不可切除胆管癌PDT治疗的进展

胆管癌是一种少见的原发性胆道恶性肿瘤,预后较差,根治性切除仅适用于少部份早期确诊的患者,大部份失去手术机会的患者采取胆道引流的姑息治疗方式治疗。胆道缓解引流是一种采用经皮或内镜插入的内镜置管术,可减轻患者骚痒、胆管炎和疼痛等症状,提高患者生活质量,但是仅有少量文献报道胆道缓解引流可提高胆管癌患者的生存时间。光动力疗法（photodynamic therapy,PDT）是一种相对新的、局部的、微创的姑息治疗方法,PDT是通过能聚集在增生组织（或肿瘤）中的光敏剂分子,是治疗不可手术切除胆管癌的标准的辅助治疗方式。     

儿童喉乳头状瘤光动力治疗的麻醉管理

目的 总结局部给药光动力疗法治疗儿童喉乳头状瘤的麻醉管理,为临床麻醉提供经验。方法 对45例行支撑喉镜下局部给药光动力疗法治疗喉乳头状瘤的患儿,采用静吸复合气管插管全身麻醉联合间断通气技术,记录入室（T0）、插管后5 min(T1)、置入支撑喉镜后5 min(T2)、敷药后5 min(T3)、照射后5 min(T4)、拔管后5 min(T5)的HR、MAP、SpO2、EtCO2,并统计手术时间、麻醉时间、苏醒时间及并发症。结果 所有患儿均顺利完成麻醉及手术治疗。手术时间为（235.9±32.7） min,麻醉时间为（260.3±36.1） min,拔管时间为（6.7±5.2） min。与T0相比,T3、T4的HR、MAP均降低,T5的SpO2降低,P<0.05,差异有统计学意义。术中EtCO2值维持在30~40 mmHg。术后1 d疼痛视觉模拟评分（VAS）为1~2分。术后57%（26例）患儿口咽分泌物明显增多。1例患儿拔管后10 min出现气道水肿呼吸困难再次插管后入住ICU。1例气管切开患儿术中间断通气反复插管出现瘤体脱落阻塞气道,迅速夹出瘤体后缓解。结论 气管插管联合间断通气技术可安全、有效用于局部给药光动力疗法治疗儿童喉乳头状瘤。     

Quality of life following photodynamic therapy for head and neck pathologies: An exploratory study

IntroductionHealthcare related quality of life (QoL) is defined as the impact one's level of health and wellbeing has on a number of domains, including physical, mental, spiritual and social functions. Photodynamic therapy (PDT), a cancer treatment modality, is increasingly used to treat or palliate head and neck pathologies. Due to the complex nature of this area of the body, both the pathology and the treatment of it can severely affect the quality of life. Thus far, no questionnaire has been developed which focuses on quality-of-life post-PDT of head and neck pathologies.Patients and methodsWe have developed the University College London Quality of Life Questionnaire for Patients undergoing PDT in the Head and Neck, using meta-tetra(hydroxyphenyl)chlorin (mTHPC) as the photosensitiser. This was modified from the University of Washington quality of life (UW-QOL) questionnaire. Thirty-eight patients who received mTHPC-PDT for various head and neck pathologies completed the questionnaire, with a mean follow-up of 56 days.ResultsAll patients reported improved QoL following mTHPC-PDT. The main problem that was reported was post-PDT pain, which is a common side effect. Visual symptoms, breathing, speaking and swallowing problems improved significantly in the 4th week following treatment and significant improvement in activities of daily living, social life, mood and anxiety were reported in the subsequent weeks.ConclusionsmTHPC-PDT confers improvement in QoL score in selected head and neck cancer patients with figures comparable to other treatment modalities. This exploratory study demonstrated patterns of QoL outcome. Further work needs to be done for survey validation and inclusion of a larger cohort which will allow optimal sub-group analysis and help guide further interventions.     

Treatment of unresectable extrahepatic cholangiocarcinoma using hematoporphyrin photodynamic therapy: A prospective study

BackgroundThe available evidence of Photodynamic therapy (PDT) combined with stent placement treatment for unresectable extrahepatic cholangiocarcinoma (EHCC) is still insufficient. It also remains unclear whether PDT influences systemic inflammatory response.AimTo explore the clinical efficacy and safety of the combination treatment and the systemic inflammatory response in patients with EHCC.MethodsPatients with unresectable EHCC underwent either the combined treatment using Hematoporphyrin PDT and stent placement (PDT + stent group, n = 12) or stent-only (stent group, n = 27). The primary end-point was overall survival. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured. Quality of life was assessed using the Karnofsky performance scale (KPS) every 3 months.ResultsAverage survival time (13.8 vs. 9.6 months), and 6-month (91.7% vs. 74.1%), and 1-year (58.3% vs. 3.7%) survival rates of PDT + stent group were significantly increased compared with the stent group. KPS scores in the PDT + stent group were significantly improved. TNF-α and IL-6 levels were significantly increased in the PDT + stent group.ConclusionHematoporphyrin-PDT combined with stent placement is an effective and safe treatment for EHCC. The treatment might promote systemic inflammatory response.     

