Mark F. Naylor

The effects of chronic sunscreen use on the histologic changes of dermatoheliosis

BACKGROUND Sunscreen application to the skin of hairless mice is effective in reversing the histologic changes associated with photoaging (solar elastosis, epidermal thickening, collagen depletion, glycosaminoglycan deposition). These reparative processes have not been studied in human beings. OBJECTIVE The aim of this study was to evaluate histologically the effects of daily application of a UVA/UVB sunscreen versus placebo. METHODS We examined 46 patients who were given either sunscreen or vehicle and asked to apply it daily for 24 months. Punch biopsy specimens were obtained from preauricular skin at 0, 12, and 24 months. Each specimen was examined for epidermal thickening and organization and dermal inflammatory infiltrate by light microscopy. Computer-generated analysis of tissue sections was used to evaluate solar elastosis. RESULTS A significant difference in solar elastosis was found between the treatment groups; however, the other features remained largely unchanged. CONCLUSION The dermal changes of photoaging may be affected differently than epidermal changes when UV radiation exposure is diminished. UVA and UVB may contribute diversely to these cutaneous changes. Computer-generated evaluation of dermatoheliosis may be more accurate than visual inspection.

Contact immunotherapy of resistant warts

Contact immunotherapy has been proved effective in the treatment of resistant warts. This report chronicles our experience with a new contact immunotherapy agent, diphenylcyclopropenone. We have achieved a cure rate of 62% in 45 patients with resistant warts of all types who came to our general dermatology clinic. Cure rates may be lower in patients who have experienced multiple treatment failures. The majority of cures were obtained within 3 to 4 months. Although it appears somewhat less effective than published reports of dinitrochlorobenzene contact immunotherapy, diphenylcyclopropenone contact immunotherapy is an effective treatment for resistant warts and avoids any potential problems from mutagenicity.

Chitin, Chitosan, and Glycated Chitosan Regulate Immune Responses: The Novel Adjuvants for Cancer Vaccine

With the development of cancer immunotherapy, cancer vaccine has become a novel modality for cancer treatment, and the important role of adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages as adjuvants for cancer vaccine. In this paper, the adjuvant properties of chitin and chitosan were discussed, and some detailed information about glycated chitosan and chitosan nanoparticles was also presented to illustrate the trend for future development.

Clinical effects of in situ photoimmunotherapy on late-stage melanoma patients: A preliminary study

Metastatic melanoma is a skin cancer with poor prognosis. In situ photoimmunotherapy (ISPI) is a promising modality for the treatment of metastatic melanoma that combines local, selective photothermal therapy with immunological stimulation. A preliminary clinical study was conducted to evaluate the safety and therapeutic effects of ISPI for late-stage melanoma patients using imiquimod as the immune modifier. Eleven patients received ISPI in one or multiple 6-week treatment cycles applied to a 200-cm2 treatment site, which usually contained multiple cutaneous metastases. ISPI consisted of three main components applied directly to the cutaneous metastases: 1) local application of topical imiquimod; 2) injection of indocyanine green (ICG); and 3) an 805 nm laser for local irradiation. All patients completed at least one cycle of treatment. The most common adverse effects were rash and pruritus at the treatment sites. No grade 4 toxicity was observed. Complete response was observed in six patients. All lesions in the treatment area of the patients responded to ISPI, eight of which achieved complete local response (CLR). CLR was observed in the non-treatment site (regional) lesions in four patients. Five patients were still alive at the time of last follow-up. The probability of 12-month overall survival was 70%. This study demonstrates that ISPI with imiquimod is safe and well tolerated. The patient response rate is promising. ISPI can be easily applied on an outpatient basis and can be combined with other modalities to improve the therapeutic response of metastatic melanoma.

Non‐melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus

Objective: To determine whether atopic dermatitis (AD) patients treated with tacrolimus ointment experienced an increased risk of non‐melanoma skin cancer (NMSC). Methods: Data were collected from 9813 adult and paediatric patients with AD who applied 0.03% or 0.1% tacrolimus ointment twice daily and were examined every 3 months during the tacrolimus ointment development programme. Results: Thirteen adult patients were diagnosed with NMSC during the follow‐up period. All patients with NMSC were white adults and 12 were over 40 years of age. Based on 1718 patient‐years of tacrolimus ointment exposure in patients⩾40 years of age, the calculated incidence of NMSC did not suggest an increased risk of first NMSC over that of a similarly aged US cohort. Conclusion: This study does not indicate an increased risk for the development of NMSC in patients with AD treated with tacrolimus ointment for a mean duration of 208 days with a maximum observation period of 1479 days.

