a fluorescence-based assessment of CPpIX in human LGG tissues related to 18F-FET PET uptake and Ki-67/MIB-1. As in HGGs, fluorescence in LGGs peaked between 7 and 8 hours after 5-ALA application, which has consequences for the timing of administration.