Antimicrobial photodynamic therapy in endodontic reintervention: A systematic review and meta-analysis

BackgroundTo evaluate the effectiveness of the use of antimicrobial photodynamic therapy (aPDT) in root canals disinfection in cases of endodontic retreatments.MethodsThis Systematic Review was registered in PROSPERO (CRD42021260013) and followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Searches were performed in the electronic databases PubMeb, Scopus, Web of Science, Embase, Web of Science, Clinical Trials and Cochrane Library. Methodological quality and risk of bias were assessed by the Cochrane Risk of Bias tool for randomized clinical trials (RCT) and by the Newcastle-Ottawa (NOS) qualifier for non-RCT (prospective) studies. Meta-analysis was performed using R software, version 3.6.3 with the “META” package assistant by the RStudio platform. The odds ratio (OR) measure of effect was calculated and the random effect model was applied with a 95% confidence interval, and heterogeneity tested by the I2 index. The certainty of evidence was rated using GRADE.ResultsRegarding the 1513 studies screened, 10 met the eligibility criteria and were included, and 8 used in the quantitative synthesis. Meta-analysis showed that all of studies data presented a significant difference before and after of antimicrobial photodynamic therapy in the microbial load reduction in secondary endondontic infections (OR 0.15 [0.07; 0.32], p < 0.0001). Overall, the studies had a low risk of bias and, the analysis of evidence by GRADE assessment was rated as moderate.ConclusionIt is suggested that aPDT is a beneficial and promising tool, showing efficacy in reducing the microbial load in cases of endodontic retreatment.     

5-Aminolevulinic acid-based photodynamic therapy of chordoma: In vitro experiments on a human tumor cell line

BackgroundChordomas are very rare tumors of the skull base and the sacrum. They show infiltrating and destructive growth and are known to be chemo- and radio-resistant. After surgical resection, the recurrence rate is high and overall survival limited. As current adjuvant treatments are ineffective, new treatment concepts are urgently needed. 5-aminolevulinic acid-based photodynamic therapy (5-ALA based PDT) showed promising results for malignant gliomas. However, it is unknown so far, whether chordomas accumulate protoporphyrin IX (PPIX) after application of 5-ALA and whether they are sensitive to subsequent 5-ALA based PDT.MethodsThe immortalized human chordoma cells U-CH2 were used as in vitro model. After incubation for 4 h or 6 h with different 5-ALA concentrations, PPIX accumulation was determined by flow cytometry. To assess sensitivity to PDT, chordoma cells were incubated at 30.000 cells/well (high cell density) or 15.000 cells/well (low cell density) with graded doses of 5-ALA (0–50 μg/ml) in 96-well plates and subsequently exposed to laser light of 635 nm wavelength (18.75 J/cm²). Cell survival was measured 24 h after exposure to laser light using the WST-1 assay.ResultsU-CH2 cells dose-dependently accumulated PPIX (ANOVA; p < 0.0001). PPIX fluorescence was significantly higher, when cells were incubated with 5-ALA for 6 h compared to 4 h at higher 5-ALA concentrations (ANOVA/Bonferroni; p ≤ 0.05 for ≥ 30 μg/ml 5-ALA). For both cell densities, a 5-ALA dose-dependent decline in viability was observed (ANOVA; p < 0.0001). Viability was significantly lower at higher 5-ALA concentrations, when 30.000 cells/wells were treated compared to 15.000 cells/well (ANOVA/Bonferroni; p ≤ 0.001 for ≥ 30 μg/ml 5-ALA). LD50 was 30.25 μg/ml 5-ALA.ConclusionThe human UCH-2 cell line was a very useful in vitro model to study different effects of 5-ALA based PDT. For the first time, it could be shown that human chordoma cells may be destroyed by 5-ALA/PDT.     