Topical Chemotherapy in Cutaneous T-cell Lymphoma: Positive Results of a Randomized, Controlled, Multicenter Trial Testing the Efficacy and Safety of a Novel Mechlorethamine, 0.02%, Gel in Mycosis Fungoides

OBJECTIVE To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients. SETTING Academic medical or cancer centers. PATIENTS In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy. MAIN OUTCOME MEASURES Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses). RESULTS Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P< .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected. CONCLUSION The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00168064.

The role of human papillomavirus in the development of pyogenic granulomas

Background Pyogenic granulomas (lobular capillary hemangiomas) and condyloma acuminata share similar locations and risk factors. Human papillomavirus (HPV) types 6 and 11 are commonly associated with condyloma acuminata, but their association with pyogenic granulomas has not been evaluated. The purpose of this study was to determine whether pyogenic granulomas contain evidence of infection with condyloma producing HPVs.

Effects of immunostimulants in phototherapy for cancer treatment

It has long been established that exogenous immunostimulants can enhance the host defense system. The use of such immunoadjuvants in most cases has often been proven non-specific, hence limiting their capability in fighting against specific foreign invasion, particularly against tumor cells, which in most cases can easily evade the host immune surveillance system. However, when the non-specific immunological enhancement is combined with other direct intervention, the immune responses could be turned to be tumor-specific. Glycated chitosan (GC), a specially designed immunoadjuvant, has been used in combination with phototherapy for cancer treatment with promising outcomes in animal studies. Here we present our results of cellular studies on the functions of GC. When used by itself, GC was not toxic to normal cells as well as to tumor cells. When GC was incubated with macrophages, it could induce significant secretion of TNFα. Furthermore, when GC was used with laser irradiation, it has significantly enhanced tumor cell destruction and immune responses.

In situ photoimmunotherapy for melanoma: an ongoing phase I clinical trial

In situ Photoimmunotherapy (ISPI) was developed to treat metastatic tumors using a combination of phototherapy and immunotherapy. It utilizes local intervention through photothermal destruction of existing solid tumors and through immune response modifier to elicit host anti-tumor responses. Such combination in pre-clinical studies has shown promise in cancer treatment by eradicating the primary tumors and also controlling metastases at distant sites. ISPI has been used in our preliminary clinical studies for melanoma patients and the outcome has been extremely encouraging. In 2006, we began enrolling patients in a new phase I immunotherapy trial for advanced cutaneous melanoma. This trial is based on our previous results which indicated that we had developed an effective treatment for advanced melanoma. Of the first six patients treated, (4 stage IV, and 2 surgically unresectable stage III), 2 of the stage IV patients are still alive, one tumor free, and one with a possible treatable recurrence after 2 1/2 years. We have also discovered that recurrences of the skin cancer can be retreated by the same technique and that treatment seems to blunt the virulence of the disease and make it more treatable. These initial results indicate that ISPI probably will have the ability to prolong survival in selected cases of advanced melanoma, and potentially cure a significant percentage of treated patients.

Cellular immunological effects of laser irradiation and immunoadjuvant application

Immune system is critical in the fight against cancer. Particular important is the responses through immune cells that regulate immunological functions. Certain cytokines enhance cancer immunity (such as IL12 and interferon gamma) and others interfere or impede cancer immunity (such as IL10). The clinical outcome can be linked to the balance of these cytokines, such as IL10 to IL12 ratio. Effective treatments often reduce the IL10:IL12 ratio, indicating higher levels of the cancer fighting IL12. To enhance immune responses, a combination of laser irradiation and concurrent use of immunostimulants has been applied for the treatment of tumors. In a recent study, an 805-nm laser in conjunction with indocyanine green (ICG) has been used to treat EMT6 mammary tumors in mice. An immunoadjuvant, glycated chitosan (GC), was intratumoral injected after the laser irradiation. Our preliminary results showed that tumor-bearing mice treated either with the immunoadjuvant alone or with the combination of laser and immunoadjuvant had lower IL10:IL12 ratios than animals that received no treatment. This may play an important in the treatment to decrease tumor size and to increase survival times of mice. Cellular activities after laser-ICG-GC treatment of DBMA-4 mammary tumors in rats also showed infiltration of immune cells to the treatment sites, indicating a possible induced immunity. The combination of laser treatment and immunotherapy has been used to treat late-stage melanoma patients; the responses, both treated primary tumors and the metastases, to the treatment have been promising. The histology of two patients, before and after treatment, is presented to show the effects of this novel treatment method.