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Metabolic FLIM (fluorescence lifetime imaging) is used to image bioenergetic status in cells and tissue. Whereas an attribution of the fluorescence lifetime of coenzymes as an indicator for cell metabolism is mainly accepted, it is debated whether this is valid for the redox state of cells. In this regard, an innovative algorithm using the lifetime characteristics of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) to calculate the fluorescence lifetime induced redox ratio (FLIRR) has been reported so far. We extended the FLIRR approach and present new results, which includes FLIM data of the various enzymes, such as NAD(P)H, FAD, as well as flavin mononucleotide (FMN). Our algorithm uses a two-exponential fitting procedure for the NAD(P)H autofluorescence and a three-exponential fit of the flavin signal. By extending the FLIRR approach, we introduced FLIRR1 as protein-bound NAD(P)H related to protein-bound FAD, FLIRR2 as protein-bound NAD(P)H related to free (unbound) FAD and FLIRR3 as protein-bound NAD(P)H related to protein-bound FMN. We compared the significance of extended FLIRR to the metabolic index, defined as the ratio of protein-bound NAD(P)H to free NAD(P)H. The statistically significant difference for tumor and normal cells was found to be highest for FLIRR1.

Hyperspectral imaging (HSI) is a new emerging modality useful for the noncontact assessment of free flap perfusion. This measurement technique relies on the optical properties within the tissue. Since the optical properties of hemoglobin (Hb) and melanin overlap, the results of the perfusion assessment and other tissue-specific parameters are likely to be distorted by the melanin, especially at higher melanin concentrations. Many spectroscopic devices have been shown to struggle with a melanin related bias, which results in a clinical need to improve non-invasive perfusion assessment, especially for a more pigmented population. This study investigated the influence of skin tones on tissue indices measurements using HSI. In addition, other factors that might affect HSI, such as age, body mass index (BMI), sex or smoking habits, were also considered. Therefore, a prospective feasibility study was conducted, including 101 volunteers from whom tissue indices measurements were performed on 16 different body sites. Skin tone classification was performed using the Fitzpatrick skin type classification questionnaire, and the individual typology angle (ITA) acquired from the RGB images was calculated simultaneously with the measurements. Tissue indices provided by the used HSI-device were correlated to the possible influencing factors. The results show that a dark skin tone and, therefore, higher levels of pigmentation influence the HSI-derived tissue indices. In addition, possible physiological factors influencing the HSI-measurements were found. In conclusion, the HSI-based tissue indices can be used for perfusion assessment for people with lighter skin tone levels but show limitations in people with darker skin tones. Furthermore, it could be used for a more individual perfusion assessment if different physiological influencing factors are respected.

Purpose Innovative, efficient treatments are desperately needed for people with glioblastoma (GBM). Methods Sixteen patients (median age 65.8 years) with newly diagnosed, small-sized, not safely resectable supratentorial GBM underwent interstitial photodynamic therapy (iPDT) as upfront eradicating local therapy followed by standard chemoradiation. 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX was used as the photosensitizer. The tumors were irradiated with light at 635 nm wavelength via stereotactically implanted cylindrical diffuser fibers. Outcome after iPDT was retrospectively compared with a positively-selected in-house patient cohort (n = 110) who underwent complete tumor resection followed by chemoradiation. Results Median progression-free survival (PFS) was 16.4 months, and median overall survival (OS) was 28.0 months. Seven patients (43.8%) experienced long-term PFS > 24 months. Median follow-up was 113.9 months for the survivors. Univariate regression revealed MGMT-promoter methylation but not age as a prognostic factor for both OS (p = 0.04 and p = 0.07) and PFS (p = 0.04 and p = 0.67). Permanent iPDT-associated morbidity was seen in one iPDT patient (6.3%). Patients treated with iPDT experienced superior PFS and OS compared to patients who underwent complete tumor removal (p < 0.01 and p = 0.01, respectively). The rate of long-term PFS was higher in iPDT-treated patients (43.8% vs. 8.9%, p < 0.01). Conclusion iPDT is a feasible treatment concept and might be associated with long-term PFS in a subgroup of GBM patients, potentially via induction of so far unknown immunological tumor-controlling processes.

Bladder cancer is a common urogenital malignancy that remains difficult to treat, particularly due to therapeutic resistance, such as resistance to cisplatin, in which cancer stem cells (CSCs) play a central role. This study investigates the combination of 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) and berbamine as a potential multimodal treatment strategy using the bladder cancer cell lines RT112 and J82, their cisplatin-resistant variants, and generated CSC-like cells. Berbamine is a natural plant compound and was confirmed in this study to have anticancer properties by inhibiting cell migration and invasion, and by inducing apoptosis. This study also showed that berbamine enhances the accumulation of protoporphyrin IX (PpIX), the photosensitizer induced by 5-ALA. 5-ALA-PDT destroys cancer cells by stimulating PpIX via 635 nm red laser light to produce reactive oxygen species (ROS). This was found to happen in all tested cell lines, whereas berbamine could modulate the cell destruction in a concentration-dependent manner and was influenced by the specific biological characteristics of the tested cell variants. CSCs showed the strongest response to the combination therapy approach, suggesting that they may represent more vulnerable cell variants to the tested treatment. Cisplatin-resistant cell lines could also be treated successfully with 5-ALA-PDT, whereas berbamine could enhance its efficacy in the cisplatin-resistant J82 LTT. These findings suggest that the combination treatment of 5-ALA-PDT and berbamine may serve as a promising approach to overcome therapeutic resistance in bladder cancer, particularly in cisplatin-resistant and CSC-enriched tumour types.