PARP inhibitors diminish DNA damage repair for the enhancement of tumor photodynamic therapy

Pancreatic cancer is a lethal malignancy and only around 4% of patients will live 5 years post-diagnosis. Photodynamic therapy (PDT) is a promising strategy for treating malignant tumors because of its high selectivity. Through the colocalization of light, oxygen and photosensitizer, a large number of reactive oxygen species (ROS) are generated under excitation at a specific wavelength of a laser, which can induce DNA damage and destroy cancer cells. However, the repair mechanism of cell will repair part of the damaged DNA, which could reduce the efficiency of PDT. The poly (ADP-Ribose) polymerase (PARP) plays a wide and multifaceted role in the cellular response to DNA damage, with growing evidence for participation in multiple pathways of DNA damage repair and genome maintenance. Cells require PARP to resolve single-strand DNA breaks (SSBs) induced by chemotherapy agents. Its inhibition is thought to result in the accumulation of damage in DNA, which may eventually lead to cell death. The combination therapy of PDT and PARP inhibitors may benefit patients. In this study, we design and synthesize a zeolitic imidazolate framework-8 (ZIF-8) to co-deliver DNA damaging agent Chlorin e6 (Ce6) and PARP inhibitor Olaparib (Ola). Ce6 and Ola demonstrate strong synergistic actions, providing a novel approach for the treatment of pancreatic cancer.     

Photodynamic therapy in cholangiocarcinoma: an overview

Cholangiocarcinoma is a challenge to manage; mortality rate is nearly as high as the incidence. Unless curative resection is performed, these tumours are rapidly fatal because they respond poorly to current therapies. Symptoms occur late in cholangiocarcinoma and curative resection can be performed in less than half of the patients. In non-resectable disease, endoprostheses insertion can relieve jaundice and improve quality of life, provided that tumour extension does not lead to diffuse intrahepatic stenoses of ductal system. However, tumour growth cannot be influenced and therefore, prognosis remains dismal. Despite the fact, that radiotherapy and chemotherapy could reduce tumour volume and growth, no survival advantage has yet been shown.Photodynamic therapy has been evaluated as an new additional, palliative option. A randomised trial comparing photodynamic therapy plus endoprostheses insertion versus endoprostheses insertion alone, indicates a considerably benefit on survival time, cholestasis and quality of life in large, advanced cholangiocarcinoma. Furthermore, few specific side effects occurred. Since photodynamic therapy is the first approach leading to an improvement of prognosis, it should be offered to patients with non-resectable cholangiocarcinoma.     

In vitro assessment of anti-tumorigenic mechanisms and efficacy of NanoALA,a nanoformulation of aminolevulic acid designed for photodynamic therapy of cancer

BackgroundThe development of nanocarriers is an important approach to increase the bioavailability of hydrophilic drugs in target cells. In this work, we evaluated the anti-tumorigenic mechanisms and efficacy of NanoALA, a novel nanoformulation of aminolevulic acid (ALA) based on poly(lactide-co-glycolide) (PLGA) nanocapsules designed for anticancer photodynamic therapy (PDT).MethodsFor this purpose, physicochemical characterization, prodrug incorporation kinetics, biocompatibility and photocytotoxicity tests, analysis of the cell death type and mitochondrial function, measurement of the intracellular reactive oxygen species production and DNA fragmentation were performed in murine mammary carcinoma (4T1) cells.ResultsNanoALA formulation, stable over a period of 90 days following synthesis, presented hydrodynamic diameter of 220 ± 8.7 nm, zeta potential of −30.6 mV and low value of polydispersity index (0.28). The biological assays indicated that the nanostructured product promotes greater ALA uptake by 4T1 cells and consequently more cytotoxicity in the PDT process. For the first time in the scientific literature, there is a therapeutic efficacy report of approximately 80%, after only 1 h of incubation with 100 μg mL⁻¹ prodrug (0.6 mM ALA equivalent). The mitochondria are probably the initial target of treatment, culminating in energy metabolism disorders and cell death by apoptosis.ConclusionsNanoALA emerges as a promising strategy for anticancer PDT. Besides being effective against a highly aggressive tumor cell line, the treatment may be economically advantageous because it allows a reduction in the dose and frequency of application compared to free ALA.     

