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Background Daylight photodynamic therapy (dPDT) and topical 5-fluorouracil (5-FU) are each effective treatments for thin grade I actinic keratosis (AKs), but less so for thicker grade II-III AKs. Prolonged topical treatment regimens can be associated with severe skin reactions and low compliance. This study compares the efficacy of sequential 4 % 5-FU and dPDT with dPDT monotherapy for multiple actinic keratoses. Methods Sixty patients with a total of 1547 AKs (grade I: 1278; grade II: 246; grade III: 23) were treated in two symmetrical areas (mean size 75 cm2) of the face or scalp, which were randomized to (i) 4% 5-FU creme twice daily for 7 days before a single dPDT procedure and (ii) dPDT monotherapy. Daylight exposure was either outdoor or indoor daylight. Results Twelve weeks after treatment 87 % of all AKs cleared after 5-FU+dPDT compared to 74 % after dPDT alone (p<0.0001). For grade II AKs, the lesion response rate increased from 55 % with dPDT monotherapy to 79 % after 5-FU+dPDT (p<0.0056). Moderate/severe erythema was seen in 88 % 5-FU+dPDT areas compared to 41 % of dPDT areas two days after dPDT. Twelve weeks after treatment 75 % of the patients were very satisfied with both treatments. Conclusions Sequential 5-FU and dPDT was more effective than dPDT monotherapy in the treatment of AKs, especially for grade II AKs. Local skin reactions were more pronounced after combination treatment, but no patients discontinued the treatment. The combination of 5-FU and dPDT is an effective treatment of large treatment areas with high compliance and satisfaction., Background: Daylight photodynamic therapy (dPDT) and topical 5-fluorouracil (5-FU) are each effective treatments for thin grade I actinic keratosis (AKs), but less so for thicker grade II-III AKs. Prolonged topical treatment regimens can be associated with severe skin reactions and low compliance. This study compares the efficacy of sequential 4 % 5-FU and dPDT with dPDT monotherapy for multiple actinic keratoses. Methods: Sixty patients with a total of 1547 AKs (grade I: 1278; grade II: 246; grade III: 23) were treated in two symmetrical areas (mean size 75 cm2) of the face or scalp, which were randomized to (i) 4% 5-FU creme twice daily for 7 days before a single dPDT procedure and (ii) dPDT monotherapy. Daylight exposure was either outdoor or indoor daylight. Results: Twelve weeks after treatment 87 % of all AKs cleared after 5-FU+dPDT compared to 74 % after dPDT alone (p<0.0001). For grade II AKs, the lesion response rate increased from 55 % with dPDT monotherapy to 79 % after 5-FU+dPDT (p<0.0056). Moderate/severe erythema was seen in 88 % 5-FU+dPDT areas compared to 41 % of dPDT areas two days after dPDT. Twelve weeks after treatment 75 % of the patients were very satisfied with both treatments. Conclusions: Sequential 5-FU and dPDT was more effective than dPDT monotherapy in the treatment of AKs, especially for grade II AKs. Local skin reactions were more pronounced after combination treatment, but no patients discontinued the treatment. The combination of 5-FU and dPDT is an effective treatment of large treatment areas with high compliance and satisfaction.

Ultraviolet radiation is the primary risk factor for keratinocyte carcinoma. Because of increasing incidence rates, new methods of photoprotection must be explored. Oral supplementation with photoprotective compounds presents a promising alternative. Phytochemical compounds like hesperidin methyl chalcone, phloroglucinol, and syringic acid are particularly of interest because of their antioxidant properties. Our primary outcome was to evaluate the effects of oral phytochemicals on photocarcinogenesis with time until tumour onset as the primary endpoint. A total of 125 hairless C3.Cg-Hrhr/TifBom Tac mice were randomised to receive tap water supplemented with either 100 mg/kg hesperidin methyl chalcone, phloroglucinol, or syringic acid, 600 mg/kg nicotinamide as a positive control, or no supplementation. The mice were irradiated with 3.5 standard erythema doses thrice weekly to induce photocarcinogenesis. Supplementation with the phytochemicals phloroglucinol and syringic acid and nicotinamide delayed tumour onset from a median of 140 days to 151 (p = 0.036), 157 days (p = 0.02), and 178 (p = 2.7·10−5), respectively. Phloroglucinol and nicotinamide supplementation reduced tumour number. Nicotinamide increased UV-induced pigmentation and reduced oedema formation, while phloroglucinol supplementation reduced epidermal thickness. These results indicate that oral supplementation with phloroglucinol and syringic acid protects against photocarcinogenesis in hairless mice, but not to the same extent as nicotinamide.

Background Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment. Objective To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds. Methods A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed. Results In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation. Conclusion 5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates. Key Words: Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement, Background: Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment. Objective: To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds. Methods: A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed. Results: In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation. Conclusion: 5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates. Key Words: Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement

Background & aims Sleep disturbances are related to hepatic encephalopathy and hyperammonaemia in patients with cirrhosis. The circadian rhythm is regulated by light stimulation of the retina via melanopsin-containing ganglion cells. The study aimed to investigate whether induced hyperammonaemia affects the pupillary light response and sleep efficiency in patients with cirrhosis. Methods The study was a single-blinded crossover trial including nine patients with cirrhosis. Sleep was evaluated by Pittsburgh Sleep Quality Index (PSQI) and monitored for twelve nights with wrist accelerometers and sleep diaries. On two experimental days, separated by one week, patients were randomized to ingest either an oral amino acid challenge (AAC) or an isocaloric glucose solution (GS). We measured pupillary light response, capillary ammonia, the Karolinska Sleepiness Scale (KSS), and two neuropsychological tests on both experimental days. Results The patients had poor self-assessed sleep quality. The amino acid challenge led to a significant increase in capillary ammonia and KSS. The time spent in bed sleeping after AAC was longer and with a reduced movement index compared to baseline but not different from GS. We found no difference in the pupillary light response or neuropsychiatric tests when comparing the effect of AAC with GS. Conclusions Patients with cirrhosis had impaired sleep quality. Induced hyperammonaemia led to increased sleepiness but had no acute effect on pupillary light response or the neuropsychiatric tests. Trial registration Registration number: NCT04771104.