Sun exposure and risk of melanoma.
Journal: Arch Dis Child. 2006 Feb;91(2):131-8.
Epub 2005 Dec 2.
Oliveria SA et al 

BACKGROUND: As skin cancer education programmes directed to children and adolescents continue to expand, an epidemiological basis for these programmes is necessary to target efforts and plan for further evaluation. AIMS: To summarise the epidemiological evidence on sun exposure during childhood and adolescence and melanoma risk. METHODS: A literature review was conducted using Medline (1966 to December 2004) to identify articles relating to sun exposure and melanoma. The review was restricted to studies that included sun exposure information on subjects 18 years of age or younger. RESULTS: Migrant studies generally indicate an increased melanoma risk in individuals who spent childhood in sunny geographical locations, and decreasing melanoma risk with older age at arrival. Individuals who resided in geographical locations close to the equator or close to the coast during childhood and/or adolescence have an increased melanoma risk compared to those who lived at higher latitudes or never lived near the coast. The intermittent exposure hypothesis remains controversial; some studies indicate that children and adolescents who received intermittent sun exposure during vacation, recreation, or occupation are at increased melanoma risk as adults, but more recent studies suggest intermittent exposure to have a protective effect. The majority of sunburn studies suggest a positive association between early age sunburn and subsequent risk of melanoma. CONCLUSION: Future research efforts should focus on: (1) clarifying the relation between sun exposure and melanoma; (2) conducting prospective studies; (3) assessing sun exposure during different time periods of life using a reliable and quantitative method; (4) obtaining information on protective measures; and (5) examining the interrelations between ability to tan, propensity to burn, skin type, history of sunburns, timing and pattern of sun exposure, number of nevi, and other host factors in the child and adolescent populations.  

Tanning and skin cancer.
Journal: Pediatr Dermatol. 2005 Nov-Dec;22(6):501-12.
Abdulla FR et al 

Skin cancer is a large and growing problem in the United States . Sun and other ultraviolet (UV) light exposures play a key role in the development of skin cancer. Pediatricians can play an important role in counseling patients and are in a position to help educate children and their families about skin cancer. The purpose of this review is to familiarize pediatricians with the magnitude of the skin cancer problem and the evidence that ultraviolet light exposure, particularly indoor tanning, contributes to this problem. We reviewed the literature on ultraviolet light and skin cancer (based on a MEDLINE search of articles using the headings "ultraviolet light" and "skin cancer") and found that skin cancer is the most rapidly growing cause of cancer deaths in the United State. There is strong epidemiologic evidence for the relationship between UV exposure and nonmelanoma skin cancer and growing evidence for the relationship between indoor tanning and melanoma. We recommend that pediatricians counsel children and their parents about UV protection. Measures such as use of sunscreen and hats for outdoor play, both at home and in school, should be encouraged.

Ultraviolet immunosuppression: mechanisms and consequences.
Journal: Dermatol Clin. 2006 Jan;24(1):19-25.
Hanneman KK et al 

It is well recognized that exposure to solar radiation has several detrimental consequences, both acute and chronic. The suppression of immune functions remains one of the most intriguing phenomena brought about by ultraviolet (UV) radiation. This concept has challenged experts from various disciplines including dermatology, immunology, and photobiology. Although controversies exist regarding the mechanisms involved, the consensus is that UV immune suppression contributes significantly to the growth of cutaneous malignancies--both melanoma and nonmelanoma skin cancer. It is therefore a critical issue to be addressed in the context of developing and using sun protection strategies.    

Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma.
Journal: Curr Opin Oncol. 2006 Mar;18(2):173-9.
Pho L et al 

PURPOSE OF REVIEW: The clinical phenotypes of familial melanoma syndromes and genetic and environmental interactions are reviewed to summarize the current status of the field and to identify gaps in molecular and clinical investigations. RECENT FINDINGS: The familial melanoma syndromes are associated with germline mutations in three highly penetrant gene products: p16, alternate reading frame, and cyclin-dependent kinase 4. Certain variants in a low-penetrance gene, MC1R, the melanocortin 1 receptor gene, increase melanoma risk to a lesser extent and act as a genetic modifier when cosegregating with a deleterious p16 gene. The penetrance of these melanoma-predisposing genes is largely influenced by ultraviolet exposure across geographic latitude. Yet cumulative studies are conflicting on whether ultraviolet radiation, including sunburns, early childhood and adolescent sun exposure, and chronic exposure, increases melanoma risk in familial melanoma. To date, the clinical phenotypes of increased number of atypical nevi and nevi body distribution are independent risk factors for melanoma risk, regardless of family history. The atypical mole syndrome cannot reliably predict melanoma germline mutations but increases melanoma risk in p16 mutation carriers. Familial melanoma patients develop melanomas earlier and are prone to developing multiple primary melanomas. Other than these two differences, familial and sporadic melanoma share similar histopathology, prognostic factors, and survival rates. SUMMARY: Familial melanoma is an excellent human model system for the investigation of melanoma. Understanding genotype-phenotype and environmental relationships in familial melanoma will likely lead to improved understanding of pathogenesis for all melanoma patients.  

Cutaneous melanoma: prognostic factors.
Journal: Cancer Control. 2005 Oct;12(4):223-9.
Homsi Jetal 

BACKGROUND: Recent data have changed our views of prognostic factors in cutaneous melanoma. While some newer methods have yielded better prognostic information, some insights have evolved as a result of large-scale population-based analyses. METHODS: We review current data on several different prognostic factors and divide these factors according to their application in localized primary melanoma or metastatic melanoma. For each prognostic factor, the level of evidence supporting its use and its applicability to clinical practice are considered. RESULTS: For localized primary melanoma, the dominant predictors of survival include lesion thickness, ulceration, and lymph node involvement. Factors such as age, sex, anatomic location, and satellite/in-transit lesions are important in localized melanoma. Factors currently being investigated are tumor vascularity, vascular invasion, mitotic rate, tumor regression, and tumor-infiltrating lymphocytes. For metastatic melanoma, the most important prognostic factors are site of metastases and the presence of elevated serum lactic dehydrogenase. The value of these prognostic factors to clinicians caring for melanoma patients is discussed. CONCLUSIONS: A better understanding of prognostic factors in cutaneous melanoma has evolved over the last decade, allowing oncologists to provide appropriate treatment for their patients. Many of the prognostic factors are interrelated. In the near future, it is expected that several molecular genetic factors will provide more insight into the prognosis of patients with melanoma.    

Should all melanoma patients undergo sentinel lymph node biopsy?
Journal: Curr Opin Oncol. 2006 Mar;18(2):185-8.  
Ra JH, McMasters KM, Spitz FR 

A Department of Surgery, Hospital of the University of Pennsylvania , Philadelphia , Pennsylvania , USA bDepartment of Surgery, University of Louisville School of Medicine , Louisville , Kentucky , USA .   PURPOSE OF REVIEW: It is now well established that sentinel lymph node biopsy is a powerful test to predict prognosis for melanoma patients. Controversy exists, however, regarding the appropriate selection of patients for sentinel lymph node biopsy, especially among patients with thin melanomas (< 1 mm Breslow thickness), thick melanomas (> 4 mm Breslow thickness), or locally recurrent melanoma. RECENT FINDINGS: The majority of the studies in the past 2 years regarding sentinel lymph node biopsy have been concerned with identifying factors that can better predict regional nodal metastasis and survival. Other studies have proposed a better risk stratification model, which includes these factors, to best select those patients at increased risk of nodal positivity. SUMMARY: Although much research has been done to select appropriate patients for sentinel lymph node biopsy based on multiple prognostic factors, further studies are necessary to completely define the indications for this procedure in patients with thin, thick and locally recurrent melanomas.    