Antimicrobial photodynamic effect of phenothiazinic photosensitizers in formulations with ethanol on Pseudomonas aeruginosa biofilms

Background dataMethylene blue (MB) and toluidine blue (TB) are recognized as safe photosensitizers (Ps) for use in humans. The clinical effectiveness of the antimicrobial photodynamic therapy with MB and TB needs to be optimized, and ethanol can increase their antimicrobial effect. Formulations of MB and TB containing ethanol were evaluated for their ability to produce singlet oxygen and their antibacterial effect on Pseudomonas aeruginosa biofilms.MethodsPhotoactivated formulations were prepared by diluting the Ps (250 μM) in buffered water (pH 5.6, sodium acetate/acetic acid), 10% ethanol (buffer: ethanol, 90:10), or 20% ethanol (buffer: ethanol, 80:20). Biofilms also were exposed to the buffer, 10% ethanol, or 20% ethanol without photoactivation. Untreated biofilm was considered the control group. The production of singlet oxygen in the formulations was measured based on the photo-oxidation of 1,3-diphenylisobenzofuran. The photo-oxidation and CFU (log₁₀) data were evaluated by two-way ANOVA and post-hoc Tukey’s tests.ResultsIn all the formulations, compared to TB, MB showed higher production of singlet oxygen. In the absence of photoactivation, neither the buffer nor the 10% ethanol solution showed any antimicrobial effect, while the 20% ethanol solution significantly reduced bacterial viability (P = 0.009). With photoactivation, only the formulations containing MB and both 10% and 20% ethanol solutions significantly reduced the viability of P. aeruginosa biofilms when compared with the control.ConclusionsMB formulations containing ethanol enhanced the antimicrobial effect of the photodynamic therapy against P. aeruginosa biofilms in vitro.     

Gonarthritis photodynamic therapy with chlorin e6 derivatives

BackgroundThe new methods of osteoarthritis treatment are in constant demand due to the complexity of the early diagnosis and therapy. Specific features of Сhlorin e6 derivative (Ce6) accumulation in knee joint tissues and the efficiency of photodynamic therapy (PDT) of gonarthritis were studied.MethodsThe experimental research was conducted on the model of posttraumatic gonarthritis on rabbits. The analysis of dynamics of change of Ce6 concentration in tissues of a knee joint was carried out by the method of fluorescent diagnostics. The intra-joint PDT was carried out using 662 nm laser with energy density of 120–150 J/cm² and a sapphire diffuser. An analysis of slices was conducted to confirm the anti-inflammatory effect through apoptosis.ResultsThe method of fluorescent spectroscopy revealed that the highest amount of Ce6 was accumulated in the synovial membrane of a damaged knee joint 2.5 h after its intravenous introduction. On 14th day after gonarthritis modeling but before PDT the synovial membrane showed signs of synovitis. On 21st day after PDT the synovial membrane possessed noticeable villous structure, and no cells of inflammatory nature were observed.ConclusionFluorescent diagnostics in knee joint tissues can be used in clinical practice of gonarthritis before, during and after PDT for monitoring the Ce6 accumulation and for treatment control. Optimal radiation energy density was determined to be 150 J/cm². In the studied time intervals (5–25 min) no dependency of PDT effect on irradiation time at the same energy density was observed. The analysis of results of clinical and morphological research shows that PDT is a low-invasive method of gonarthritis treatment with a high degree of efficiency and selectivity.     

Photo-activated elimination of Aggregatibacter actinomycetemcomitans in planktonic culture: Comparison of photodynamic therapy versus photothermal therapy method

BackgroundPeriodontal pathogens are the main factors responsible for periodontal diseases and considering the limitations of conventional mechanical debridement, new treatment approaches are under investigation. This study was designed to evaluate and compare the antibacterial effects of two different systems of photodynamic and photothermal therapy on Aggregatibacter actinomycetemcomitans as the main pathogen involved in aggressive Periodontitis.MethodsCultures of Aggregatibacter actinomycetemcomitans were exposed to 662 nm laser in presence of Radachlorin^® photosensitizer (photodynamic group) or 810 nm laser in presence of EmunDo^® photosensitizer (photothermal group), then bacterial suspension of each well in the study groups were diluted and subcultured on the surface of Muller-Hinton agar plates. subsequently the number of colony forming units per milliliter of the wells were determined and checked by analysis of variance and Tukey test (p < 0.05).ResultsAggregatibacter actinomycetemcomitans suspensions showed significant reduction in both groups of photodynamic and photothermal therapy with no priority.ConclusionBased on the results of this study, photodynamic and photothermal therapy can be proposed as a new promising approaches for bacterial elimination in periodontal diseases.     

