Photochemical Therapy Research Articles

Regenerative Retinal Laser and Light Therapies (RELITE): Proposal of a New Nomenclature, Categorization, and Trial Reporting Standard.

Numerous laser and light therapies have been developed to induce regenerative processes in the choroid/retinal pigment epithelium (RPE)/photoreceptor complex, leaving the neuroretina undamaged. These therapies are applied to the macula for the treatment of various diseases, most prominently diabetic maculopathy, retinal vein occlusion, central serous chorioretinopathy, and age-related macular degeneration. However, the abundance of technologies, treatment patterns, and dosimetry protocols has made understanding these therapies and comparing different approaches increasingly complex and challenging. To address this, we propose a new nomenclature system with a clear categorization that will allow for better understanding and comparability between different laser and light modalities. We propose this nomenclature system as an open standard that may be adapted in future toward new technical developments or medical advancements. A systematic literature review of reported macular laser and light therapies was conducted. A categorization into a standardized system was proposed and discussed among experts and professionals in the field. This paper does not aim to assess, compare, or evaluate the efficacy of different laser or dosimetry techniques or treatment patterns. The literature search yielded 194 papers describing laser techniques, 50 studies describing dosimetry, 272 studies with relevant clinical trials, and 82 reviews. Following the common therapeutic aim, we propose "regenerative retinal laser and light therapies (RELITE)" as the general header. We subdivided RELITE into four main categories that refer to the intended physical and biochemical effects of temperature increase (photothermal therapy, PTT), RPE regeneration (photomicrodisruption therapy, PMT), photochemical processes (photochemical therapy, PCT), and photobiomodulation (photobiomodulation therapy, PBT). Further, we categorized the different dosimetry approaches and treatment regimens. We propose the following nomenclature system that integrates the most important parameters to enable understanding and comparability: Pattern-Dosimetry-Exposure Time/Frequency, Duty Cycle/Irradiation Diameter/Wavelength-Subcategory-Category. Regenerative retinal laser and light therapies are widely used for different diseases and may become valuable in the future. A precise nomenclature system and strict reporting standards are needed to allow for a better understanding, reproduceable and comparable clinical trials, and overall acceptance. We defined categories for a systematic therapeutic goal-based nomenclature to facilitate future research in this field.

Globus Lucidus: A porcine study of an intracranial implant designed to deliver closed, repetitive photodynamic and photochemical therapy in glioblastoma

ObjectiveHerein we describe initial results in a porcine model of a fully implantable device designed to allow closed, repetitive photodynamic treatment of glioblastoma (GBM). MethodsThis implant, Globus Lucidus, is a transparent quartz glass sphere with light-emitting diodes releasing wavelengths of 630 nm (19.5 mW/cm2), 405 nm (5.0 mW/cm2) or 275 nm (0.9 mW/cm2). 5-aminolevulinic acid was the photosensitizing prodrug chosen for use with Globus Lucidus, hence the implants illuminated at 630 nm or 405 nm. An additional 275 nm wavelength-emittance was included to explore the effects of photochemical therapy (PCT) by ultraviolet (UV) light. Twenty healthy domestic pigs underwent right-frontal craniotomies. The Globus Lucidus device was inserted into a surgically created right-frontal lobe cavity. After postoperative recovery, irradiation for up to 30 min daily for up to 14 d, or continuous irradiation for up to 14.6 h was conducted. ResultsSurgery, implants, and repeated irradiations using the different wavelengths were generally well tolerated. Social behavior, wound healing, body weight, and temperature remained unaffected. Histopathological analyses revealed consistent leukocyte infiltration around the intracerebral implant sites with no significant differences between experimental and control groups. ConclusionThis Globus Lucidus porcine study prepares the groundwork for adjuvant, long-term, repeated PDT of the GBM infiltration zone. This is the first report of a fully implantable PDT/PCT device for the potential treatment of GBM. A preclinical effectivity study of Globus Lucidus PDT/PCT is warranted and in advanced stages of planning.

