Photodynamic therapy of gynecologic neoplasms after presensitization with hematoporphyrin derivative

Five patients with various gynecologic neoplasms were treated with photodynamic therapy using 630-nm light delivered from an argon dye laser system following the intravenous injection of hematoporphyrin derivative (HpD). A patient with multifocal squamous cell cancer of the vagina had no evidence of disease 15 months after her first photodynamic therapy treatment. Autopsy nine months after the first treatment of another patient with multifocal invasive cancer of the vagina and parametrium showed no evidence of tumor on the surface of the vagina. Eight months after treatment of an 8 X 12 cm area of Bowen's disease of the vulva and thigh, there was no evidence of disease. Vaginal bleeding from breast cancer metastatic to the endometrium was controlled by one treatment until the patient expired five months later from her disease. Adenocarcinoma metastatic to the vaginal cuff showed partial response when vaginectomy was performed five weeks after photodynamic therapy.     

Photodynamic therapy for superficial bladder cancer

In photodynamic therapy, a photosensitizing drug is activated by visible light and in the presence of oxygen, results in local cell death. This evolving modality is now being used to treat and palliate a very wide variety of human solid tumors and carcinoma-in-situ lesions. With regard to bladder cancer, advances in drug development and modern light delivery techniques mean that photodynamic therapy shows promise in the treatment of superficial bladder cancer resistant to conventional treatments.     

Medical and surgical approaches to vulvar intraepithelial neoplasia

Vulvar intraepithelial neoplasia (VIN) is a precursor to invasive vulvar carcinoma. The two major types of VIN, usual and differentiated, differ in epidemiology, pathogenesis, clinical manifestations, pathology, and malignant potential. Usual VIN commonly occurs in younger women. It is associated with human papillomavirus and tends to have multifocal and multicentric involvement. Differentiated VIN is frequently associated with benign vulvar dermatoses such as lichen sclerosus and lichen simplex chronicus. It occurs in older women and typically is unifocal and unicentric. Clinicians must have a high suspicion for VIN, which is diagnosed by biopsy. Surgical excision has been the standard treatment in order to prevent progression to invasive disease. The objectives of treatment have expanded to include preservation of normal vulvar function and anatomy. Therefore, management options are being investigated, including topical therapy, laser excision and vaporization, and photodynamic therapy. All can be effective in both eliminating disease and maintaining relatively normal‐appearing and functioning anatomy.     

Dye Sensitizers for Photodynamic Therapy

Photofrin^® was first approved in the 1990s as a sensitizer for use in treating cancer via photodynamic therapy (PDT). Since then a wide variety of dye sensitizers have been developed and a few have been approved for PDT treatment of skin and organ cancers and skin diseases such as acne vulgaris. Porphyrinoid derivatives and precursors have been the most successful in producing requisite singlet oxygen, with Photofrin^® still remaining the most efficient sensitizer (quantum yield = 0.89) and having broad food and drug administration (FDA) approval for treatment of multiple cancer types. Other porphyrinoid compounds that have received approval from US FDA and regulatory authorities in other countries include benzoporphyrin derivative monoacid ring A (BPD-MA), meta-tetra(hydroxyphenyl)chlorin (m-THPC), N-aspartyl chlorin e6 (NPe6), and precursors to endogenous protoporphyrin IX (PpIX): 1,5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), hexaminolevulinate (HAL). Although no non-porphyrin sensitizer has been approved for PDT applications, a small number of anthraquinone, phenothiazine, xanthene, cyanine, and curcuminoid sensitizers are under consideration and some are being evaluated in clinical trials. This review focuses on the nature of PDT, dye sensitizers that have been approved for use in PDT, and compounds that have entered or completed clinical trials as PDT sensitizers.     

