Background: Patients suffering from malignant gliomas have a poor prognosis. For the surgical treatment of these tumors, 5‐aminolevulinic acid (5‐ALA) has become a new standard.Aims: This review intends to provide an overview over current status, significance, limitations, and future perspectives of 5‐ALA based fluorescence guided surgery and photodynamic therapy for brain tumor patients.Materials and Methods: From peer reviewed publications on the many aspects connected with this topic, those with potential clinical relevance were selected and put in the context of our own experience.Results and Discussion: The high tumor selectivity of accumulation of fluorescent protoporphyrin IX (PpIX) after systemic administration of 5‐ALA enables intra‐operative fluorescence guidance, which is unimpaired by brainshift and does not require expensive equipment. The neurosurgical aim of complete resection of enhancing tumor can now more easily be achieved, which improves prognosis in these patients. Nevertheless, despite better surgery tumors will inevitably recur. In order to further prolong survival, the phototoxic properties of PpIX are presently being exploited in clinical trials of post‐operative or interstitial photodynamic therapy (PDT).Conclusion: 5‐ALA based fluorescence guidance and PDT offer an intriguing new option for the management of malignant gliomas. Lasers Surg. Med. 50:399–419, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals LLC

Background: Oral application of 20 mg/kg body weight of 5-aminolevulinic acid (ALA) leads to a highly specific accumulation of fluorescent Protoporphyrin IX (PPIX) in malignant glioma tissue. In the past few years, we have participated in several clinical studies designed to investigate fluorescence guided resection (FGR) and photodynamic therapy (PDT). Methods: PPIX selectivity and PPIX bleaching during PDT were assessed with spectroscopic measurements. FGR was performed in 18 clinics in Germany (ALA-Glioma Study Group, participants see end of paper) in a phase III trial comprising an ALA group and a white-light group. PDT was performed with microlens fibers or cylindrical diffusers postsurgically to the resection bed. Additionally, a protocol for the interstitial stereotactic placement of cylindrical diffusers was established and applied on patients with recurrent, inoperable glioblastoma. Results: Compared to normal cortex, mean PPIX fluorescence in vital tumor was found more than 100-fold increased. During PDT, the PPIX fluorescence bleached to 8%, 16%, and 1% of the initial intensity for the 100, 150, and 200 J/cm² groups (median values). FGR: Contrast-enhancing tumor was completely resected in 65% of patients in the ALA group compared to 36% in the white-light group (p < 0.0001). Progression-free survival was superior in the ALA group compared to white-light patients with cumulative 6 months progression-free survival rates of 41% and 21% (p = 0.0003), respectively. Interstitial PDT can be performed with multiple radial diffusers approximately 10 mm apart, 200 mW/cm, and an irradiation time of one hour.

Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4–87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)—isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)—for their second, 9 (20.5%)—for the third or further recurrence. The median iPDT target volume was 3.34 cm³ (range, 0.50–22.8 cm³). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4–9.8) months and the median PRS was 13.0 (95% CI, 9.2–16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response.

Injury to parathyroid glands during thyroid and parathyroid surgery is common and postoperative hypoparathyroidism represents a serious complication. Parathyroid glands possess a unique autofluorescence in the near-infrared spectrum which could be used for their identification and protection at an early stage of the operation. In the present study parathyroid autofluorescence was visualized intraoperatively using a standard Storz laparoscopic near-infrared/indocyanine green (NIR/ICG) imaging system with minor modifications to the xenon light source (filtered to emit 690 nm to 790 nm light, less than 1% in the red and green above 470 nm and no blue light). During exposure to NIR light parathyroid tissue was expected to show autofluorescence at 820 nm, captured in the blue channel of the camera. Over a period of 5 years, we investigated 205 parathyroid glands from 117 patients. 179 (87.3%) glands were correctly identified by their autofluorescence. Surrounding structures such as thyroid, lymph nodes, muscle, or adipose tissue did not reveal substantial autofluorescence. We conclude that parathyroid glands can be identified by their unique autofluorescence at an early stage of the operation. This may help to preserve these fragile structures and their vascularization and lower the rate of postoperative hypocalcemia.

Review paper and Proceedings of the Inaugural Meeting of the Head and Neck Optical Diagnostics Society (HNODS) on March 14^th 2009 at University College London. The aim of our research must be to provide breakthrough translational research which can be applied clinically in the immediate rather than the near future. We are fortunate that this is indeed a possibility and may fundamentally change current clinical and surgical practice to improve our patients' lives.

A phase zero evaluation of a new fluorescence imaging technique for diagnosing cervical intraepithelial neoplasia (CIN) was performed. The fluorescence imaging prototype performed quantitative imaging of Protoporphyrin induced by a topically applied aminolevulinic acid using double ratio (DR) fluorescence imaging technique developed by our group. A total of 38 patients were in the protocol, with 16 colposcopically selected for biopsy. Fluorescence images of these 16 patients were taken, 19 sites were biopsied, and the disease was staged histopathologically. DR fluorescence imaging of the cervix using our general purpose prototype appeared to be cumbersome but feasible. In four cases strongly localized fluorescent hotspots were observed at the location where the disease was colposcopically visible. In the other cases the fluorescence showed a more diffuse multifocal image. The value of the DR determined at the site of biopsy correlated in a statistically significant way with the histopathologically determined stage of the disease [Spearman rank correlation, r=0.881, p<0.001 (confidence interval 0.7044–0.9552)]. This suggests that noninvasive staging of CIN using this technique is feasible. We believe that the results of this study justify the development of a dedicated device that combines regular white light colposcopy with DR fluorescence imaging.