An overview of ultraviolet radiation, sunscreens, and photo-induced dermatoses.
Journal: Dermatol Clin. 2006 Jan;24(1):9-17.
Lowe NJ 

The incidence of sunlight-induced skin aging and skin cancers, particularly melanoma skin cancer, has been increasing in many parts of the world. Authorities are recommending primary prevention programs to reduce cutaneous photodamage and skin carcinogenesis. An integral component of these programs is the use of protective clothing and effective sunscreens. Most modern sunscreens have highly efficient absorption or reflecting capabilities throughout ultraviolet B, partly ultraviolet A, and in some instances infrared wavelengths. Over the last several years, more efficient sunscreening ingredients have been developed for improved skin protection. More recently, direct evidence has demonstrated the effectiveness of sunscreens in their ability to reduce the incidence of solar keratoses. This article reviews the protectiveness of sunscreens and assays that predict their levels of protection.    

Melanoma immunotherapy
Journal: Med Sci (Paris). 2006 Feb;22(2):183-187.
Ghiringhelli F and Zitvogel L.  

Melanoma incidence increases and conventional antitumor therapies are often ineffective, encouraging the design of novel therapies. Several lines of evidence support the notion of an immunological control of melanoma growth. Based on this information, active immunotherapy (vaccination) and adoptive immunotherapy trials (T cell therapy) were conducted in metastatic melanoma patients. The proof of principle of effective immunotherapy was brought up by pionnering trials using tumor infiltrated lymphocytes in lymphodepleted recipients or anti-CTLA4 Ab leading to tumor eradication but also autoimmune diseases. With the identification and characterization of tumor antigens recognized by cytotoxic T lymphocytes, the utilization of tumor rejection antigens along with adjuvants become available as tumor vaccines. The last five years have witnessed the emergence of dendritic cell based-vaccines that were efficient in priming and/or boosting T cell responses in normal volunteers and patients. This review highlights preclinical bases of cancer vaccines, their clinical development and discusses their limits. Correlations between immunomonitoring and tumor regressions await larger trials. double dagger.    

Prognosticators of melanoma, the melanoma report, and the sentinel lymph node.
Journal: Mod Pathol. 2006 Feb;19 Suppl 2:S71-87.
Crowson AN et al 

Since the 1960s, the clinical characteristics of melanoma, its histopathology and its biological basis have been the subject of intense study at pigmented lesion clinics in North America, Europe, and Australia . More recently, the immense database of the Melanoma Committee of the American Joint Committee on Cancer (AJCC) has been exploited through complex mathematical models to measure the impact of various histologic features of primary melanomas and of sentinel lymph node deposits and to correlate these parameters with patient survival. The wealth of modern information available to pathologists and clinicians has become of vital interest to the prognostication of the individual patient with melanoma. The purpose of this review is to bring to the attention of anatomic pathologists the essential characteristics of the pathology report for primary cutaneous melanoma in the modern era.Modern Pathology (2006) 19, S71-S87. doi:10.1038/modpathol.3800517.    

Unusual variants of malignant melanoma.
Journal: Mod Pathol. 2006 Feb;19 Suppl 2:S41-70.
Magro CM et al 

A potential diagnostic pitfall in the histologic assessment of melanoma is the inability to recognize unusual melanoma variants. Of these, the more treacherous examples include the desmoplastic melanoma, the nevoid melanoma, the so-called 'minimal-deviation melanoma,' melanoma with prominent pigment synthesis or 'animal-type melanoma,' and the malignant blue nevus. Also problematic are the unusual phenotypic profiles seen in vertical growth phase melanomas; these include those tumors whose morphological peculiarities mimic cancers of nonmelanocytic lineage and those melanomas that express aberrant antigenic profiles not commonly associated with a melanocytic histogenesis. Metaplastic change in melanoma, balloon cell melanoma, signet-ring cell melanoma, myxoid melanoma, small cell melanoma and rhabdoid melanoma all have the potential to mimic metastatic and primary neoplasms of different lineage derivations. Abnormal immunohistochemical expression of CD 34, cytokeratins, epithelial membrane antigen, and smooth muscle markers as well as the deficient expression of S100 protein and melanocyte lineage-specific markers such as GP100 protein (ie HMB-45 antibody) and A103 (ie Melan-A) also present confusing diagnostic challenges. In this review, we will discuss in some detail certain of these novel clinicopathologic types of melanoma, as well as the abnormal phenotypic expressions seen in vertical growth phase melanoma.Modern Pathology (2006) 19, S41-S70. doi:10.1038/modpathol.3800516.  

Systemic strategies for chemoprevention of skin cancers in transplant recipients.
Journal: Clin Transplant. 2005 Dec;19(6):726-34.
Kovach BT et al 

BACKGROUND: Solid organ transplant recipients (OTRs) are a growing population at high risk for cutaneous neoplasms, resulting in significant post-transplant morbidity and mortality. Management of malignant and pre-malignant cutaneous lesions in transplant recipients is challenging, making prevention of such neoplasms paramount. The objectives of the present study are to review and analyze systemic strategies for chemoprevention of malignant and pre-malignant cutaneous neoplasms in OTRs. METHODS: MEDLINE and PubMed searches were performed to identify studies with original data quantifying the effects of systemic agents on the development of malignant cutaneous neoplasms in patients with solid organ transplants. RESULTS: We identified nine studies describing 111 transplant recipients that quantified the effects of oral retinoids on cutaneous neoplasms. A majority of the studies found a decrease in the number of malignant and pre-malignant cutaneous lesions in patients treated with systemic retinoids, with several studies noting increased benefit in those patients with multiple previous skin cancers. Multiple studies described a rebound effect, with increased numbers of neoplasms occurring following discontinuation of retinoids. Side effects often limited dosing, but required discontinuation of retinoids in a minority of patients. No studies were identified that adequately quantified the effects of other systemic agents on skin cancer incidence in this population. CONCLUSIONS: Although systemic retinoids are frequently used for chemoprevention of cutaneous malignancies in OTRs, the data supporting their use are composed largely of small uncontrolled case reports and case series. However, the available data suggest that retinoids have chemopreventative effects in this population. Although optimal dosing and indications for initiation of systemic retinoid therapy are not conclusive from the data, it suggests that retinoids are most effective in patients with multiple previous non-melanoma skin cancers. Side effects and beneficial effects were noted across a wide range of doses, suggesting that retinoids should be initiated at a low dose and increased as tolerated to a minimally effective dose. Further investigation through randomized controlled trials is needed to further clarify the tolerability and efficacy of multiple dosing regimens on the incidence of pre-malignant and malignant lesions in transplant recipients. The therapeutic role of other systemic agents in the transplant population has not been established.    

Malignant melanoma in pregnancy.
Journal: Obstet Gynecol Clin North Am. 2005 Dec;32(4):559-68.  

This article provides a concise overview of issues relating to melanoma and pregnancy, including pregnancy-associated risk and prognosis, and briefly summarizes results from relevant reports that have been published in recent years. The bulk of evidence amassed over the past half century suggests that pregnancy does not significantly affect the risk of developing malignant melanoma. Further, pregnancy does not seem adversely to influence overall survival from the disease. Most studies found no difference in overall survival between pregnant and nonpregnant women with melanoma. Recent reports from large-scale, population-based studies support these conclusions.    

