Skin Cancer Therapy Research Articles

Evidence supporting a role for dihydroorotate dehydrogenase, bioenergetics, and p53 in selective teriflunomide-induced apoptosis in transformed versus normal human keratinocytes

We have demonstrated previously that the dihydroorotate dehydrogenase (DHODH) inhibitor teriflunomide (TFN) encourages apoptosis in transformed human keratinocytes. Here we sought to determine if this cytotoxic effect could be restricted to transformed keratinocytes relative to their normal human epidermal keratinocyte (NHEK) counterparts, and ascertain a potential mechanistic basis for the selectivity. The NHEK cells proliferated much slower than the premalignant HaCaT and malignant COLO 16 keratinocytes, and exogenous uridine added to the culture medium did not affect this growth. Similarly, DHODH expression and the bioenergetic characteristics of the normal cells were markedly dissimilar from those observed in the transformed cells indicating that de novo pyrimidine synthesis was involved with keratinocyte proliferation. Moreover, a short-term exposure to TFN caused a wild-type p53 response in the NHEK cells illustrating that pyrimidine metabolic stress could regulate this tumor suppressor protein in the normal cells. TFN-induced apoptosis occurred primarily in S phase HaCaT cells. This cell death was sensitive to uridine, an antioxidant, and a caspase inhibitor, and the suppression of Bcl-X(L) and the induction of Mn superoxide dismutase preceded it. These events suggested that mitochondrial/redox stress was involved with the cytotoxic effect of TFN. Conversely, a long-term exposure to TFN caused G(0)/G(1) arrest in the NHEK cells, which supported a cytoprotective role for p53 against TFN-induced apoptosis. Together, these results propose that TFN could be useful in the prevention or therapy of non-melanoma skin cancers and possibly other hyperproliferative keratinocytic diseases.

Menopausal Hormone Therapy and Risks of Melanoma and Nonmelanoma Skin Cancers: Women’s Health Initiative Randomized Trials

Case-control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women's Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone). Postmenopausal women aged 50-79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16,608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N = 10,739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided. Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually. Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.

Optical coherence tomography-guided photodynamic therapy for skin cancer: case series

Optical coherence tomography-guided photodynamic therapy for skin cancer: case series

Optical coherence tomography-guided photodynamic therapy for skin cancer: Case series

Optical coherence tomography-guided photodynamic therapy for skin cancer: Case series

Physicians may inadequately counsel inflammatory bowel disease patients about immunosuppressive therapy and risk of nonmelanoma skin cancer

Physicians may inadequately counsel inflammatory bowel disease patients about immunosuppressive therapy and risk of nonmelanoma skin cancer

Photodynamic Therapy–Induced Immunosuppression in Humans Is Prevented by Reducing the Rate of Light Delivery

Photodynamic therapy (PDT) of non-melanoma skin cancers currently carries failure rates of 10-40%. The optimal irradiation protocol is as yet unclear. Previous studies showed profound immunosuppression after PDT, which may compromise immune-mediated clearance of these antigenic tumors. Slower irradiation prevents immunosuppression in mice, and may be at least as effective as high-fluence-rate PDT in preliminary clinical trials. The photosensitizers 5-aminolaevulinic acid and/or methyl aminolaevulinate were applied to discrete areas on the backs of healthy Mantoux-positive volunteers, followed by narrowband red light irradiation (632 nm) at varied doses and fluence rates. Delayed type hypersensitivity (Mantoux) reactions were elicited at test sites and control sites to determine immunosuppression. Human ex vivo skin received low- and high-fluence-rate PDT and was stained for oxidative DNA photolesions. PDT caused significant, dose-responsive immunosuppression at high (75 mW cm(-2)) but not low (15 or 45 mW cm(-2)) fluence rates. DNA photolesions, which may be a trigger for immunosuppression, were observed after high-fluence-rate PDT but not when light was delivered more slowly. This study demonstrates that the current clinical PDT protocol (75 mW cm(-2)) is highly immunosuppressive. Simply reducing the rate of irradiation, while maintaining the same light dose, prevented immunosuppression and genetic damage and may have the potential to improve skin cancer outcomes.