A systematic review and network meta-analysis of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

Various treatments for acne vulgaris exist, but little is known about their comparative effectiveness in relation to acne severity. To identify best treatments for mild-to-moderate and moderate-to-severe acne, as determined by clinician-assessed morphological features. We undertook a systematic review and network meta-analysis of randomized controlled trials (RCTs) assessing topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, published up to May 2020. Outcomes included percentage change in total lesion count from baseline, treatment discontinuation for any reason, and discontinuation owing to side-effects. Risk of bias was assessed using the Cochrane risk-of-bias tool and bias adjustment models. Effects for treatments with ≥ 50 observations each compared with placebo are reported below. We included 179 RCTs with approximately 35 000 observations across 49 treatment classes. For mild-to-moderate acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with benzoyl peroxide (BPO) [mean difference 26·16%, 95% credible interval (CrI) 16·75-35·36%]; physical - chemical peels, e.g. salicylic or mandelic acid (39·70%, 95% CrI 12·54-66·78%) and photochemical therapy (combined blue/red light) (35·36%, 95% CrI 17·75-53·08%). Oral pharmacological treatments (e.g. antibiotics, hormonal contraceptives) did not appear to be effective after bias adjustment. BPO and topical retinoids were less well tolerated than placebo. For moderate-to-severe acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with lincosamide (clindamycin) (44·43%, 95% CrI 29·20-60·02%); oral pharmacological - isotretinoin of total cumulative dose ≥ 120 mg kg-1 per single course (58·09%, 95% CrI 36·99-79·29%); physical - photodynamic therapy (light therapy enhanced by a photosensitizing chemical) (40·45%, 95% CrI 26·17-54·11%); combined - BPO with topical retinoid and oral tetracycline (43·53%, 95% CrI 29·49-57·70%). Topical retinoids and oral tetracyclines were less well tolerated than placebo. The quality of included RCTs was moderate to very low, with evidence of inconsistency between direct and indirect evidence. Uncertainty in findings was high, in particular for chemical peels, photochemical therapy and photodynamic therapy. However, conclusions were robust to potential bias in the evidence. Topical pharmacological treatment combinations, chemical peels and photochemical therapy were most effective for mild-to-moderate acne. Topical pharmacological treatment combinations, oral antibiotics combined with topical pharmacological treatments, oral isotretinoin and photodynamic therapy were most effective for moderate-to-severe acne. Further research is warranted for chemical peels, photochemical therapy and photodynamic therapy for which evidence was more limited. What is already known about this topic? Acne vulgaris is the eighth most common disease globally. Several topical, oral, physical and combined treatments for acne vulgaris exist. Network meta-analysis (NMA) synthesizes direct and indirect evidence and allows simultaneous inference for all treatments forming an evidence network. Previous NMAs have assessed a limited range of treatments for acne vulgaris and have not evaluated effectiveness of treatments for moderate-to-severe acne. What does this study add? For mild-to-moderate acne, topical treatment combinations, chemical peels, and photochemical therapy (combined blue/red light; blue light) are most effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy (light therapy enhanced by a photosensitizing chemical) are most effective. Based on these findings, along with further clinical and cost-effectiveness considerations, National Institute for Health and Care Excellence (NICE) guidance recommends, as first-line treatments, fixed topical treatment combinations for mild-to-moderate acne and fixed topical treatment combinations, or oral tetracyclines combined with topical treatments, for moderate-to-severe acne.

NIR‐triggered Tandem Photothermal and Photochemical Cancer Therapy Based on Nanoscale MOFs under Hypoxic Conditions