Cutaneous melanoma susceptibility and progression genes.
Journal: Cancer Lett. 2005 Dec 18;230(2):153-86.
de Snoo FA, Hayward NK 

This review aims to provide an up-to-date view on our understanding of the molecular genetics of melanoma development. It gives an overview of genes (and loci) currently known to be substantially involved in melanoma predisposition and progression. Broadly, the review falls into 3 sections: genes/loci involved in melanoma susceptibility through germline mutation, tumor suppressor genes somatically mutated or deleted in melanoma, and oncogenes mutated somatically in melanoma. The main cellular pathways in which these genes are involved are summarized and discussed. From this it is evident that abberations of cell cycle regulation, DNA repair and receptor-mediated signal transduction are important for melanocytic neoplasia.  

Cutaneous melanoma: methods of biopsy and definitive surgical excision.
Journal: Dermatol Ther. 2005 Sep-Oct;18(5):387-93.
Riker AI et al 

The proper method of biopsy and definitive surgical excision of cutaneous melanoma is vital for optimal patient outcome. Clearly, the present authors' understanding of the pathophysiology of cutaneous melanoma continues to change at a rapid pace. Indeed, as the present authors' research efforts begin to expose some of the mysteries of melanoma, so do they begin to better understand the intricacies of this dreaded cancer. This article will highlight methods of biopsy for melanoma and the management of the primary tumor. The present authors review current recommendations for excision margins for the primary tumor, usefulness of lymphoscintigraphy, timing of definitive surgical excision, and issues unique for head and neck melanoma.  

Sentinel node biopsy for thin melanomas: which patients should be considered?
Journal: Cancer Control. 2005 Oct;12(4):230-5.
Puleo CA et al 

BACKGROUND: As the incidence of melanoma increases, thin melanomas are being diagnosed at an increasingly frequent rate. Currently available prognostic factors are limited in their ability to reliably discriminate which patients will manifest regional nodal metastasis and would be identified early through sentinel node biopsy. METHODS: We summarized our experience with sentinel node biopsy for patients with cutaneous melanomas less than 1.00 mm in Breslow thickness, with evaluation of Clark level as a predictor of positive sentinel node metastasis. RESULTS: Among the 409 patients identified, micrometastases were found in the sentinel node in 20 patients, for an overall incidence of nodal progression of 4.9%. A total of 252 (62%) were Clark level II or III (11 of whom had a positive sentinel node) and 157 (38%) were Clark level IV (9 of whom had a positive sentinel node). We reviewed the literature to identify reliable indicators that might be helpful in determining which patients with "thin melanomas" would be likely to manifest regional progression to warrant routinely undergoing a preoperative lymphoscintigraphy followed by a sentinel node biopsy. CONCLUSIONS: Based on available data, patients with melanomas between 0.75 and 1.00 mm are appropriate candidates to be considered for sentinel node biopsy after discussing the likelihood of finding evidence of nodal progression, the risks of sentinel node biopsy (including the risk of a false-negative result), and the lack of proven survival benefit from any form of surgical nodal staging.    

Melanoma immunotherapy: past, present, and future.
Journal: Curr Pharm Des. 2005;11(27):3461-73.  

The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells.    

Treatment strategy for cutaneous malignant melanoma.
Journal: Int J Clin Oncol. 2005 Oct;10(5):311-7.
Tsutsumida A et al 

The incidence of cutaneous malignant melanoma has been rising in Japan . With education, recent advances in accurate diagnosis and establishment of the concept, more lesions are being diagnosed as early melanomas, for which there is a high cure rate. However, many patients will still present with thicker lesions or nodal involvement, which carries a significantly worse prognosis. Recently there have been advances in the management and treatment of cutaneous melanoma. This article reviews the clinical evidence behind the current treatment recommendations for primary and recurrent cutaneous melanoma in Japan .    

Melanoma and ionizing radiation: is there a causal relationship?
Journal: Radiat Res. 2005 Nov;164(5):701-10.
Fink CA and Bates MN 

This review was initiated in response to concerns that ionizing radiation could be a cause of melanoma. Studies presenting the relative risks for melanoma after external ionizing radiation exposure were in seven categories: (1) The Canadian Radiation Dose Registry, (2) nuclear industry workers, (3) subjects near nuclear test blasts, (4) survivors of the atomic bombings of Japan , (5) airline pilots and cabin attendants, (6) recipients of medical radiation, and (7) radiological technicians. Relative risks for leukemia in each of the studies were used to confirm the likelihood of exposure to ionizing radiation. When studies within a category were compatible, meta-analytic methods were used to obtain combined estimates of the relative risk, and a meta-regression analysis of melanoma relative risk compared to leukemia relative risk was used to examine consistency across exposure categories. Generally, exposure categories with elevated relative risks of leukemia had proportionately elevated relative risks of melanoma. This suggests that people exposed to ionizing radiation may be at increased risk of developing melanoma, although alternative explanations are possible. Future epidemiological studies of ionizing radiation effects should include melanoma as an outcome of interest.    

Screening for cutaneous melanoma.
Journal: Surg Oncol Clin N Am. 2005 Oct;14(4):799-811.
Lange JR and Balch CM 

Current data do not support widespread population-based screening for melanoma. While the incidence of melanoma is high, the overall mortality is low, and thus any potential benefit of screening the general population is hard to demonstrate. No randomized controlled trial showing reduction in mortality has ever been completed and, given the expense and time necessary for such a trial, probably will never be completed. The idea of skin screening remains appealing for this common, visible malignancy which is eminently treatable when detected early. Efforts should be focused on populations at particularly high risk of developing melanoma and on those at high risk of death from melanoma once diagnosed. Persons in kindreds of familial melanoma, and persons who have atypical mole syndrome, those who have a prior diagnosis of melanoma, or those who have diagnosed atypical nevi are all reasonable candidates for routine screening, based on lower-level evidence in the absence of randomized clinical trials targeting these groups. Programs targeting persons of low socioeconomic status and targeting white men over the age of 50 could address groups known to beat especially high risk of melanoma mortality.    

New developments in the staging of melanoma.
Journal: Cancer Invest. 2005;23(6):561-7.
Baruch AC et al 

As the incidence of melanoma increases, so does the search for new staging techniques that may provide important prognostic information and aid in the detection of early metastatic disease. The application of molecular techniques may provide powerful new tools in this search. This review summarizes recent findings obtained by means of conventional RT-PCR, cDNA arrays, and proteomics in the investigation of human melanoma. The molecular tools discussed in this review demonstrate how global transcript and protein analysis might contribute not only to the staging of melanoma, but may hold great promise in improving the diagnosis and treatment of this disease.    

Clinical applications of sentinel lymph-node biopsy for the staging and treatment of solid neoplasms.
Journal: Minerva Chir. 2005 Aug;60(4):217-33.  
Gipponi M.  