Acne vulgaris, a prevalent chronic inflammatory skin disorder, is often characterized by hyperactive sebaceous glands and excessive sebum production, presenting a significant therapeutic challenge. While 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is clinically effective in treating moderate to severe acne, the molecular mechanisms underlying its therapeutic effects remain largely unexplored. In this study, we investigated the impact of ALA-PDT on lipid metabolism in an acne-like mouse model and in immortalized human sebocytes (XL-i-20), focusing on the role of the OLR1-Wnt/β-catenin pathway. We employed transcriptomic analysis, lipid staining, and gene silencing techniques to dissect the molecular interactions induced by ALA-PDT. Our findings revealed that ALA-PDT significantly reduces lipogenesis by upregulating OLR1, which in turn suppresses the SREBP1-FAS axis, thereby decreasing lipid accumulation in sebocytes. Furthermore, activation of the OLR1-Wnt/β-catenin pathway was essential for these lipogenic effects, as silencing OLR1 or activating Wnt/β-catenin signaling reversed lipogenesis inhibition. This study elucidates a novel mechanistic pathway in ALA-PDT-mediated acne treatment, highlighting OLR1 as a promising target for future therapeutic strategies.

Objectives In vitro investigations of Ho:YAG laser-induced stone fragmentation were performed to identify potential impacts of different pulse durations on stone fragmentation characteristics. Materials and methods A Ho:YAG laser system (Swiss LaserClast, EMS S.A., Nyon, Switzerland) with selectable long or short pulse mode was tested with regard to its fragmentation and laser hardware compatibility properties. The pulse duration is depending on the specific laser parameters. Fragmentation tests (hand-held, hands-free, single-pulse-induced crater) on artificial BEGO stones were performed under reproducible experimental conditions (fibre sizes: 365 and 200 µm; laser settings: 10 W through combinations of 0.5, 1, 2 J/pulse and 20, 10, 5 Hz, respectively). Results Differences in fragmentation rates between the two pulse duration regimes were detected with statistical significance for defined settings. Hand-held and motivated Ho:YAG laser-assisted fragmentation of BEGO stones showed no significant difference between short pulse mode and long pulse mode, neither in fragmentation rates nor in number of fragments and fragment sizes. Similarly, the results of the hands-free fragmentation tests (with and without anti-repulsion device) showed no statistical differences between long pulse and short pulse modes. Conclusion The study showed that fragmentation rates for long and short pulse durations at identical power settings remain at a comparable level. Longer holmium laser pulse duration reduces stone pushback. Therefore, longer laser pulses may result in better clinical outcome of laser lithotripsy and more convenient handling during clinical use without compromising fragmentation effectiveness.

Background: The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. Methods: A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. Results: In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis–tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. Conclusions: In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care.

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.

In a former study, interstitial photodynamic therapy (iPDT) was performed on patients suffering from newly diagnosed glioblastoma (n = 11; 8/3 male/female; median age: 68, range: 40–76). The procedure includes the application of 5-ALA to selectively metabolize protoporphyrin IX (PpIX) in tumor cells and illumination utilizing interstitially positioned optical cylindrical diffuser fibers (CDF) (2–10 CDFs, 2–3 cm diffusor length, 200 mW/cm, 635 nm, 60 min irradiation). Intraoperative spectral online monitoring (SOM) was employed to monitor treatment light transmission and PpIX fluorescence during iPDT. MRI was used for treatment planning and outcome assessment. Case-dependent observations included intraoperative reduction of treatment light transmission and local intrinsic T1 hyperintensity in non-contrast-enhanced T1-weighted MRI acquired within one day after iPDT. Intrinsic T1 hyperintensity was observed and found to be associated with the treatment volume, which indicates the presence of methemoglobin, possibly induced by iPDT. Based on SOM data, the optical absorption coefficient and its change during iPDT were estimated for the target tissue volumes interjacent between evaluable CDF-pairs at the treatment wavelength of 635 nm. By spatial comparison and statistical analysis, it was found that observed increases of the absorption coefficient during iPDT were larger in or near regions of intrinsic T1 hyperintensity (p = 0.003). In cases where PpIX-fluorescence was undetectable before iPDT, the increase in optical absorption and intrinsic T1 hyperintensity tended to be less. The observations are consistent with in vitro experiments and indicate PDT-induced deoxygenation of hemoglobin and methemoglobin formation. Further investigations are needed to provide more data on the time course of the observed changes, thus paving the way for optimized iPDT irradiation protocols.

Worldwide, more individuals have iron deficiency than any other health problem. Most of those affected are unaware of their lack of iron, in part because detection of iron deficiency has required a blood sample. Here we report a non-invasive method to optically measure an established indicator of iron status, red blood cell zinc protoporphyrin, in the microcirculation of the lower lip. An optical fibre probe is used to illuminate the lip and acquire fluorescence emission spectra in ∼1 min. Dual-wavelength excitation with spectral fitting is used to distinguish the faint zinc protoporphyrin fluorescence from the much greater tissue background fluorescence, providing immediate results. In 56 women, 35 of whom were iron-deficient, the sensitivity and specificity of optical non-invasive detection of iron deficiency were 97% and 90%, respectively. This fluorescence method potentially provides a rapid, easy to use means for point-of-care screening for iron deficiency in resource-limited settings lacking laboratory infrastructure. Iron deficiency, the most common health problem in the world, has required a blood test for diagnosis. Here, the authors show that iron deficiency can be detected non-invasively and quickly by measuring the fluorescence of red blood cell zinc protoporphyrin in the microcirculation of the lip.