AbstractDue to the limited penetration depth of visible light and insufficient oxygen supply in hypoxic tumor tissues, the development of near‐infrared (NIR) triggered and oxygen‐independent photodynamic therapy (PDT) to generate active radicals is necessary for cancer treatment. Herein, we developed a NIR‐triggered photothermal therapy (PTT) and oxygen‐independent PDT system based on metal‐organic frameworks (MOFs), which integrated indocyanine green (ICG) and 2,2’‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH) as NIR‐triggered photothermal units and temperature‐sensitive free radical initiator into ZIF‐8, respectively. AIPH was introduced into ZIF‐8 via a one‐pot strategy with high loading capacity (125 mg g−1). Through the irradiation of 808 nm laser, the ICG units could efficiently absorb NIR light to rapidly raise the local temperature to 44 °C within 3 minutes. Meanwhile, the local high temperature further induced the AIPH to continuously generate toxic alkyl radicals (R−C⋅). The combination of PTT and free radical therapy is significantly better than the single treatment mode. More importantly, the NIR‐triggered synergistic therapy could induce extensive apoptosis of cancer cells in hypoxic conditions, which sheds new light on the development of MOFs‐based photochemical therapy platform in the actual tumor microenvironment.

β-Cyclodextrin-cholic acid-hyaluronic acid polymer coated Fe3O4-graphene oxide nanohybrids as local chemo-photothermal synergistic agents for enhanced liver tumor therapy

Synergistic photochemical therapy with high performance and weak side effects is of great importance in hepatocellular carcinoma (HCC) treatment, therefore ingenious construct of nano-based therapy agents with accurate drug delivery and high photothermal conversion efficiency is of critical to the cancer therapy. Herein, an organic-inorganic hybrid nanomaterial (MGO@CD-CA-HA) has been constructed successfully by coating the β-cyclodextrin-cholic acid-hyaluronic acid polymer (CD-CA-HA) onto the Fe3O4-graphene oxide (MGO). The MGO@CD-CA-HA revealed satisfactory multiple-targeted features including the cholic acid supplied hepatic-target, CD44-receptor target of hyaluronic acid and magnetic target of Fe3O4. Meanwhile, the hydrophobic antitumor drug camptothecin (CPT) was easily loaded by MGO@CD-CA-HA to form the MGO@CD-CA-HA/CPT nanocomposite, and the maximum theoretical adsorption capacity can reach 847.4 mg/g. Based on the facile photothermal response of MGO, the near-infrared radiation (808 nm) induced local hyperthermia was directly generated the apoptosis of tumor cells while triggered the release of CPT. Comparing with other kinds of cancer cells and normal hepatocyte cells, this PCT system provides a significant inhibitory effect for the liver cancer cells in vitro. Furthermore, the synergistic photochemical therapy presented the strong antitumor effect (the tumor inhibition rate > 90 %) in vivo. Thus, this study provided a promising multiple-targeted nanocarrier for chemo-photothermal combination therapy of liver cancer.