Endoscopic photodynamic therapy for oesophageal disease

Photodynamic therapy is a very important technique for the eradication of widespread oesophageal mucosal disease which has the potential to degenerate to cancer. Patients unsuitable or unwilling to undergo radical therapy can be cured using photodynamic therapy. We predominantly treat patients with high-grade dysplasia in Barrett's oesophagus. Lesions that are visible macroscopically are removed using endoscopic mucosal resection. The remaining area is then treated in 5 cm segments at 3 monthly intervals with separate photosensitisation using endoscopic photodynamic therapy.     

Photodynamic therapy (PDT) of lung cancer: experience of the Tokyo Medical University

Endoscopic low (Photodynamic therapy (PDT)) or high (vaporization) power laser treatment has been recognized as a lung-sparing local therapeutic modality that can achieve remarkable responses. This paper reviews the experience of our institution since 1978 in the treatment of lung cancer using laser. Endoscopic ablation of tracheobronchial malignancies is mainly intended to reduce respiratory distress and improve quality of life. Effective results were obtained in 143 (81%) of the 177 lesions. PDT is extremely attractive and has been used for the various purposes. In the curative PDT for centrally located early stage lung cancer, complete response (CR) rate was achieved in 86.4% (165 out of 191 lesions). Overall 5-year survival rate was 57.6% and the lung cancer specific 5-year survival rate was 92.5%. With regard to palliative PDT to opening obstructed bronchi in advanced cases, more than 50% opening of the obstruction was accomplished in 75%. Preoperative PDT was performed in 32 patients with lung cancer for the purpose of either reducing the extent of resection or increasing operability. The initial purpose of PDT was achieved in 27 of 32 patients treated. Conversion to an operable condition was achieved in 4 of 5 originally inoperable cases. In 23 of 27 patients who were originally candidates for pneumonectomy, it became possible to reduce the extent of resection to lobectomy or sleeve lobectomy. PDT could be used to treat peripheral tiny lung cancers safely and without unacceptable effects on surrounding tissue. The authors believe that PDT has a great potential and will achieve further development in the future.     

Effect of 5-aminolevulinic acid photodynamic therapy on Candida albicans biofilms: An in vitro study

BackgroundIn this study, the photoinactivation of 5-aminolevulinic acid (ALA) has been investigated on Candida albicans biofilms in vitro.MethodsAfter culture and proliferation of Candida albicans biofilms in vitro, the metabolic activity was confirmed using XTT reduction assay. Then, the suitable incubation time and concentration of ALA were determined by measuring PpIX accumulation quantities. Photosensitivity of the biofilms treated with ALA solution was studied in optical doses of 50, 100, 200 and 300 J/cm² while light irradiation was applied by a red light semiconductor. Finally, rapid immunofluorescence staining method using the LIVE/DEAD FungaLight Yeast Viability Kit and XTT assay were conducted to visualize and quantify the antifungal effect of ALA-PDT on Candida albicans biofilms.ResultsA 5 h incubation time and 15 mM ALA concentration were determined for this study. Photoinactivation of ALA-PDT on Candida albicans biofilms showed a significant increase of protoporphyrin IX (PpIX) in the biofilms. The metabolic activity of Candida albicans biofilms tread with ALA-PDT confirmed the inhibition efficacy compared with control groups. Upon radiation at 300 J/cm², cells in Candida albicans biofilms were 74.45% inhibited.ConclusionsPpIX can be absorbed in biofilm-grown Candida albicans in vitro and under appropriate parameters, photochemistry can be triggered by light in combination with ALA and inhibits Candida albicans biofilms effectively.     

Barrett's oesophagus and photodynamic therapy (PDT)

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma. This cancer has the fastest growing incidence of any solid tumour in the Western world. Surveillance of Barrett's oesophagus is routinely undertaken to detect early malignant transformation. However, ablative endoscopic treatments are available and these can obliterate the abnormal epithelium, allowing neo-squamous re-growth. Photodynamic therapy (PDT) using haematoporphyrin derivative (HpD)/porfimer sodium (Photofrin^®), m-tetrahydroxyphenyl chlorin (mTHPC) and 5-aminolaevulinic acid (ALA) utilise such a technique. In this non-thermal method of ablation, the photosensitisers, together with light and oxygen, produce local tissue destruction. The use of PDT ablation of Barrett's oesophagus is reviewed.     

Skin fluorescence following photodynamic therapy with NPe6 photosensitizer

BackgroundThe second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period.MethodsThe NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10 min after NPe6 administration as well as at the time of PDT (4–5 h after administration), at discharge (2 or 3 days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT.ResultsNine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2–3 days after administration) in most cases and it decreased at 1 or 2 weeks after PDT.ConclusionsThe fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT.