Allograft and overall survival of patients with posttransplant skin cancer.

BACKGROUND: Little is known about the possible association between nonmelanoma skin cancer (NMSC) and allograft survival and overall patient survival. OBJECTIVE: To determine the association between posttransplant NMSC and early to mid-term allograft survival and overall patient survival after kidney, liver, or heart transplantation. METHODS AND MATERIALS: We retrospectively reviewed patients identified from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. The study included adult recipients of kidney (n=46,216), liver (n=8,049), and heart (n=8,519) transplants from 1996 to 2001. RESULTS: Multivariate analysis showed that kidney recipients with NMSC had a significantly lower risk of allograft loss (relative risk (RR)=0.55, p<.001) and death (RR=0.55; p<.001) within 5 years of transplantation than recipients without NMSC. Significantly lower risk of death was also observed for liver recipients (RR=0.28, p<.001) and heart recipients (RR=0.25; p<.001) with NMSC. CONCLUSIONS: Longer early to mid-term allograft and overall survival was seen in patients with NMSC, but long-term survival rates must be examined to determine whether mortality rates increase later for patients with NMSC, as noted in previous studies.

Cross-validation of murine UV signal transduction pathways in human skin.

Acute UVB irradiation of mouse skin results in activation of phospatidyinositol-3 (PI-3) kinase and mitogen-activated protein kinase (MAPK) pathways leading to altered protein phosphorylation and downstream transcription of genes. We determined whether activation of these pathways also occurs in human skin exposed to 4x minimal erythemic dose of UVB in 23 volunteers. Biopsies were taken prior to, at 30 min, 1 and 24 h post-UVB. In agreement with mouse studies, the earliest UV-induced changes in epidermis were seen in phospho-CREB (two- and five-fold at 30 min and 1 h) and in phospho-MAPKAPK-2 (three-fold at both 30 min and 1 h). At 1 h, phospho-c-JUN and phospho-p38 were increased five- and two-fold, respectively. Moreover, phospho-c-JUN and phospho-p38 were further increased at 24 h (12- and six-fold, respectively). Phospho-GSK-3beta was similarly increased at all time points. Increases in phospho-p53 (12-fold), COX-2 (four-fold), c-FOS (14-fold) and apoptosis were not seen until 24 h. Our data suggest that UVB acts through MAPK p38 and PI-3 kinase with phosphorylation of MAPKAPK-2, CREB, c-JUN, p38, GSK-3beta and p53 leading to marked increases in c-FOS, COX-2 and apoptosis. Validation of murine models in human skin will aid in development of effective skin cancer chemoprevention and prevention strategies.

Adherence assessment using medication weight in a phase IIb clinical trial of difluoromethylornithine for the chemoprevention of skin cancer.

OBJECTIVE: Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of a phase IIb topical chemoprevention trial. METHODS: One hundred and twenty-four eligible participants were randomized to one of four arms [34 to difluoromethylornithine (DFMO) plus triamcinolone, 31 to DFMO plus placebo, 31 to placebo plus triamcinolone, and 28 to double placebo] for 6 months of treatment for actinic keratosis. Adherence was assessed at each clinic visit by weighing each tube of dispensed and returned medication and the participant's study diary. RESULTS: Self-reported adherence was consistently higher than adherence measured by returned medication weight (96.5% versus 71.3%, 94.6% versus 82.4%, 95.3% versus 69.5%, and 95.8% versus 66.8% for DFMO, DFMO placebo, triamcinolone, and triamcinolone placebo, respectively; P < 0.001). Most participants (59.2%) recorded 100% adherence on the study diary; however, using the weight adherence, only 10.2% were completely adherent to the study regimen. CONCLUSIONS: Self-reported diary measures seem to overestimate adherence when compared with weighing the returned medication vessel. It is recommended that future clinical trials involving topical applications incorporate medication weights as a primary measure of adherence because it is objective, quantitative, inexpensive, noninvasive, and easy to use.

Skin cancer in organ transplant recipients: effect of pretransplant end-organ disease.