A case report and discussion of Lichen myxedematosus

A case of myxedematous lichen is reported. A 60 years old male presented with pigmentation and pruritus for 2 years, and aggravated for 1 month. He was admitted to Hainan Fifth People's Hospital on March 6, 2019. Two years ago, there was no obvious inducement for the patient to have plaque on his face, which gradually increased, hardened and appeared dark brown pigmentation. With the gradual development of the disease, trunk skin appeared rough, hypertrophy, hardening and pigmentation, hand joints appeared stiff and affected activity. Special examination showed diffuse yellowish brown patches and plaques on the forehead, which were distributed in a grid shape, and scattered with atrophic hypopigmentation spots. Black and brown patches were scattered on the back, partially fused into pieces. Sclerotic and atrophic white plaques can be seen in the neck. The skin of the front chest and back is slightly thickened, and obviously hardened. It can still be pinched up. The skin lesions have no tenderness. The joints of the fingers are stiff and the movement is limited. Skin biopsy: The trochanterellus of epidermis disappeared, fibroblasts were arranged in the whole dermis, and some of them were disordered. Ashen blue staining showed that there were clumps of positive material deposition between collagen fibers and around hair follicles in the whole dermis, which was consistent with lichen myxedematosus (LM). The patient was treated with thalidomide 50 mg 3 times a day, prednisone 30 mg orally and acitretin 10 mg twice a day orally, combined with twice a week photochemical therapy (PUVA), external application of allantoin ointment, desonide cream, Halometasone Cream. On June 10, 2019, the patient's condition gradually became stable when he came to the follow-up visit, so the drug dosage was reduced to prednisone 15 mg once a day and acitretin 10 mg twice a day, once a week for photochemical therapy, and topical plaster continued. On September 8, 2019, the patient's condition was further improved when he came to the follow-up visit, so the patient's oral medication was reduced to acitretin 10 mg/d, and allantoin ointment was applied externally. On December 1, 2019, the patient's condition had improved significantly (the patient refused to take photos). Continued treatment was given to the case. 摘要： 报道1例黏液水肿性苔藓案例。患者男,60岁,因全身皮肤变硬伴色素沉着、瘙痒2年,加重1月,于2019年3 月6日就诊于海南省第五人民医院。患者2年前无明显诱因面部皮肤出现斑块,并逐渐增大、变硬及出现黑褐色色素 沉着。随病情逐渐发展,躯干皮肤出现粗糙,肥厚,变硬及色素沉着,手关节出现僵硬且影响活动。专科检査额部见弥 漫性黄褐色斑片、斑块,呈网格状分布,其上散在萎缩性色素减退斑。背部散在黑褐色斑片,部分融合成片。颈部可见 硬化萎缩性白色斑块。前胸后背皮肤轻度增厚,明显变硬,仍可捏起,皮损无触痛。指关节较僵硬,活动受限。皮肤病 理活检:表皮突变平消失,真皮全层见较多的成纤维细胞排列,部分混乱,阿申蓝染色:真皮全层的胶原纤维间、毛囊周 围见团块状阳性物质沉积,结合临床符合黏液水肿性苔藓（Lichen myxedematosus,LM)。予以沙利度胺50 mg 3次/d,强 的松30 mg顿服及阿维A 10mg2次/d 口服治疗,并结合每周两次的光化学疗法(PUVA),外擦尿囊素软膏、地奈德乳 膏,卤米松乳膏。2019年6月10日患者前来复诊时病情逐渐稳定,遂将药物用量减至强的松15 mg顿服及阿维A 10 mg 2次/d,每周一次光化学疗法,外用膏药继续。2019年9月8日患者前来复诊,病情进一步好转,遂将患者口服药 物减为阿维A 10 mg/d,外擦尿囊素软膏。2019年12月1日患者再次前来复诊,病情已明显好转(患者拒绝拍照）。遂对 该病例临床症状及治疗进行讨论。

Targeted photosensitizer delivery: A prospective approach to vitiligo photochemotherapy

Aim. In this work, the authors set out to develop an effective method for the intrafollicular delivery of “Ammi majus fructuum furocumarines” photosensitizer (AMFF) followed by UVA irradiation (λ = 320–400 nm). Materials and methods. The proposed delivery method consists in using calcium carbonate particles acting as AMFF carriers. In vivo monitoring of hair follicle filling was carried out via optical coherence tomography, as well as by means of analyzing epilated hair using confocal laser scanning microscopy. Following the administration of free and encapsulated AMFF to three healthy volunteers, the character of UVA-induced skin pigmentation was registered under dermatoscopic examination. Results. The obtained results demonstrate a profuse filling of hair follicles with calcium carbonate particles, thus confirming the possibility of intrafollicular photosensitizer delivery. It was established that exposure to UVA irradiation causes intense pigment accumulation in the area of AMFF carrier administration. Conclusion. The proposed method of the targeted photosensitizer delivery allows photochemical therapy to be improved.