A review of the clinical applications of sentinel lymph node (sN) biopsy has been performed with the aim of defining the rationale, the methods of detection, the accuracy, and the current indications to sN biopsy in different solid neoplasms. In melanoma patients, sN biopsy represents a standard procedure for staging purpose, although its therapeutic value is still under examination. The sN is an accurate method for the pathologic staging of the axilla in patients with early stage breast cancer, and it can be useful for the selection of patients with axillary metastasis who should undergo standard axillary dissection. In gynecologic malignancies, appreciable results are available in patients with vulvar and cervical cancer only. Patients with squamous cell vulvar cancer may benefit by sN biopsy because a complete bilateral inguino-femoral lymph-node dissection may be avoided whenever the sN is free of metastasis. As regards to cervical cancer, further studies are required with the combined technique (blue dye injection and gamma-probe guided surgery), which seems more promising, before abandoning pelvic lymphadenectomy in patients with histologically-negative sN. The experience in urologic cancer deals mainly with penile and prostate cancer; the modern procedures for the dynamic detection of sN are going to clarify its role in the surgical management of penile cancer; as regards to prostate cancer, very preliminary results suggest that the sN biopsy may enhance the pathologic staging of this neoplasm compared to modified pelvic lymphadenectomy, due to the individual variability of the lymphatic drainage of this cancer. In patients with clinically node-negative squamous head and neck cancer, the reliability of sN-guided neck lymph node dissection seems promising. The sN biopsy is also technically feasible in patients with differentiated thyroid cancer; however, the future role of this procedure in the clinical decision-making of these patients remains to be defined due to the questionable biological meaning of nodal metastases. Patients with non-small-cell lung cancer should be investigated by means of radiotracers injected at the time of thoracotomy or under CT-scan guidance in order to achieve a satisfactory identification rate (over 80%); the focused histopathologic staging of the sN improves current pathologic staging by conventional bi-valve assessment of all the lymph nodes of the surgical specimen; moreover, the prognostic role of isolated N2 metastasis can be better elucidated. In patients with gastrointestinal malignancies, the intraoperative lymphatic mapping with sN biopsy have suggested that the lymphatic drainage of the gastrointestinal tract is much more complicated than other sites, skip metastasis being rather frequent. In patients with gastric cancer, current data show that it can be detected by means of peritumoral injection of indocyanine green; the detection of tumor positive lymph nodes beyond the perigastric area could select patients amenable to D2 lymphadenectomy. As regards to colorectal cancer patients, the focused analysis of the sN may reveal disease that might otherwise go undetected by conventional surgical and pathological methods, and those patients which are upstaged can benefit by adjuvant chemotherapy. Finally, in patients with Merkel cell carcinoma, notwithstanding the limited experiences with sN biopsy, sN histology seems to predict regional lymph node status and may aid in selecting which patients are amenable to therapeutic lymph node dissection.    

Childhood melanoma: update and treatment.
Journal: Int J Dermatol. 2005 Sep;44(9):715-23.
Huynh PM et al 

Childhood melanoma is a rare but potentially fatal disease that is important to include in the differential diagnosis of any pigmented lesion in a child. The best prognosis is achieved with early diagnosis and definitive surgical excision. Adjuvant chemotherapy and immunotherapy are options for those with more advanced tumors. Melanoma in children must be treated as aggressively as in adults because childhood melanoma may be equally devastating.    

Therapeutic vaccines for melanoma: current status.
Journal: BioDrugs. 2005;19(4):247-60.
Faries MB and Morton DL 

Considerable clinical research is focused on improving systemic treatments for melanoma. Unfortunately, the disease is generally resistant to standard chemotherapy, and surgical excision remains the best treatment option whenever possible. However, complete spontaneous regression of melanoma has been observed in some patients, a phenomenon thought to be mediated by the immune system. This has stimulated attempts to manipulate the immune system for therapeutic purposes. Vaccination is a form of active specific immunotherapy, such that the response against the tumor is actively generated by the patient's immune system, and is directed against a particular cellular target or specific membrane antigen. Numerous approaches to vaccination for melanoma have been investigated, and have become more complex as our understanding of anti-tumor immunity has increased. Vaccines have been shown to induce measurable immunologic responses that may be correlated with improved clinical outcomes in patients with melanoma. Large phase III clinical trials using peptide, ganglioside, and whole-cell tumor antigens are ongoing. Although anti-tumor vaccination has shown promising results in patients with melanoma, to date no vaccine has been approved for routine therapy of melanoma. Recently, a phase III trial evaluating the Canvaxin whole-cell vaccine in stage IV melanoma was halted because of a low likelihood of significant benefit. However, a larger phase III trial for patients with stage III disease was continued and results are awaited with interest.  

Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors.
Journal: Eur J Cancer. 2005 Sep;41(14):2040-59.
Gandini S et al

A systematic meta-analysis of observational studies of melanoma and family history, actinic damage and phenotypic factors was conducted as part of a comprehensive meta-analysis of all major risk factors for melanoma. Following a systematic literature search, relative risks were extracted from 60 studies published before September 2002. Fixed and random effects models were used to obtain pooled estimates for family history (RR = 1.74, 1.41-2.14), skin type (I vs. IV: RR = 2.09, 1.67-2.58), high density of freckles (RR = 2.10, 1.80-2.45), skin colour (Fair vs. Dark: RR = 2.06, 1.68-2.52), eye colour (Blue vs. Dark: RR = 1.47, 1.28-1.69) and hair colour (Red vs. Dark: RR = 3.64, 2.56-5.37), pre-malignant and skin cancer lesions (RR = 4.28, 2.80-6.55) and actinic damage indicators (RR = 2.02, 1.24-3.29). Sub-group analysis and meta-regression were carried out to explore sources of between-study variation and bias. Sensitivity analyses investigated reliability of results and publication bias. Latitude and adjustment for phenotype were two study characteristics that significantly influenced the estimates.    

Adjuvant therapies in the treatment of stage II and III malignant melanoma.
Journal: Surgeon. 2005 Aug;3(4):245-56.
Kavanagh D et al 

BACKGROUND: The incidence of cutaneous melanoma has increased during the past three decades. The development of sentinel lymph node biopsy has facilitated better staging. Despite these improvements, 5-year survival rates for American Joint Committee on Cancer stage II and III disease range from 50%-90%. METHODS: A review of the current literature concerning adjuvant therapies in patients with stage II and III malignant melanomas was undertaken. RESULTS: The focus of adjuvant therapies has shifted from radiotherapy, BCG and levamisole to newer biological agents. Interferon, interleukin and vaccines have been evaluated but none of these agents have demonstrated an increase in overall survival in patients with stage II and III melanoma. Interferon can prolong disease-free interval. CONCLUSION: At present, no adjuvant therapy improves overall survival in patients with stage II and III melanoma. New staging allows more accurate stratification of patients for clinical trials.  

UV-induced skin cancers
Journal: J Dtsch Dermatol Ges. 2005 Sep;3 Suppl 2:S26-31.
Honigsmann H et al

In this review the epidemiology and pathogenetic aspects of UV-induced malignant skin tumours (basal cell carcinoma, squamous cell carcinoma and melanoma) are discussed with regard to current literature. Whereas present knowledge, in particular, gained from experimental data, permits substantial conclusions about the development of squamous cell carcinoma, the situation for basal cell carcinoma and melanoma does not appear to be unequivocally clear. One reason for this can be explained by the fact that there exist no adequate animal models for these tumours that could exactly reflect the biological behaviour in man. Although there is no doubt about a causal role of sun exposure, this relationship is based on mere epidemiological facts.    

Sunscreens - which and what for?
Journal: Skin Pharmacol Physiol. 2005 Nov-Dec;18(6):253-62. Epub 2005 Aug 19.
Maier T and Korting HC 

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright 2005 S. Karger AG, Basel    

Immunotherapy for melanoma: the good, the bad, and the future.
Journal: Curr Oncol Rep. 2005 Sep;7(5):383-92.
Poehlein CH, Ruttinger D, Ma J, Hu HM, Urba WJ, Fox BA.  

The past 20 years have seen remarkable advances in our understanding of the molecular and cellular processes controlling the development of an anticancer immune response. These advances have spawned a renaissance in the field of cancer immunotherapy, the original targeted therapy, during which investigators have pushed the envelope and translated promising strategies into investigational therapeutics in patients with cancer. An approach that combined nonmyeloablative lymphodepleting chemotherapy with adoptive transfer of tumor-specific CD4 and CD8 T cells exhibited an initial objective response rate of 51% for patients with stage IV melanoma. Although this strategy is extremely challenging, one can expect technological advances that may simplify this approach and further improve outcome.    