Micrographic surgery of skin cancer in German hospitals 2005–2006

Surgical therapy of skin cancer includes conventional wide excision and micrographic surgery (MS). Little is known about the population-wide spread of MS for the treatment of skin cancer. The aim was to estimate the in-hospital use of MS for the treatment of skin cancer in Germany. We used nationwide DRG data from 2005 through 2006. We identified hospitalizations with a main diagnosis of cutaneous malignant melanoma (CMM) (ICD-10: C43) or non-melanoma skin cancer (NMSC) (ICD-10: C44). MS was identified by OPS procedure codes including 5-895.1, 5-895.3, 5-212.1, 5-181.1, 5-181.4, 5-181.6, 5-182.1, 5-091.1, or 5-091.3. We identified 52 660 and 98 484 hospitalizations with a primary diagnosis of CMM and NMSC respectively; 54.6% and 36.5% of NMSC and CMM-related admissions with local skin cancer treatment included MS. The relative frequency of MS varied by anatomic subsite of the skin cancer and by region of the hospital. Local infections were the most frequent complications after MS with 3.2-4.0% for NMSC and 2.3-2.9% for CMM followed by haemorrhages. Dehiscence of the operation wound is a rare event with risks ranging between 0.1% and 0.3%. Micrographic surgery is frequently used for the local treatment of NMSC and varies considerably across Federal States of Germany. It is difficult to speculate how many MS might be performed in private or ambulatory settings in Germany. As MS requires surgical expertise, technical support and dermatopathology, we speculate that MS is much less frequently undertaken in private practices in Germany.

Letter: Response: Electroporation Therapy of Skin Cancer in the Head and Neck Area

Letter: Response: Electroporation Therapy of Skin Cancer in the Head and Neck Area

Photodynamic therapy of non-melanoma skin cancers

In this prospective study duly approved from Institutional Ethics Review Committee for research in medicine, PAEC General Hospital Islamabad, Pakistan, we investigate the efficacy, safety and tolerability along with cosmetic outcome of topical 5-aminolaevulinic acid photodynamic therapy for superficial nonmelanoma skin cancers (NMSCs) and their precursors. Patients with Histological diagnosis of NMSCs and their precursors were assessed for PDT, after photographic documentation of the lesions and written consent, underwent two (2) sessions of PDT in one month (4 weeks) according to standard protocol. A freshly prepared 20% 5-ALA in Unguentum base was applied under occlusive dressing for 4–6 h as Drug Light Interval (DLI) and irradiated with light of 630 nm wavelength from a diode laser at standard dose of 90 J/cm2. Approximately 11% patients reported pain during treatment which was managed in different simple ways. In our study we regularly followed up the patients for gross as well as histopathological response and recurrence free periods during median follow-up of 24 months. Regarding Basal cell carcinomas complete response was observed in 86.2% (25/29), partial response in 10.3% (3/29) and recurrence during first year in 3.5% (1/29) lesions. All the lesions which showed partial response or recurrence were nBCCs. Regarding Actinic Keratosis complete response was observed in 95.3% (20/21), partial response in 4.7% (1/21) while Bowen’s disease showed 100% (2/2) results. 81.8% (9/11) Squamous Cell Carcinomas showed complete, 9% (1/11) partial response and 9% (1/11) presented with recurrence after 3 months. We observed excellent and good cosmetic results along with tumor clearance in our study. Treatment sessions were well tolerated with high level of patient’s satisfaction and only minor side effects of pain during treatment sessions and inflammatory changes post photodynamic therapy were observed. We concluded that 5-ALA PDT is an effective and safe emerging treatment modality for management of superficial non-melanoma skin cancers and their precursors with better cosmetic outcome and minor side effects.

A new approach for skin tumor treatment: from delivery system characterization to in vivo evaluation.

Topical therapy for skin cancer is considered ineffective, due to insufficient penetration of the anticancer drug into the tumor located in the deep layers of the skin. The aim of this work was to investigate a new system, Tumorep DS, tailored to deliver the anti-cancer actives into the tumor cells in the deep skin and to induce cell differentiation. Tumorep DS containing 5-fluorouracil (5-FU) anticancer drug and a sulfoxide derivative, as a differentiation agent, was characterized and tested for storage stability. The system was tested in cell lines, in vitro and in animal models. Experiments were carried out on five cell types: three tumorigenic (TE.354.T, ES-2, and Mel624), one precancerous (HaCaT), and a primary keratinocyte (human normal keratinocytes) cell culture. Treatment of keratinocytes with Tumorep DS resulted in reduction in the percent of keratin 14-positive cells, suggesting its ability to induce cell differentiation. Skin penetration was assessed in vitro in Franz diffusion cells and in vivo. The antitumor effect of the new system evaluated in two skin cancer animal models showed a significant repression of tumor development, which was significantly better statistically than a 5-FU commercial product. Tumorep DS was found to be safe to the skin when tested in vitro in the EpiDerm™ skin irritation test and in animals.