PEGylated doxorubicin cloaked nano-graphene oxide for dual-responsive photochemical therapy

Graphene oxide (GO) owns huge surface area and high drug loading capacity for aromatic molecules, such as doxorubicin (DOX). However, its biocompatibility is poor and it might agglomerate in physiological conditions. Chemical modification of GO with hydrophilicpolymer, especially PEGylation, was a common method to improve its biocompatibility. But the chemical modification of GO was complicated, and its drug loading capacity might be reduced because of the occupation of its functional groups. In this study, DOX-PEG polymers with different PEG molecular weights were synthesized to modify nano graphene oxide (NGO) to simultaneously realize the solubilization of NGO and the high loading capacity of DOX. The result showed that the drug release of NGO@DOX-PEG was pH sensitive. NIR irradiation could augment the drug release, cellular uptake, cytotoxicity and nuclear translocation of nanodrugs. Among the three kinds of nanodrugs, NGO@DOX-PEG5K was superior to others. It suggested that after conjugating with PEG, the bond between DOX-PEG and NGO was weakened, which resulted in a better drug release and treatment effect. In summary, the NIR and pH dual-responsive NGO@DOX-PEG nanodrugs were developed by noncovalent modification, and it demonstrated excellent biocompatibility and photochemical therapeutic effect, presenting a promising candidate for antitumor therapy, especially NGO@DOX-PEG5K.

Research progress of topical treatment of oral chronic graft versus host disease: a review

Oral cavity is one of the main organs involved in chronic graft versus host disease (cGVHD). Oral cGVHD seriously affects the patient's quality of life. Topical use of glucocorticoid and other agents is the primary topical treatment of oral cGVHD, oral photochemical therapy and various new methods have also been applied in patients recently. These important adjuvant therapies are based on the systemic use of drugs such as immunosuppressive agents, and sometimes, may be the only effective treatment for oral cGVHD. This review will focus on the application of topical agent treatment and oral photochemotherapy in oral cGVHD patients.

Antibacterial Actions and Potential Phototoxic Effects of Volatile oils of Foeniculum sp. (fennel), Salvia sp. (sage), Vitis sp. (grape), Lavandula sp. (lavender)

In the present study, the volatile compounds of essential oil of Foeniculum vulgare (fennel), Salvia officinalis (sage), Vitis vinifera (grape), Lavandula angustifolia (lavender) were analysed by gas chromatography-mass spectrometry (GC-MS) using the Nist and Willey libraries. It was determined that the main components of Foeniculum sp. were anethole (41.11%), carvacrol (9.18%). whereas main components of Salvia sp were 1.8 cineole (34.09%), caryophyllene (10.95%), camphor (9.44%), α-pinene (8.42%). Vitis sp. contained linoleic acid (36.98%), 2,4-decadienal (30.79%). Finally, volatile component of Lavandula sp. was linalool (33.57%), linalyl acetate (30.74%). Photoxic antibacterial activity of volatile oil of those plants against Escherichia coli (ATCC 25293), Klebsiella pneumoniae (10031), Salmonella thyphimurium, Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 25925), Enterococcus feacalis (ATCC 29212) were examined by using disc diffusion method. We demonstrated that volatile oil effectively can be activated by a standard LED light. In vitro, significant phototoxicity was demonstrated by volatile oil of Foeniculum sp. and Vitis sp. (P < 0.05), while minor phototoxicity was induced by Lavandula sp. Therefore, volatile oil of plant can be considered as a potential photosensitizer in the photochemical therapy.

Photonanomedicine: a convergence of photodynamic therapy and nanotechnology.

As clinical nanomedicine has emerged over the past two decades, phototherapeutic advancements using nanotechnology have also evolved and impacted disease management. Because of unique features attributable to the light activation process of molecules, photonanomedicine (PNM) holds significant promise as a personalized, image-guided therapeutic approach for cancer and non-cancer pathologies. The convergence of advanced photochemical therapies such as photodynamic therapy (PDT) and imaging modalities with sophisticated nanotechnologies is enabling the ongoing evolution of fundamental PNM formulations, such as Visudyne®, into progressive forward-looking platforms that integrate theranostics (therapeutics and diagnostics), molecular selectivity, the spatiotemporally controlled release of synergistic therapeutics, along with regulated, sustained drug dosing. Considering that the envisioned goal of these integrated platforms is proving to be realistic, this review will discuss how PNM has evolved over the years as a preclinical and clinical amalgamation of nanotechnology with PDT. The encouraging investigations that emphasize the potent synergy between photochemistry and nanotherapeutics, in addition to the growing realization of the value of these multi-faceted theranostic nanoplatforms, will assist in driving PNM formulations into mainstream oncological clinical practice as a necessary tool in the medical armamentarium.