Follow-up in patients with localised primary cutaneous melanoma.
Journal: Lancet Oncol. 2005 Aug;6(8):608-21.
Francken AB et al

Follow-up services for patients with localised cutaneous melanoma are widely discussed but there is no international consensus. Our aim was to discuss frequency and duration of follow-up, type of health professional involved, optimum intensity of routine investigation, and patients' satisfaction with follow-up. Searches of the published work were directed at publications between January, 1985, and February, 2004 on recurrences, subsequent primary melanoma, routine tests, and patients' satisfaction. In a selection of 72 articles, 2142 (6.6%) recurrences were reported, 62% of which were detected by the patients themselves. 2.6% of patients developed a subsequent primary melanoma. Most investigators do not support high-intensity routine follow-up investigations. Of the various follow-up investigations requested by physicians, only medical history and physical examination seem to be cost effective. Lymph-node sonography seems to be a promising method for detection, although survival benefit remains to be proven. Patients were found to be anxious about follow-up visits, although other research showed that provision of information to patients was much appreciated. Published work on the follow-up of patients with cutaneous melanoma has mainly been retrospective and descriptive. Recommendations can be given with only a low grade of evidence. For meaningful guidelines to be developed, prospective, high-quality methodological research is needed.    

Cutaneous melanoma: update on prevention, screening, diagnosis, and treatment.
Journal: Am Fam Physician. 2005 Jul 15;72(2):269-76.
Rager et et al 

Melanoma is an increasingly common malignancy, and it affects a younger population than most cancers. Risk factors for melanoma include white race, sun sensitivity, family history of melanoma, and melanocytic nevi. Sunburn and intermittent sun exposure appear to increase the risk of developing melanoma. The role of population-based screening for skin cancer remains unclear. Consistent screening results in the diagnosis of thinner melanomas, but there is no evidence that this leads to decreased mortality. The ABCDs--asymmetry, border, color, diameter--can be used as a guide to differentiate melanoma from benign lesions. Suspicious pigmented lesions should undergo full thickness biopsy. Treatment consists of surgical resection, lymph node evaluation, and systemic therapy for some patients. Prognosis depends on the stage at diagnosis. Patients with melanoma require dose follow-up because they are at risk for recurrence and diagnosis of a second primary tumor. Preventive strategies for melanoma should emphasize seeking shade when outdoors, wearing protective clothing, and avoiding exposure during the peak sunlight hours.    

Increasing number of skin cancer cases--also among the younger
Journal: Lakartidningen. 2005 Jun 27-Jul 10;102(26-27):1972-5.
Tarstedt M et al

The incidence of skin cancer has been increasing for several years. This is the case in malignant melanoma as well as in squamous cell carcinoma and basal cell carcinoma. Skin cancer is most common among the elderly, but is now also more frequently found in younger people. Surgery is often the treatment of choice and this is still the case in malignant melanoma and most cases of squamous cell carcinoma. For basal cell carcinoma, Bowen's disease and actinic keratoses, however, alternative treatments should be considered. Today, dermatologists can offer patients with skin cancer several new treatments besides surgery. These new treatments seem to have the same efficacy but better cosmetic results compared to earlier treatments.    

The perimeter technique for lentigo maligna: an alternative to Mohs micrographic surgery.
Journal: J Surg Oncol. 2005 Aug 1;91(2):120-5.
Mahoney MH et al 

BACKGROUND: Lentigo maligna (LM) presents a challenge for complete surgical excision because of its extensive subclinical spread and predilection for the face. OBJECTIVE: To report our experience using the staged perimeter technique as an alternative to Mohs micrographic surgery for treatment of LM. METHODS: The perimeter procedure was performed on 11 patients with LM between March 2003 and June 2004. Data on patient and lesion characteristics, number of stages required to obtain clear margins, and follow-up was obtained by chart review. RESULTS: A mean of 1.9 stages were required to achieve clear margins. A mean of 7 tissue specimens were sent to pathology per patient for evaluation. After a mean follow-up of 4.7 months, all patients were free of recurrence. CONCLUSIONS: The perimeter technique is a simple method of margin-controlled excision of LM. The main advantage is that all margins are examined with permanent sections. The main drawback is that multiple operative sessions are required to complete the procedure. This technique does not require specific Mohs training and is therefore applicable to non-Mohs surgeons. Copyright 2005 Wiley-Liss, Inc.  

The role of sentinel lymph node biopsy in the management of thin melanoma.
Journal: Am J Surg. 2005 Aug;190(2):196-9.
Wong SL 

The lifetime risk for developing thin (< or =1 mm) melanoma continues to increase steadily. Although generally associated with an excellent prognosis, it also has a proven capacity to metastasize. There has been increasing interest in using sentinel lymph node biopsy to improve staging for thin melanoma. However, it is difficult to define clinicopathologic factors that reliably predict the presence of nodal metastasis. The prognostic significance of a positive sentinel lymph node in thin melanoma remains to be defined.    

Novel agents in development for the treatment of melanoma.
Journal: Expert Opin Investig Drugs. 2005 Jul;14(7):885-92.
Tarhini AA and Agarwala SS 

In 2005, melanoma is estimated to affect 55,000 Americans. Of these, 7700 are estimated to die from the disease. Immunological approaches have yielded the only newly FDA-approved agents for melanoma in 30 years, which includes high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma. A survival advantage was shown in two of three randomised clinical trials with high-dose IFN-alpha2b in the high-risk adjuvant setting. However, both agents are associated with high cost and toxicity rates. A number of novel therapeutic agents are undergoing active clinical investigation. The more promising of these will be discussed in this review, including bcl-2 antisense therapy, v-raf murine sarcoma viral oncogene homologue B1 inhibition, heat-shock proteins, anti-alphavbeta3 integrin monoclonal antibody, thalidomide and newer immunomodulatory drugs, and anti-cytotoxic T lymphocyte-associated protein-4 monoclonal antibody.  

Malignant melanoma: a review.
Journal: Niger Postgrad Med J. 2005 Jun;12(2):125-30.
Dauda MM and Shehu SM

  The incidence of malignant melanoma the most malignant of all skin neoplasms, has doubled within the last 10 years. Exposure to high intensity sunlight, racial susceptibility, hormonal status, age, environmental factors as well as injury have all been shown to play a role individually or synergistically in the activation of the melanocytic oncogen. Controversies still exist in which factors actually determine prognosis, in patients with advanced malignant melanoma. Management has remained even more controversial, with surgical excision, with or without lymphadenectomy, radiotherapy, chemotherapy, laser therapy and more recently immunotherapy and intra-arterial neutron thermal capture therapy, having their proponents and opponents.    

