Marjam J. Barysch

Cancer-Testis Antigens and Immunosurveillance in Human Cutaneous Squamous Cell and Basal Cell Carcinomas

Purpose: Nonmelanoma skin cancer is the most common cancer and comprises basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The incidence of SCC increases drastically in immunosuppressed individuals, suggesting a critical role of the immune system in controlling SCC. To find an explanation for the selective immunosurveillance of SCC, we investigated the expression of cancer-testis (CT) antigens and MHC class I (MHC-I) and the infiltration by immune cells in BCC and SCC. Experimental Design: We determined the expression of 23 different CT-antigens in 63 BCC and 40 SCC biopsies of immunocompetent and in 20 biopsies of immunosuppressed SCC patients by reverse transcription-PCR and immunohistochemistry. IgG responses to 36 tumor antigens were measured by Western blotting and ELISA. MHC-I expression and CD8+ T-cell infiltration were analyzed by immunohistochemistry in BCC and SCC of immunocompetent and immunosuppressed patients and in imiquimod-treated BCC patients. Results: We found expression of at least one CT-antigen in 81% of BCC and in 40% of SCC. We did not detect CT-antigen–specific serum IgG. Most SCC, but not BCC, expressed MHC-I and were infiltrated with CD8+ cells. Imiquimod-treated BCC expressed MHC-I and were infiltrated by CD8+ T cells. Conclusions: We propose that immunosurveillance controls SCC, but not BCC, because the latter lacks MHC-I. This fits with the increased incidence of SCC in immunosuppressed individuals and may explain the relatively low prevalence of CT-antigen expression in SCC as a result of CD8+ T-cell–driven immunoediting. Clin Cancer Res; 16(14); 3562–70. ©2010 AACR.

Vitamin D, Ultraviolet Exposure, and Skin Cancer in the Elderly

Ultraviolet (UV) radiation has both beneficial and harmful effects on the human body. Its most important beneficial effect may be vitamin D production in the skin, also known as vitamin D photosynthesis. This is of particular interest for the elderly who often show vitamin D-deficiency. Intentional UV exposure has been recommended by different institutions in order to increase vitamin D levels. Nevertheless, UV radiation directly causes DNA damage and is verifiably responsible for carcinogenesis, potentially resulting in lethal skin cancers. Unfortunately, skin cancer incidence is rising worldwide, and there is still a lack of appropriate treatment for metastasized types. The only proven and avoidable risk factor is UV radiation. It has been shown that the earlier UV protection is started, the greater the benefit in terms of skin cancer prevention. Nevertheless, even if UV protection is started at older ages, individuals will benefit measurably. Because UV radiation is neither a reliable nor a safe method of achieving healthy vitamin D levels, intentional UV radiation is not recommended to increase vitamin D levels. In order to prevent skin cancer, UV protection is to be conducted as commonly recommended, by minimizing sun exposure, and especially sunburn, with appropriate sun protective behaviors, e.g. usage of sunscreen and clothing (hat, sunglasses, long sleeves, and pants). Infants must be protected with extra care. Tanning beds must be avoided.

Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions.

Abstract:  We have investigated the staining patterns of primary and metastatic melanoma lesions using F8, L19 and F16. These three clinical‐stage antibodies are currently being studied in clinical trials for the pharmacodelivery of cytokines or therapeutic radionuclides to neoplastic sites in patients with cancer. Frozen sections of 24 primary and 29 metastatic melanoma lesions were stained, using immunofluorescence procedures, with biotinylated preparations of the F8, L19 and F16 antibodies, which are specific to the alternatively spliced extra domain A and extra domain B domains of fibronectin and A1 domain of tenascin‐C, respectively. Blood vessels were costained using von Willebrand factor–specific antibodies. In primary cutaneous melanoma lesions, F16 and F8 (but not L19) strongly stained the basal lamina at the interface between epidermis and dermis, with a strikingly complementary pattern. By contrast, metastatic melanoma lesions displayed a strong and diffuse pattern of immunoreactivity with all three antibodies. It was found that the extracellular matrix in melanoma undergoes extensive remodelling during the transition from primary to metastatic lesions. The intense staining of metastatic melanoma lesions by the F8, L19 and F16 antibodies provides a strong rationale for the use of these antibodies and their derivatives for the treatment of melanoma patients and possibly for the personalized choice of the best performing antibody in individual patients.

Long-Term Recurrence Rate of Large and Difficult to Treat Cutaneous Squamous Cell Carcinomas after Superficial Radiotherapy

Background: Surgical excision is the gold standard for cutaneous squamous cell carcinoma (cSCC), however its application is limited in specific cases. Superficial radiotherapy (RTx) is an alternative treatment option, but long-term follow-up data are limited. Objective: To determine the outcome of superficial RTx of cSCC in correlation to histological differentiation grade and tumor localization. Methods: The outcome of 180 large cSCCs after superficial RTx between 1960 and 2004 was retrospectively reviewed. Results: Mean tumor size was 3.5 cm2 (SD 7.5) and mean follow-up period was 4.9 years (SD 4.7). Relapse-free survival was 95.8 and 80.4% after 1 and 10 years. Two-year relapse-free survival was 94.8% for good, 88.9% for moderate and 85.7% for poor differentiated tumors. Five-year relapse-free survival was highest in cSCCs located around the eyes (100%) and cheeks (90.9%). Conclusion: Superficial RTx is an effective alternative for cSCC if surgery is difficult due to localization or concomitant disease.