Indocyanine Green Derivative Covalently Conjugated with Gold Nanorods for Multimodal Phototherapy of Fibrosarcoma Cells.

A hydrophilic indocyanine green derivative (ICG-Der-02) was covalently doped into mesoporous silica-coated gold nanorods (AuNRs/mSiO2). The self-synthesized derivative offers one carboxyl functional group on a side chain, which enables ICG-Der-02 to be covalently linked to nanomaterials and reduces the probability of leakage/desorption of the dye. The detection of infrared luminescence around 1270 nm confirmed that 102 is efficiently generated by the nanocomposite (AuNRs/mSiO2-ICG-Der-02). Furthermore, a second layer of silica was coated onto the nanocomposite, which then was conjugated with the α(v) integrin-targeting cyclic peptide (RGD-4C). The cell tests showed that the resulting nanoconjugate (AuNRs/mSiO2-ICG-Der-02/RGD-4C) was able to bind preferentially to HT-1080 human fibrosarcoma cells. Due to the synergistic effect of the produced nanoconjugates, a dual-modality photothermal and photochemical therapy was successfully achieved by 808 nm irradiation. Compared to using photothermal or photochemical therapy alone, the dual-modality photothermal/photochemical therapeutic strategy proved to be more damaging to HT-1080 cells and enhanced the effectiveness of photodestruction. Our work presents a novel approach to the multimodal treatment of fibrosarcoma and shows promise for future use in cancer theranostics.

Riboflavin/UVA Photochemical Therapy for Severe Infectious Keratitis

To describe the antibacterial activity of treatment with riboflavin and ultraviolet A light (UVA) in cases of severe infectious keratitis. A retrospective analysis was performed of an interventional case series in which 6 eyes of 6 patients with severe infectious keratitis, all of whom were refractive to multidrug conventional therapy, were treated with riboflavin/UVA. The procedure was conducted according to the standardized protocol of corneal collagen crosslinking (CXL) for keratoconus. Best spectacle-corrected visual acuity and clinical outcomes were evaluated before and during the follow-up period. Five of the 6 patients showed rapid reduction in symptoms and decreased infiltrate size after riboflavin/UVA photochemical therapy. Signs of infection and inflammation mostly resolved within 1 to 2 weeks after the treatment. Despite this therapy, one patient continued to deteriorate, and penetrating keratoplasty was performed. The adjunctive use of riboflavin/UVA photochemical therapy has a positive effect on refractory infectious keratitis. The treatment seems to be safe and effective and should be considered as part of the first-line therapy in severe cases of infectious keratitis.

Inhibitory effect of M007-mediated photodynamic therapy on proliferation of human hepatoma SMMC-7721 cells

Objective To investigate the effect of new photosensitizer M007-mediated photodynamic therapy on human hepatoma SMMC-7721 cells in vitro and proliferation capacity of the residual cells. Methods Subcultured SMMC-7721 human hepatocellular carcinoma cells lines, methylene blue derivatives M007 as the photosensitizer, setting different concentrations of M007-PDT groups （2,4,16 μmol/L）, multi-photo source system illuminates 1 x 106 cells in 630-660 nm wave length for 10 min （luminous power density is 0. 036 W/cm2 ,the light dosage is 2. 16 J/cm2） ,analyzing cell mortality and manner of death by flow cytometry, Methyl thiazol tetrazolium （MTT） test and colony formation assay to assess residual cell proliferation. Results When the M007 concentration in 2,4,16 μmol/L, the cell mortality in M007-PDT groups were （ 68.50±3.33 ） %, （96. 70±2. 63 ） %, （99. 30±0. 30） % respectively; in 2,4 and 6μmol/L M007-PDTgroups, residual cell growth curve is low and flat, and the optical density value is not increased with the incubation time （P 〉 0.05 ） ,4,16μmol/L M007-PDT groups failed to form a colony, but 2μmol/L M007- PDT group had a few colony formation occasionally. Conclusion M007 doses in 4,16 μmol/L,M007 mediated photodynamic therapy on SMMC-7721 cell line has the exactly inactivated effect, and the residual cells lost long-term proliferative capacity in vitro. Key words: Carcinoma, hepatocellular; Photochemical therapy; Proliferation

UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study

The aim of this work as to investigate the photochemical interaction used in corneal crosslinking (CXL) as the primary therapy for bacterial keratitis. A prospective non-randomized study was conducted including 16 patients with a clinical diagnosis of bacterial keratitis. No patient had any prior antibiotic treatment for the current infection. Photography and microbial culturing of the infected cornea were performed. Riboflavin was topically administered for 20 min and ultraviolet light (UVA) exposure settings for treatment of keratoconus were used. After the procedure, clinical examinations were done at least once daily until signs of improvement had been established. The frequency of examinations was thereafter reduced. Antibiotic therapy was initiated if infectious progression was suspected. The trial was registered at ISCRTN.org (no: 21432643). All eyes responded to the photochemical treatment with improvement in symptoms and signs of reduced inflammation. Epithelial healing was achieved in all cases. Antibiotic administration was necessary in two cases. One patient required a human amniotic membrane transplant. This trial illustrates that photosensitization of riboflavin using UVA at 365 nm has the potential to induce healing in patients with microbial keratitis. The results from the treatment of these 16 patients with corneal ulcers indicate that UVA-riboflavin photochemical therapy merits a controlled study in order to assess its efficacy and safety compared to antibiotics.

The family of furocoumarins: Looking for the best photosensitizer for phototherapy

Furocoumarins are widely used as photosensitizers in photochemical therapies against different skin disorders such as psoriasis and vitiligo. Absorption of near-UV light by the chromophore triggers a set of photoreactions related to the therapeutic properties of the technique: linkage of a furocoumarin to thymine DNA nucleobases preventing proliferation of pathogenic cells, or generation of highly reactive singlet oxygen in damaged tissues. The family of furocoumarins has been studied in depth for many years seeking a drug having the most remarkable set of properties to act as a photosensitizer. For this purpose, understanding the underlying photochemical mechanisms behind the effectiveness of this therapy is required. We have undertaken a quantum-mechanical study on the photophysics and photochemistry of several relevant furocoumarins: psoralen, 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen (5-MOP), 4,5′,8-trimethylpsoralen (TMP), 3-carbethoxypsoralen (3-CPS), and khellin, analyzing the most efficient way in which the lowest excited triplet state, as protagonist of the photosensitizing action, is populated from the initially promoted singlet states. The results point out to khellin, in particular, and 5-MOP, as the most efficient photosensitizers.

Multilineage engraftment with minimal graft-versus-host disease following in utero transplantation of S-59 psoralen/ultraviolet a light-treated, sensitized T cells and adult T cell-depleted bone marrow in fetal mice.

Although engraftment following in utero stem cell transplantation can readily be achieved, a major limitation is the low level of donor chimerism. We hypothesized that a lack of space for donor cells in the recipient marrow was one of the primary reasons for failure to achieve significant engraftment, and that donor T cells could make space in an allogeneic mismatched setting. We found that 3 x 10(5) C57BL/6 (B6) naive CD3(+) cells coinjected with B6 T cell-depleted bone marrow (TCDBM) into 14- to 15-day-old BALB/c fetuses resulted in multilineage engraftment (median, 68.3%) associated with severe graft-vs-host disease (GvHD; 62 vs 0% with TCDBM alone). When 1.5 x 10(5) CD4(+) or CD8(+) cells were used, low levels of engraftment were seen vs recipients of 1.5 x 10(5) CD3(+) cells (2.4 +/- 1.1 and 6.6 +/- 3.9 vs 20.4 +/- 10.4%, respectively). To test the hypothesis that proliferation of T cells in response to alloantigen resulted in GvHD and increased engraftment, we pretreated naive T cells with photochemical therapy (PCT) using S-59 psoralen and UVA light to prevent proliferation. GvHD was reduced (60-0%), but was also associated with a significant reduction in engrafted donor cells (53.4 +/- 4.2 to 1.7 +/- 0.5%). However, when B6 T cells were sensitized to BALB/c splenocytes, treated with PCT, and coinjected with TCDBM, there was a partial restoration of engraftment (13.3 +/- 2.4% H2Kb(+) cells) with only one of nine animals developing mild to moderate GvHD. In this study we have shown that PCT-treated T cells that are cytotoxic but nonproliferative can provide an engraftment advantage to donor cells, presumably by destroying host hemopoietic cells without causing GvHD.

Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer

Endoscopic laser treatment was initially applied for gastrointestinal bleeding, but has been actively extended, especially in Japan, to the curative treatment of early upper gastrointestinal cancers. We have treated 10 cases of early gastric cancer and 1 case of early esophageal cancer by Nd-YAG laser radiation, and 2 cases of early gastric cancer by photochemical therapy (PCT) with argon laser + hematoporphyrin derivative. Also, 62 cases of advanced cancer were treated, 10 of the esophagus and 52 of the stomach, for bleeding (18 cases) or stenosis (34 cases). The cases were nonresectable or they were patients who refused surgery. Satisfactory results were obtained by treatment with YAG laser, but have not yet been obtained with PCT. In order to find indications for the possible extension of endoscopic laser therapy to operable cases of early gastric cancer, we studied lymph node metastases in 200 cases of early gastric cancer surgically treated by us. It was found that early gastric cancers (both mucosal and submucosal) measuring less than 2 cm in diameter, of type I, IIa, and IIc (without ulcer scar), had no lymph node metastases and such cases can be treated by local therapy--such as endoscopic laser therapy. In palliative endoscopic laser therapy for complications of advanced gastrointestinal cancers, there are no major problems with active performance. We obtained a high (90%) hemostatic rate in bleeding cases of upper gastrointestinal cancer and a satisfactory (65%) rate of dilating effect in cases of cancerous stenosis at the esophagus and cardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Synergistic Effect of Photochemical Donor Pretreatment and Cyclosporin Therapy of the Recipient on Rat Renal Allograft Survival

Dose-response studies of cyclosporin (CsA) established that doses of 2 mg/kg body weight on 4 consecutive days (0-3) or higher gave complete suppression of rejection and permanent survival of all rat kidney allografts, while a dose of 2 mg/kg body weight on day 0 was much less effective in preventing deleterious rejection (30% permanent survival). Photochemical pretreatment of the kidney donor with 8-methoxypsoralen (8-MOP) and direct long-wave ultraviolet irradiation (UVA) of the kidney (PUVA) therapy) significantly prolonged the subsequent graft survival in allogeneic recipients. Forty per cent of the animals survived more than 100 days. However, when PUVA-treated kidney allografts were transplanted into temporary CsA immunosuppressed recipients (2 mg/kg on day 0) the graft survival rate was further improved. Seventy per cent of the PUVA + CsA-treated recipients survived permanently. Therefore, a synergistic effect of PUVA pretreatment and low-dose CsA therapy on rat renal allograft survival was demonstrated. The results suggested a possible clinical application of this treatment regimen in order to avoid high nephrotoxic CsA doses.

Hematoporphyrinオリゴマーの光化学的性質

Hematoporphyrin derivatives (HpD) and photofrin II have been studied extensively for photochemical therapy. Recently newly prepared porphyrin oligomer (average molecular weight, 3000) were measured and compared with those of HpDs. As the fluorescence intensity of the porphyrin oligomer was very small in aqueous solution, the porphyrin oligomer may be coagulated. In micellar solution and in the tumor cell, however the fluorescence intensity increased sharply and was easily detected. Triplet life time of the porphyrin oligomer was longer than HpDs. The porphyrin oligomer seems to be suitable for photochemical therapy.