Quantitative fluorescence imaging of protoporphyrin IX through determination of tissue optical properties in the spatial frequency domain

The ability to quantitatively determine tissue fluorescence is of interest for the purpose of better understanding the details of photodynamic therapy of skin cancer. In particular, we are interested in quantifying protoporphyrin IX (PpIX) in vivo. We present a method of correcting fluorescence for effects of native tissue absorption and scattering properties in a spatially resolved manner that preserves the resolution of the fluorescence imaging system, based off a homogeneous representation of tissue. Validation was performed using a series of liquid turbid phantoms having varying concentrations of absorber, scatterer, and fluorophore (PpIX). Through the quantification of tissue optical properties via spatial frequency domain imaging, an empirical model based on Monte Carlo simulations was deployed to successfully decouple the effects of absorption and scattering from fluorescence. From this we were able to deduce the concentration of the PpIX to within 0.2 μg/ml of the known concentration. This method was subsequently applied to the determination of PpIX concentration from in vivo normal skin where the model-based correction determined a concentration of 1.6 μg/ml, which is in agreement with literature.

A dynamic model for ALA-PDT of skin: simulation of temporal and spatial distributions of ground-state oxygen, photosensitizer and singlet oxygen

Singlet oxygen direct dosimetry and photosensitizer fluorescence photobleaching are being investigated and applied as dosimetric tools during 5-aminolevulinic acid (ALA)-induced protophorphyrin IX (PpIX) photodynamic therapy (PDT) of normal skin and skin cancers. The correlations of photosensitizer fluorescence and singlet oxygen luminescence (SOL) emission signals to distribution and cumulative dose are difficult to interpret because of the temporal and spatial variations of three essential components (light fluence rate, photosensitizer concentration and oxygen concentration) in PDT. A one-dimensional model is proposed in this paper to simulate the dynamic process of ALA-PDT of normal human skin in order to investigate the time-resolved evolution of PpIX, ground-state oxygen and distributions. The model incorporates a simplified three-layer semi-infinite skin tissue, Monte Carlo simulations of excitation light fluence and both PpIX fluorescence and SOL emission signals reaching the skin surface, -mediated photobleaching mechanism for updating PpIX, and distributions after the delivery of each light dose increment, ground-state oxygen supply by diffusion from the atmosphere and perfusion from blood vessels, a cumulative -dependent threshold vascular response, and the initial non-uniform distribution of PpIX. The PpIX fluorescence simulated using this model is compared with clinical data reported by Cottrell et al (2008 Clin. Cancer Res. 14 4475–83) for a range of irradiances (10–150 mW cm−2). Except for the vascular response, one set of parameters is used to fit data at all irradiances. The time-resolved depth-dependent distributions of PpIX, and at representative irradiances are presented and discussed in this paper, as well as the PDT-induced vascular response at different depths. Tissue hypoxia and shutdown of oxygen supply occur in the upper dermis, where PpIX is also preserved at the end of treatment.

Optical coherence tomography-guided photodynamic therapy for skin cancer: Case study

Photodynamic therapy (PDT) has been identified as a successful therapy for skin cancer. This case study investigates the role of optical coherence tomography (OCT) in lesion (squamous cell carcinoma) mapping, assisting the surgeon to correctly deliver PDT and monitor the outcome. Optical coherence tomographic images were acquired pre-treatment to assess tumour extent and margins to enable guidance of the PDT. Tomographic images taken post-PDT up to 6 months revealed complete response to the treatment and no recurrence. OCT-guided PDT is one of the promising approaches to efficiently discriminate between tumor involved and noninvolved margins. It reduces the untoward healthy tissue necrosis and provides an encouraging monitoring of the healing process.

Integrating spheres for improved skin photodynamic therapy

The prescribed radiant exposures for photodynamic therapy (PDT) of superficial skin cancers are chosen empirically to maximize the success of the treatment while minimizing adverse reactions for the majority of patients. They do not take into account the wide range of tissue optical properties for human skin, contributing to relatively low treatment success rates. Additionally, treatment times can be unnecessarily long for large treatment areas if the laser power is not sufficient. Both of these concerns can be addressed by the incorporation of an integrating sphere into the irradiation apparatus. The light fluence rate can be increased by as much as 100%, depending on the tissue optical properties. This improvement can be determined in advance of treatment by measuring the reflectance from the tissue through a side port on the integrating sphere, allowing for patient-specific treatment times. The sphere is also effective at improving beam flatness, and reducing the penumbra, creating a more uniform light field. The side port reflectance measurements are also related to the tissue transport albedo, enabling an approximation of the penetration depth, which is useful for real-time light dosimetry.