Cutaneous effects of smoking.
Journal: J Cutan Med Surg. 2004 Nov-Dec;8(6):415-23.
Freiman A et al

BACKGROUND: Cigarette smoking is the single biggest preventable cause of death and disability in developed countries and is a significant public health concern. While known to be strongly associated with a number of cardiovascular and pulmonary diseases and cancers, smoking also leads to a variety of cutaneous manifestations. OBJECTIVE: This article reviews the effects of cigarette smoking on the skin and its appendages. METHODS: A literature review was based on a MEDLINE search (1966-2004) for English-language articles using the MeSH terms cutaneous, dermatology, tobacco, skin, and smoking. An additional search was subsequently undertaken for articles related to smoking and associated mucocutanous diseases, with the focus on pathogenesis and epidemiologic data. Articles presenting the highest level of evidence and latest reports were preferentially selected. RESULTS: Smoking is strongly associated with numerous dermatologic conditions including poor wound healing, wrinkling and premature skin aging, squamous cell carcinoma, psoriasis, hidradenitis suppurativa, hair loss, oral cancers, and other oral conditions. In addition, it has an impact on the skin lesions observed in diabetes, lupus, and AIDS. The evidence linking smoking and melanoma, eczema, and acne is inconclusive. Anecdotal data exist on the possible protective effects of smoking in oral/genital aphthosis of Behcet's disease, herpes labialis, pyoderma gangrenosum, acral melanoma, and Kaposi's sarcoma in AIDS patients. CONCLUSIONS: An appreciation of the adverse cutaneous consequences of smoking is important. Dermatologists can play an integral role in promoting smoking cessation by providing expert opinion and educating the public on the deleterious effects of smoking on the skin.    

The role of ultraviolet irradiation in malignant melanoma
Journal: Hautarzt. 2005 Jul;56(7):687-96; quiz 697.
Berking C.  

The incidence of melanoma has been rising during the past 40 years and may be the result of lifestyle changes that have led to an increased sun exposure in fair-skinned people. Ultraviolet radiation (UVR) is believed to be the main causative factor in melanoma development with an acute intermittent exposure being more relevant than a chronic cumulative one. While UVB (280-320 nm) can directly cause DNA damage (UVB fingerprint mutations) in the cells of the epidermis, UVA (320-400 nm) induces damage indirectly by the formation of reactive oxygen species. Since UV-associated mutations are rare in melanoma, it is speculated that UVR supports melanoma development by indirect effects, e.g. immunosuppression or stimulation of growth factors in the skin. Taken together, animal models and epidemiological data suggest a UVA-associated pathogenesis of melanoma that puts into question the effectiveness of sunscreens in melanoma prevention.    

UV-induced skin cancer: similarities--variations.
Journal: J Dtsch Dermatol Ges. 2005 Jul;3(7):493-503.
Boukamp P.  

Skin cancer, the most common cancer world wide, encompasses different tumor entities, the keratinocyte-derived basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) as well as the neuroectodermal malignant melanoma (MM) and the neuroendocrine Merkel cell carcinomas (MCC). While knowledge is significantly increasing about genetic changes contributing to BCCs and MMs, our understanding for the development and progression of SCCs and MCCs is still fragmentary. This review, thus, aims, on the one hand to summarize the present knowledge without claiming completeness and, on the other hand, to provide information on the HaCaT in vitro skin carcinogenesis model that is used to evaluate the functional consequence of genetic aberrations believed to play a role in skin cancer development and progression.    

Metastatic melanoma: is biochemotherapy the future?
Journal: Med Oncol. 2005;22(2):101-11.
Alexandrescu DT et al 

Current treatment options in metastatic melanoma are of limited efficacy. Achievement of durable responses with biological agents, and the possibility to complement the higher response rate of chemotherapy and combined chemotherapy by prolonged duration of responses, led to development of biochemotherapy. Although a clear improvement in response rate (40-60% OR) resulted in some studies of the combined modality, several phase III studies had mixed results on the duration of survival. Various timeframes between the administration of chemotherapy and biologics have been tested, ranging between concurrent biochemotherapy, 1 d (immediately sequential), and up to 3 wk (long sequence or alternating). An analysis of the trend of responses and survival versus the duration of the chemobiotherapy sequence showed that, as the timeframe between chemo and bio components increases, the overall survival, survival of complete responders, and survival of partial responders appear to increase, but the effect is only present for the chemo-bio, and not for the bio-chemo sequence. Because there is no current explanation for this observation, it appears possible that the interaction between components of biochemotherapy results in a double effect: an increase in the immediate response reflected in the OR, CR, PR on one side, and an increase in survival on the other side. An analysis of mechanisms involved in the response leads us hypothesize that macrophage activation, as measured by the neopterin levels, may correlate with the survival of patients undergoing biochemotherapy, while the generation of nitric oxide, acting synergistically with chemotherapy in producing tumor cell killing, may be reflected in the overall response rate seen with the biochemotherapy combinations.    

Lentigo maligna : prognosis and treatment options.
Journal: Am J Clin Dermatol. 2005;6(3):151-64.
Stevenson O and Ahmed I.  

Lentigo maligna is a premalignant melanocytic neoplasm occurring on the sun-exposed skin of the middle-aged and elderly. It is believed to represent the in situ phase of lentigo maligna melanoma and, as such, cure is usually the aim of treatment. However, factors such as site and size of lesion and patient co-morbidities may influence the treatment modality undertaken. Surgical excision is the treatment of choice to obtain clinical and histologic clearance, but many other modalities have been used with variable success. Mohs micrographic surgery is associated with the lowest recurrence rate at 4-5%, but conventional surgery, cryotherapy and radiotherapy also yield good results, with recurrence rates in the order of 7-10%. Other treatments have been tried but currently there are not enough data to support their routine use. In order to make the best decision regarding appropriate management of lentigo maligna, the dermatologist or surgeon must be aware of all the options available and the evidence supporting their use.    

Skin cancer in the elderly.
Journal: In Vivo. 2005 May-Jun;19(3):643-52.
Syrigos KN et al

With the significant increase in the average life-span in the industrial world, skin cancer has become a great health concern. There are various epidemiological, biological and molecular data suggesting that skin cancer is predominantly a disease of the elderly, since approximately 53% of skin cancer-related deaths occur in persons more than 65 years old. With regard to the management of elderly patients with skin cancer, this should be individualized depending upon the clinical performance status, and age alone should not constitute an obstruction for the administration of the optimal treatment. Since elderly patients with melanoma have a worse prognosis, emphasis should be given to primary and secondary prevention. Physicians treating elderly patients should be trained in an individualized approach to these patients and encouraged to participate in programs for the early detection of suspicious skin lesions.    

Treatment of metastatic malignant melanoma.
Journal: Curr Treat Options Oncol. 2005 May;6(3):185-93.
Atallah E and Flaherty L.  

The rapid increase in incidence of malignant melanoma has not been associated with better therapeutic options over the years. Single-agent chemotherapy or immunotherapy remain the treatments of choice when systemic therapy is offered. Dacarbazine (DTIC) is the chemotherapy of choice with a response rate of 16%. Other chemotherapies, including cisplatinum, paclitaxel, docetaxel and the DTIC analogue temozolomide, have shown activity in this disease. Based on their single-agent activity, several combination chemotherapies have been investigated with preliminary results that appeared promising. However, in randomized phase III trials the two most active chemotherapy combination regimens, cisplatin, vinblastine, and DTIC (CVD) and the Dartmouth regimen (DTIC, cisplatin, bischloroethylnitrosourea , and tamoxifen), did not prove to be superior to single-agent DTIC for overall survival. Immunotherapy with either interleukin (IL)-2 or interferon (IFN) has demonstrated response rates of 10% to 15% in appropriately selected patients. In patients who achieve a complete response, responses can be of greater durability than those with chemotherapy. However, IL-2 and IFN administration are associated with multiple side effects, and only physicians experienced in the management of such therapies should administer them. The potential benefit of combining chemotherapy with immunotherapy has led to multiple phase II trials of biochemotherapy that appeared to be associated with higher response rates and longer median survivals. However, several phase III trials have been completed that have not consistently demonstrated an improvement in either response rates or overall survival, and these approaches to therapy cannot be routinely recommended outside the context of a clinical trial. The surgical resection of isolated metastatic disease has demonstrated an important palliative benefit in those patients who present with solitary single-organ disease with the exception of the liver. Radiation has an important role in the palliative management of brain metastasis and symptomatic bony metastasis. Both stereotactic radiosurgery and whole brain radiotherapy have been used alone and in combination to benefit patients in this troubling clinical circumstance. Isolated limb perfusion and a newer technique, isolated limb infusion have demonstrated high response rates for those uncommon patients who develop recurrent disease isolated to a limb. In our opinion, if complete metastasectomy is not feasible and in the absence of brain metastases, single-agent IL-2 is a good initial treatment choice in appropriately selected patients. Single-agent chemotherapy with DTIC is the treatment of choice for patients who are not candidates for IL-2. Adoptive immunotherapy combining nonmyeloablative chemotherapy with high-dose IL-2 is a potentially promising therapeutic strategy under investigation. Targeted therapy is also an area of promising development as single agents, in combination, and combined with chemotherapy. The latter will be the focus of at least one upcoming cooperative group phase III trial.    