Intense pulsed light.

In addition to lasers, intense pulsed light (IPL) sources are widely used in medicine to treat various indications, such as vascular lesions, irregular pigmentation and hypertrichosis. In contrast to lasers, IPL systems are broadband flash lamps that emit polychromatic incoherent light ranging from visible to infrared (500-1,300 nm). Optical filters are used to tailor the polychromatic light to specific needs. As a broad range of wavelengths are delivered, treatment of multiple chromophores--including melanin, hemoglobin, water and collagen--within the same exposure is possible.

Management of Split-Thickness Skin Graft Donor Sites: A Randomized Controlled Trial of Calcium Alginate versus Polyurethane Film Dressing

Background: Split-thickness skin graft (STSG) donor sites sometimes cause more postoperative morbidity for patients than the wound covered with the graft. Yet, there is no consensus on which dressings are best suited to treat these donor sites. Objective: To evaluate two commonly used modern wound dressings in the postoperative healing of STSG donor sites in a prospective randomized controlled trial. Methods: 38 patients were randomly assigned to treatment of an STSG donor site with an alginate dressing or a polyurethane film dressing. The primary outcome measures were postoperative pain scores, secondary outcome variables were time to epithelialization, dressing changes and complications. Results: Postoperative pain on day 1 was significantly lower in the polyurethane film group (2.05 vs. 0.79, p = 0.035) as compared to the alginate group. This difference was not detected on day 5 (0.89 vs. 0.53, p = 0.52). Time to epithelialization did not differ significantly between the two dressing groups. There were more dressing changes in the polyurethane film group and problems with leakage. Conclusion: Whereas film dressings resulted in initially lower pain scores, alginate dressings caused fewer additional dressing changes and less leakage.

Basal cell carcinoma: A paradigm for targeted therapies

Introduction: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012. Areas covered: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials. Expert opinion: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary.

Facial Blaschkitis: Case and Review

We report on a 15-year-old female with a 3-month history of a pruritic, erythematous cutaneous eruption on the right cheek and perioral area. The lesion had a linear distribution following the lines of Blaschko. Histopathological findings and direct immunofluorescence were compatible with chronic cutaneous lupus erythematosus (LE). Treatment with topical steroids and systemic antimalarial agents over 2 months showed hardly any improvement contrary to similar cases reported in the literature in the past. Histological findings move this case close to LE. However, the unusual clinical presentation as well as the resistance to antimalarial drugs do not fully allow to confirm this suspicion. Therefore, we recommend to call this new entity LE-like facial Blaschkitis of the adult.

In vivo profiling reveals immunomodulatory effects of sorafenib and dacarbazine on melanoma

Sorafenib is a multi-kinase inhibitor used alone or in combination with dacarbazine to treat metastasized melanoma. Our study investigated the relationship between metabolic response assessed by PET-CT and global transcriptome changes during sorafenib and dacarbazine therapy in patients with advanced melanoma. We conducted an open-label, investigator-initiated study that enrolled 13 sorafenib-naïve Stage IV melanoma patients, whose metastases were accessible for repeated biopsies. Treatment regimen included orally administered sorafenib and intravenous dacarbazine. Biopsies of skin or superficial lymph node metastases were taken before treatment (baseline), during sorafenib and after dacarbazine therapy and used for transcriptional profiling and validation experiments. Serum samples were evaluated for cytokine production. Metabolic response to therapy was observed in 45.5% of patients. The study drugs were well tolerated. We observed a clear upregulation of interferon (IFN)-stimulated immune response genes in profiled metastases. The IFNγ-induced gene signature seemed to be enhanced after addition of dacarbazine to sorafenib. Serum IFNγ also increased during therapy, particularly after addition of dacarbazine. Induction of IFNγ stimulated genes correlating with increased serum IFNγ was predictive of better clinical outcome and responders who had significantly higher serum IFNγ levels lived longer. Our data reveal in situ changes in melanoma metastases during treatment with sorafenib and dacarbazine and suggest an additional mechanism of action through immunomodulation.

A Prospective Trial Comparing Q-Switched Ruby Laser and a Triple Combination Skin-Lightening Cream in the Treatment of Solar Lentigines

BACKGROUND Quality-switched (QS) laser therapy is a safe and well-established treatment option for removing solar lentigines. Triple combination therapy (TCT) with the active pharmaceutical ingredients hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03% is often used for skin-lightening. OBJECTIVE This prospective, open-label trial compares the efficacy and safety of a QS Ruby laser (QSRL) and a TCT in the treatment of solar lentigines. METHODS In total, 15 patients with symmetrically distributed solar lentigines on the back of both hands were included. The lesions on the back of the right hand were treated in one or 2 sessions with a QSRL, the ones on the back of the left hand with a TCT for 7 weeks accompanied by UV protection. Clinical results were evaluated 4 weeks, 8 weeks, and 20 weeks after baseline. RESULTS Treatment with QSRL provided significant lightening (p = .01) compared with TCT. Both procedures were generally well-tolerated. Comparing the side effects, the laser produced significantly more crusting and hyperpigmentation than the TCT. CONCLUSION Both QSRL and TCT were capable in reducing solar lentigines in Fitzpatrick skin Type I to IV with an acceptable side effect profile. The QSRL provides faster, superior, and long lasting lightening compared with TCT.