Non‐invasive management of non‐melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy

Background Patients with genodermatosis such as Gorlin syndrome (GS) and Xeroderma pigmentosum (XP) require a close follow‐up for early diagnosis and treatment of skin cancer. We aimed to evaluate the efficacy of methyl‐aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with GS and XP, and to determine the utility of reflectance confocal microscopy (RCM) in the diagnosis and the evaluation of therapeutic response. Patients and methods We included four patients with GS and two siblings with XP. Single or multiple lesions in localized areas were treated with 1–3 cycles of MAL PDT. RCM was performed before and 3 months after the treatment in target lesions in all the patients. Patients were followed up for 3 years. Results In XP patients, we treated 13 pigmented BCCs on the face. All the lesions responded to the treatment and six lesions showed a complete clinical clearing. In GS patients, facial or trunk areas with multiple BCCs were treated (up to 200). Complete clinical remission was obtained in 25–67% of the lesions. Some nodular and pigmented lesions failed to achieve a complete remission. RCM could identify already described confocal features for BCC. Tumour remissions could be assessed by this technique. Conclusions Methyl‐aminolevulinate PDT may be useful for the treatment of superficial BCC in GS and XP. In some nodular lesions, PDT may complement surgery reducing tumour size. RCM may be regarded in the future as a complementary technique in BCC for the diagnosis and post‐treatment assessment to non‐invasive therapeutic modalities.     

5‐aminolevulinic acid induce apoptosis via NF‐κB/JNK pathway in human oral cancer Ca9–22 cells

J Oral Pathol Med (2010) 40 : 483–489 Background: 5‐aminolevulinic acid‐based photodynamic therapy (5‐ALA‐PDT) is being used to treat oral pre‐cancerous and cancerous lesions with some encouraging clinical outcomes. However, the exact mechanisms behind the photodynamic treatment are still not fully elucidated. Method: Flow cytometry, TdT‐mediated dUTP nick end labeling assay and Western blot analysis were used to investigate the effects of 5‐ALA‐PDT on human oral cancer Ca9–22 cells. Results: We found that 5‐ALA‐PDT induces apoptosis in Ca9–22 cells. Western blotting showed that 5‐ALA‐PDT activates both the caspase‐8 and caspase‐9 pathways, which differed from previous studies conducted in other cell types. Activation of JNK was evident as early as 30 min. The caspases activation was inhibited by JNK inhibitor SP600125. Treatment with NF‐κB inhibitor Bay 11‐7082 (Bay) completely abrogated ALA‐PDT‐induced JNK activation. In addition, Bay and SP600125 almost completely abolished ALA‐PDT‐induced apoptosis. Conclusion: These results demonstrate significant involvement of caspase‐8 and ‐9 and their upstream NF‐κB‐JNK pathways in ALA‐PDT‐induced apoptosis. Future studies on how NF‐κB and JNK activity regulate ALA‐PDT response should provide a better strategy for the treatment of oral cancer.     

Penetration enhancement of two topical 5‐aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation

Please cite this paper as: Penetration enhancement of two topical 5‐aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation. Experimental Dermatology 2010; 19 : 806–812. Abstract: 5‐Aminolaevulinic acid (ALA) is used in photodynamic therapy (PDT). Response rates of PDT vary widely, which may be because of the limited uptake of topically applied photosensitisers. We investigated skin penetration and fluorescence induction of protoporphyrin IX (PpIX) after applying either 20% ALA cream or 20% aminolaevulinic acid solution on laser‐stripped stratum corneum (SC) in an ex vivo full‐thickness porcine skin model. Both formulations are used in clinical practice. To enhance the skin penetration of ALA, we used two different 2940‐nm erbium:yttrium–aluminium–garnet (Er:YAG) laser systems to partially ablate the SC: continuous and fractional ablation. Different fluences were applied ranging from 0.5 to 1.5 J/cm² (continuous ablation) and from 4 to 24 J/cm² (fractional ablation). Fluorescence microscopy was used for detecting PpIX‐induced fluorescence. Compared to skin without laser pretreatment, mean fluorescence intensity (MFI) of PpIX was enhanced 13.8‐fold after continuous ablation with 1.0 J/cm² and 7.3‐fold after fractional ablation with 4 J/cm²; each laser procedure was followed by 4‐h incubation with lipophilic ALA cream. Optimal parameters for continuous ablation without damage to the epidermis were 1 J/cm² for both formulations, fractional ablation was best with 4 J/cm². Histological evaluations of laser‐treated skin showed necrosis and apoptosis, depending on light dose. In laser‐stripped skin, PpIX fluorescence was detected earlier and reached deeper epidermal layers than in untreated skin. Continuous laser ablation induced higher PpIX fluorescence levels than fractional ablation. This method offers a promising new tool for enhancing ALA penetration in PDT without damaging the underlying tissue.