BACKGROUND: Solid organ transplant recipients are at increased risk for posttransplant neoplasms. OBJECTIVE: Our purpose was to determine whether various diseases causing end-organ failure are associated with different degrees of risk of skin cancer development after transplantation. METHODS: The Organ Procurement and Transplantation Network/United Network for Organ Sharing Transplant Tumor Registry was searched for the incidence of skin cancer among kidney, liver, and heart transplant recipients in the United States between 1996 and 2001. Multivariate analysis was used to determine the association between disease diagnosis and posttransplant skin cancer. RESULTS: Transplant recipients with specific pretransplant diseases, such as polycystic kidney disease and cholestatic liver disease, were at increased risk for skin cancer. Patients with diabetes mellitus had a lower incidence of skin cancer after kidney transplantation. LIMITATIONS: The study had only a brief follow-up period, indirect assessment of photodamage, and possible underreporting. CONCLUSION: Transplant recipients with a history of certain diseases warrant intensive skin cancer surveillance and strict sun-protective practices.

Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin.

PURPOSE: Previously, we reported the results of a Phase III, placebo-controlled trial in 2297 randomized participants with moderately severe actinic keratoses wherein 25000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50000 or 75000 IU/day would be both safe and more efficacious in skin cancer chemoprevention. EXPERIMENTAL DESIGN: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25000, 50000, or 75000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sun-damaged skin. RESULTS: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25000 IU/day, 50000 IU/day, and 75000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25000 and 50000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor alpha, retinoic acid receptor beta, and retinoid X receptor alpha at the 50000 IU/day vitamin A dose. CONCLUSIONS: The vitamin A doses of 50000 and 75000 IU/day for 1 year proved safe and equally more efficacious than the 25000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.

A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) are precancerous epidermal lesions found most frequently on areas of the skin exposed to the sun. Several case studies published recently have indicated that 5% imiquimod cream, currently licensed for the treatment of genital warts, may be an effective treatment for AK. OBJECTIVE: To assess the efficacy and safety of imiquimod for the treatment of AK. DESIGN: Patients in this randomized, double-blind, vehicle-controlled study applied 5% imiquimod cream or vehicle to AK lesions 3 times per week for a maximum of 12 weeks or until lesions had resolved. In the event of an adverse reaction, application of imiquimod was reduced to 1 or 2 times per week. Rest periods were also allowed if necessary. SETTING: A specialized outpatient dermatology clinic within a state-funded hospital in Germany. PATIENTS: The study population was aged 45 to 85 years. Of 52 patients screened, 36 men and women with AK confirmed by histological diagnosis were enrolled. Patients were excluded from the study if they did not have a histological diagnosis for AK, if they were older than 85 years, or if they did not comply with the protocol. All patients had responded to a notice asking for volunteers. MAIN OUTCOME MEASURES: The number and appearance of lesions were evaluated before, during, and after treatment. All adverse effects were recorded. RESULTS: Lesions treated with 5% imiquimod cream were clinically cleared in 21 (84%) of 25 patients and partially cleared in 2 (8%). Clearance was histologically confirmed 2 weeks after the last application of imiquimod in all patients clinically diagnosed as lesion free. Only 10% of patients treated with imiquimod were clinically diagnosed with recurrence 1 year after treatment. No reduction in the size or number of AK lesions was observed in vehicle-treated patients. Adverse effects reported by patients treated with imiquimod included erythema, edema, induration, vesicles, erosion, ulceration, excoriation, and scabbing. However, imiquimod was well tolerated since all patients completed the 12-week treatment. Only a few, mild adverse reactions to the vehicle cream were reported. CONCLUSION: Application of 5% imiquimod cream for 12 weeks is an effective and well-tolerated treatment for AK.

Phase 1 study of topical perillyl alcohol cream for chemoprevention of skin cancer.

Perillyl alcohol (POH) is a natural product derived from plants such as cherry and lavendin. Previous studies have indicated that topical POH inhibits ultraviolet (UV) B-induced skin carcinogenesis in vivo, and it may be an effective chemopreventive agent for skin cancer. We performed a 1-mo, first-in-man, Phase 1 trial of topically administered POH cream in human subjects. Endpoints included safety and evaluation of any histopathological changes in skin after 1 mo use of POH cream. We randomized 25 subjects with normal, healthy skin with little or no sun damage and no history of skin cancer in a double-blind fashion to receive topical POH (0.76% wt/wt) on 1 forearm with placebo cream applied to the other forearm twice daily for 30 days. Subjects were monitored for toxicity, and a 4 mm punch biopsy in the treated area was performed at the end of study for histopathological evaluation. The topical cream was well tolerated. No serious cutaneous toxicities, systemic toxicities, or histopathological abnormalities were observed. A total of 8 subjects (32%) reported mild adverse events possibly or probably related to use of cream including reversible appearance of 1 to 2 small papules. However, there was no significant difference between lesions appearing on the POH treated forearm vs. the placebo-treated forearm.

Using optical coherence tomography to evaluate skin sun damage and precancer.

BACKGROUND AND OBJECTIVES: Optical coherence tomography (OCT) is a depth resolved imaging modality that may aid in identifying sun damaged skin and the precancerous condition actinic keratosis (AK). STUDY DESIGN/MATERIALS AND METHODS: OCT images were acquired of 112 patients at 2 sun protected and 2 sun exposed sites, with a subsequent biopsy. Each site received a dermatological evaluation, a histological diagnosis, and a solar elastosis (SE) score. OCT images were examined visually and statistically analyzed. RESULTS: Characteristic OCT image features were identified of sun protected, undiseased, sun damaged, and AK skin. A statistically significant difference (P<0.0001) between the average attenuation values of skin with minimal and severe solar elastosis was observed. Significant differences (P<0.0001) were also found between undiseased skin and AK using a gradient analysis. Using image features, AK could be distinguished from undiseased skin with 86% sensitivity and 83% specificity. CONCLUSION: OCT has the potential to guide biopsies and provide non-invasive measures of skin sun damage and disease state, possibly increasing efficiency of chemopreventive agent trials.

Skin cancer as a contraindication to organ transplantation.

Skin cancer is the most common malignancy worldwide. When patients with a history of skin cancer present for organ transplantation, the vast majority are appropriate candidates. However, there is little guidance in the literature regarding the advisability of transplantation in patients with a history of high-risk skin cancer. With limited allograft resources, it is important to allocate organs to patients who will derive the most benefit. Adverse outcomes that may be associated with prior skin cancer include recurrence, metastasis, or death from relapse or decreased quality of life from numerous new primary skin cancers. This review provides prognostic guidance to transplant physicians evaluating transplantation candidates who have a history of skin cancer.

Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: An open-label trial.

BACKGROUND: Preliminary studies indicate that topically applied immune response modifiers may be an effective and safe method of treating actinic keratoses (AKs). OBJECTIVE: Our aim was to study the potential efficacy of topical 5% imiquimod cream in the treatment of facial or scalp AKs and improve the safety profile by using a novel "cycle" dosing regimen. METHODS: This pilot study is an open-label trial that included 25 patients who had between 5 and 20 discrete AKs within a cosmetic unit of the forehead, scalp, or cheek. Treatment consisted of once-daily application of 5% imiquimod cream, 3 times a week for 4 weeks. to the entire cosmetic unit, followed by a rest period of 4 weeks. The cycle was repeated if any AKs remained after a complete 8-week cycle. A maximum of 3 cycles was permitted (24 weeks). Thirty-three sites in 25 patients were evaluated. RESULTS: Compliance was excellent with a very tolerable safety profile. Complete clearing of all AKs was noted in 82% (27/33) of anatomic sites in 25 study subjects. Almost half the sites (15/33) were clear at the end of the first cycle. A "therapeutic interval" was noted during the rest period wherein clinical inflammation subsided but AKs continued to clear. An added effect was the uncovering and clinical appearance and subsequent eradication of incipient (subclinical) AKs in the treatment area. CONCLUSION: There was excellent compliance with the cycle therapy regimen. The observations and hypotheses made in this pilot study will be tested in controlled, randomized trials with larger study populations. The identification of a therapeutic interval may prove to be beneficial in formulating individualized dosing regimens.

Acute surgical complications: cause, prevention, and treatment

The acute complications that may result in failure of the surgical procedure are discussed. These include bleeding, hematoma, infection, dehiscence, and necrosis. The background of each is covered in detail and an attempt is made to show the interrelationships among them. The purpose of this communication is to aid in the recognition, treatment, and prevention of these acute surgical complications.