Melanoma treatment update.
Journal: Dermatol Clin. 2005 Apr;23(2):323-33.
Tsao H and Sober AJ

Except for high-dose interferon as adjuvant therapy in stage III disease, little success has emerged over the last 20 years for metastatic melanoma. Recent advances in melanoma biology suggest that disarming oncogenic mechanisms in melanoma may be an attractive approach to therapy. For instance, sustained expression of Bcl2 has been associated with an increased resistance to apoptosis, and recently, anti-sense-mediated reduction of Bcl2 levels was shown to chemosensitize patients to dacarbazine, dimethyl triazino imidazole carboxomide, or DTIC. Likewise, the identification of activating mutations in the RAS signaling pathway, including the NRAS and BRAF genes, opens up new therapeutic options for RAS and RAF inhibitors. A more thorough understanding of melanoma biology and tumor immunology will undoubtedly yield new promise for patients with advanced disease.      

Is psychotherapy good for your health?
Journal: Am J Psychother. 2004;58(4):386-405.
Luborsky L et al 

This is a dedicated review of the evidence for the relation of having a period of psychotherapy and then comparing it with a measure of improved physical health. We aimed to make it the first intended-to-be-complete review of this type. Three inter-related types of studies were examined: Type 1: reduction in physical illnesses through psychotherapy, especially for the patient's survival time during the interval between diagnosis and an end point, Type 2: reduction in pain in relation to receiving psychotherapy, and Type 3: reduction in costs of treatment in relation to receiving psychotherapy. To find the relevant studies on these topics, we performed a literature search using both Psychinfo and Medline databases. An average of the effect sizes under each type was taken to calculate the mean effect size along with its confidence interval. Our results (1) on survival time for the combined severe patients, did not reach even the lowest significant level of effect size, although the low severity patients seemed to fit the hypothesis better, but the other two reduction topics, (2) and (3), clearly did achieve it.    

Malignant melanoma--future prospects.
Journal: Acta Dermatovenerol Croat. 2005;13(1):36-43.
Lugovic L et al

As the incidence and already high mortality rates of malignant melanoma have been steadily increasing in recent decades, the early detection and excision of malignant melanoma have imposed as the most important task. Staging of malignant melanoma is determined according to the level of invasion ( Clark level) and vertical thickness (Breslow scale). Besides operative therapy, which is the only effective treatment for malignant melanoma, postoperative adjuvant chemotherapy, immunotherapy, radiotherapy, and biologic therapy also are of great importance. In recent years, immunologic strategies including tumor vaccine and adjuvant therapy with interferon-alfa have been attempted to improve survival of patients with more advanced malignant melanoma. A recent melanoma research has focused on target therapy such as immunotherapy (vaccines, monoclonal antibodies, dendritic cells) and gene therapy. Genetic immunization has become an attractive strategy for the development of melanoma vaccines, because a number of antigens recognized by cellular components of the immune system have been identified at the molecular level. Numerous chemotherapeutic agents have shown activity in the treatment of metastatic malignant melanoma, such as dacarbazine (dimethyl triazene imidazole carboxamide); other agents have been used, however, with less success. However, a very modest effect was recorded in advanced malignant melanoma. There are many experimental trials using combined therapy for malignant melanoma, including chemotherapy (dimethyl triazene imidazole carboxamide) and biologic therapy (interleukin (IL)-2, interferon (IFN)-gamma, IFN-alfa). The results obtained open particularly interesting prospects in the field of malignant melanoma with high relevance for its development and progression. Molecular therapeutics and vaccine development will probably be an important focus for the future melanoma treatment.    

Tanning beds, sunlamps, and risk of cutaneous malignant melanoma.
Journal: Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):562-6.    
Gallagher RP et al

BACKGROUND: A number of studies have been conducted evaluating the risk of cutaneous malignant melanoma after exposure to sunlamps and/or sunbeds. The proportion of subjects in the individual studies who have reported exposure has, in general, been modest, and the resulting risk estimates for melanoma have been unstable with wide 95% confidence intervals (95% CI). The inconclusive results seen in individual studies have resulted in confusion as to the carcinogenicity of these devices. METHODS: We conducted a systematic review and meta-analysis of these studies. A review of the literature from Jan 1, 1984 to April 2004 using MEDLINE identified 12 case-control studies and 1 cohort study which quantitatively evaluated the use of sunlamps and/or sunbeds and subsequent melanoma. After applying exclusion/inclusion criteria, 9 case-control and 1 cohort study provided data for the analysis. Summary odds ratios (OR) and 95% CIs for sunlamp/sunbed use and subsequent melanoma were calculated using a random-effect model. RESULTS: Ten studies provided data for assessment of melanoma risk among subjects who reported "ever" being exposed compared with those "never" exposed. A positive association was found between exposure and risk (summary OR, 1.25; 95% CI, 1.05-1.49). Significant heterogeneity between studies was present. Evaluation of the metrics "first exposure as a young adult" (5 studies) and "longest duration or highest frequency of exposure" (6 studies) also yielded significantly elevated risk estimates (summary OR, 1.69; 95% CI, 1.32-2.18, and 1.61; 95% CI, 1.21-2.12, respectively, with no heterogeneity in either analysis). CONCLUSIONS: Results indicate a significantly increased risk of cutaneous melanoma subsequent to sunbed/sunlamp exposure.

Mechanisms underlying UV-induced immune suppression.
Journal: Mutat Res. 2005 Apr 1;571(1-2):185-205. Epub 2005 Jan 21.
Ullrich SE

Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US dollars 650 million a year, and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US dollars 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression.    

Mutations induced by ultraviolet light.
Journal: Mutat Res. 2005 Apr 1;571(1-2):19-31. Epub 2005 Jan 20.  

The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA bases. We also discuss the role of DNA damage-tolerant DNA polymerases in UV lesion bypass and mutagenesis.    

Melanoma vaccines: what we know so far.
Journal: Oncology ( Williston Park ). 2005 Jan;19(1):97-108; discussion 108, 111-2, 115.
Bystryn JC and Reynolds SR.    

Vaccines are a promising but still experimental treatment for melanoma. They are intended to stimulate immune responses against melanoma and by so doing, increase resistance against and slow the progression of this cancer. Key requirements for vaccines to be effective are that they contain antigens that can stimulate tumor-protective immune responses and that some of these antigens are present on the tumor to be treated. Unfortunately, these antigens are still not known. To circumvent this problem, polyvalent vaccines can be constructed containing a broad array of melanoma-associated antigens. Several strategies are available to construct such polyvalent vaccines; each has advantages and disadvantages. Clinical trials have shown that vaccines are safe to use and have much less toxicity than current therapy for melanoma. Vaccines can stimulate both antibody and T-cell responses against melanoma, with the type of response induced, its frequency, and its magnitude depending on the vaccine and the adjuvant agent used. A growing body of evidence suggests that vaccines can be clinically effective. This evidence includes correlations between vaccine-induced antibody or T-cell responses and improved clinical outcome, clearance of melanoma markers from the circulation, improved survival compared to historical controls, and most convincingly, two randomized trials in which the recurrence-free survival of vaccine-treated patients was significantly longer than that of control groups.  