Electroporation Therapy of Skin Cancer in the Head and Neck Area

Electroporation therapy is a new cancer treatment modality in which a locally applied electrical field enhances cell membrane permeability, allowing greater intracellular accumulation of a chemotherapeutic agent. To evaluate the efficacy of electroporation therapy in treating basal cell and squamous cell carcinomas of the skin. Six patients with skin cancer of the head and neck were treated using electroporation therapy with intratumorally injected bleomycin. Orbital growth, facial nerve proximity, or proximity to cartilage of the external meatus complicated four of these tumors. The intention was curative. The follow-up period was 24 months and included biopsies after 8 weeks. In four of the six patients, one treatment was enough to eradicate the tumor. In one patient, the tumor persisted even after a second treatment with electroporation therapy. A septal cartilage perforation was the only major complication. The cosmetic results were very satisfactory. One additional recurrence was recorded 6 months after the follow-up period Electroporation therapy is a promising new cancer treatment that should be further evaluated as an alternative to surgery, especially in complicated skin cancer.

Methods for quantifying intrafollicular drug delivery: a critical appraisal

Importance of the field: In recent years there has been increasing awareness that the hair follicles and their associated pilosebaceous structures may act as significant permeation pathways and/or reservoirs for topically applied drugs. This has implications in terms of dermatological therapy for acne, hirsutism, alopecias or certain skin cancers as well as systemic drug delivery. As the processes modulating follicular drug penetration are poorly understood at present, there is an emergent need for methodologies that can quantify follicular drug penetration and deposition. So far, a review article specifically dedicated to these methodological aspects has not yet been written.Areas covered in this review: This paper reviews the available quantitative follicular methodologies that have been developed over the years, describing the advantages and disadvantages of each approach. This review covers comparative techniques that are based on measuring drug flux through ‘follicle-free’ and ‘follicle-containing’ integuments, the skin sandwich, differential stripping and optical imaging-based technologies. Techniques for measuring drug–sebum interactions are also discussed.What the reader will gain: The reader will develop an understanding of the complexities involved in quantifying drug delivery through follicles and pilosebaceous units. The Expert opinion section will give the reader insights into how more broad-ranging future research could allow identification of the most useful methods for quantifying follicular drug transport.Take home message: This is still a poorly understood field. It clearly warrants much larger scale studies than have been performed so far involving multiple techniques and multiple drugs.

Teriflunomide encourages cytostatic and apoptotic effects in premalignant and malignant cutaneous keratinocytes

Teriflunomide (TFN) reportedly inhibits de novo pyrimidine synthesis and exhibits anti-inflammatory, disease-modifying activities invivo. These qualities would suggest that TFN could be useful in skin cancer chemoprevention or therapy. We investigated some mechanistic aspects of this tenet by characterizing the effects of TFN on premalignant and malignant human cutaneous keratinocytes. TFN promoted a dose- and/or time-dependent cytostasis and in these cells, which was followed by apoptosis. These features occurred in the presence of a physiological concentration of uridine in the culture medium. The short-term S phase arrest triggered by TFN was reversible in the malignant keratinocytes, and the indirect apoptosis induction was apparently preceded by mitochondrial disruption and reactive oxygen species production in both the premalignant and malignant keratinocytes. Respiration deficient malignant keratinocytes were resistant to the acute cytostatic and latent apoptotic effects of TFN implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiring cells. These novel mechanistic findings support a role for TFN in skin cancer chemoprevention and therapy.

Targeted therapy for skin cancers: current status and future prospects

靶向肿瘤治疗指通过干扰参与肿瘤生长与进展的特定分子阻断肿瘤生长及扩散的治疗方法.皮肤肿瘤的靶向治疗始于1997年美国FDA批准利妥昔单抗(rituximab)用于治疗难治性B细胞非霍奇金淋巴瘤.近年来该领域取得较大进展,但同时也面临许多挑战。

Plesiotherapy for non-melanoma skin cancer: Innovating to overcome!

Background:The non-surgical management of non-melanoma skin cancers is an area requiring clinical investigation. Radiotherapy has a role in treatment for a defined subset of patients.Aims:The application of radiotherapy is subject to availability of proper equipment, non-availability of which precludes appropriate radiotherapy in most centers in third world countries.Materials and Methods:The introduction of innovations is needed to circumvent this. Plesiotherapy is such a mode of therapy for non-melanoma skin cancer.Methods:The introduction of innovations is needed to circumvent this. Plesiotherapy is such a mode of therapy for non-melanoma skin cancer.Results:In this paper we present successful management of a cohort of non-melanoma skin cancer patients with plesiotherapy using stepping source192 Ir HDR source.Conclusions:Plesiothrapy is an effective mode of therapy for non-melanoma skin cancer.

Comparison of photodynamic therapy for skin cancers and pre-cancers with δ-aminolevulinic acid

Objective The aim of the study was to compare the effects of photodynamic therapy (PDT) with δ-aminolevulinic acid (ALA) for patients with different kinds of skin cancers and pre-cancers.