Biomarkers for melanoma.
Journal: Curr Opin Oncol. 2005 Mar;17(2):167-71.  

PURPOSE OF REVIEW: Given the capricious nature of melanoma, biomarkers that provide significant insight into the behavior of melanoma would greatly aid in identifying patients at risk for disease progression, those whose disease has progressed subclinically, and those who would benefit from currently available systemic therapies. This review focuses on molecular prognostic markers in primary melanoma, markers that aid in the detection of metastatic melanoma, and markers predictive of systemic therapy. RECENT FINDINGS: Significant advances have been made in the field of melanoma biomarkers. Utilization of paraffin-embedded tissue and multiple markers have improved the RT-PCR assays for detection of melanoma cells in lymph node tissue as well as peripheral blood. Lymphangiogenesis has been identified as a novel mechanism for melanoma progression, and candidate markers in the NF-kappaB signaling pathway have been identified to play a key role in melanoma: tumor vasculature interactions. Loss of heterozygosity has been used to identify potential candidates for biochemotherapy. Furthermore, serum S100B protein has been shown to be superior to lactate dehydrogenase in predicting prognosis and response to treatment for patients with advanced melanoma. SUMMARY: Although recent studies have contributed greatly to the development of melanoma markers, it is anticipated that the application of gene expression profiling and proteomics techniques to melanocytic neoplasms will result in the identification of even more effective biomarkers for melanoma than those currently in clinical use.    

Cutaneous melanoma: pathogenesis and rationale for chemoprevention.
Journal: Crit Rev Oncol Hematol. 2005 Mar;53(3):225-39.
Demierre MF and Sondak VK

OBJECTIVE: To critically review aspects of melanoma pathogenesis that lend themselves to a chemoprevention strategy. To discuss potential candidate chemoprevention agents with an emphasis on the lipid lowering drugs, the statins, currently, the most promising agents. DATA SOURCES: A retrospective review of the literature. STUDY SELECTION: Studies included those relevant to melanoma pathogenesis, to the scientific rationale of chemoprevention, and pertinent epidemiologic, pre-clinical, and clinical studies. The referenced study designs and methodologies varied. DATA EXTRACTION AND SYNTHESIS: Data were extracted by two reviewers, and the main results are presented in a quantitative descriptive manner. CONCLUSION: Melanoma is a preventable disease by altering behavior (sun exposure) among at-risk individuals. There is also considerable evidence to suggest that melanoma development may be prevented or delayed by drugs of sufficiently low toxicity to make clinical trials of chemoprevention feasible and potentially successful. Among potential candidate agents, statins have compelling data for long-term safety and sufficient pre-clinical and clinical evidence for efficacy to justify their evaluation in well-designed trials in high-risk individuals, incorporating intermediate biologic endpoints.    

Ultraviolet radiation and skin cancer: molecular mechanisms.
Journal: J Cutan Pathol. 2005 Mar;32(3):191-205.
Hussein MR 

Every living organism on the surface of the earth is exposed to the ultraviolet (UV) fraction of the sunlight. This electromagnetic energy has both life-giving and life-endangering effects. UV radiation can damage DNA and thus mutagenize several genes involved in the development of the skin cancer. The presence of typical signature of UV-induced mutations on these genes indicates that the ultraviolet-B part of sunlight is responsible for the evolution of cutaneous carcinogenesis. During this process, variable alterations of the oncogenic, tumor-suppressive, and cell-cycle control signaling pathways occur. These pathways include (a) mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor-suppressor gene in basal cell carcinomas, (b) an activated mitogenic ras pathway and mutated p53 in squamous cell carcinomas, and (c) an activated ras pathway, inactive p16, and p53 tumor suppressors in melanomas. This review presents background information about the skin optics, UV radiation, and molecular events involved in photocarcinogenesis.  

Management of lentigo maligna.
Journal: Dermatol Nurs. 2004 Dec;16(6):495-8, 505, 523.
Christenson LJ

Lentigo maligna melanoma is a melanoma in situ on sun-damaged skin. It is a variably brown-pigmented flat patch on the head or neck of elderly patients. Its growth is generally slow, but it can become an invasive form of melanoma. Multiple reported treatment options are reviewed. Wide-margin Mohs micrographic surgery with peripheral permanent pathologic confirmation of a clear margin is recommended as treatment of choice.  

Sun exposure and mortality from melanoma.
Journal: J Natl Cancer Inst. 2005 Feb 2;97(3):195-9.
Berwick M et al

BACKGROUND: Melanoma incidence and survival are positively associated, both geographically and temporally. Solar elastosis, a histologic indicator of cutaneous sun damage, has also been positively associated with melanoma survival. Although these observations raise the possibility that sun exposure increases melanoma survival, they could be explained by an association between incidence and early detection of melanoma. We therefore evaluated the association between measures of skin screening and death from cutaneous melanoma. METHODS: Case subjects (n = 528) from a population-based study of cutaneous melanoma were followed for an average of more than 5 years. Data, including measures of intermittent sun exposure, perceived awareness of the skin, skin self-screening, and physician screening, were collected during in-person interviews and review of histopathology and histologic parameters (i.e., solar elastosis, Breslow thickness, and mitoses) for all of the lesions. Competing risk models were used to compute risk of death (hazard ratios [HRs], with 95% confidence intervals [CIs]) from melanoma. All statistical tests were two-sided. RESULTS: Sunburn, high intermittent sun exposure, skin awareness histories, and solar elastosis were statistically significantly inversely associated with death from melanoma. Melanoma thickness, mitoses, ulceration, and anatomic location on the head and neck were statistically significantly positively associated with melanoma death. In a multivariable competing risk analysis, skin awareness (with versus without, HR = 0.5, 95% CI = 0.3 to 0.9, P = .022) and solar elastosis (present versus absent, HR = 0.4, 95% CI = 0.2 to 0.8, P = .009) were strongly and independently associated with melanoma death after adjusting for Breslow thickness, mitotic index, and head and neck location, which were also independently associated with death. CONCLUSIONS: Sun exposure is associated with increased survival from melanoma.    

Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure.
56: Eur J Journal: Cancer. 2005 Jan;41(1):45-60.
Gandini S et al.    

A systematic revision of the literature was conducted in order to undertake a comprehensive meta-analysis of all published observational studies on melanoma. An extensive analysis of the inconsistencies and variability in the estimates was performed to provide some clues about its Epidemiology. Following a systematic literature search, relative risks (RRs) for sun exposure were extracted from 57 studies published before September 2002. Intermittent sun exposure and sunburn history were shown to play considerable roles as risk factors for melanoma, whereas a high occupational sun exposure seemed to be inversely associated to melanoma. The country of study and adjustment of the estimates adjuste for phenotype and photo-type were significantly associated with the variability of the intermittent sun exposure estimates (P = 0.024, 0.003 and 0.030, respectively). For chronic sun exposure, inclusion of controls with dermatological diseases and latitude resulted in significantly different data (P = 0.05 and 0.031, respectively). Latitude was also shown to be important (P = 0.031) for a history of sunburn; studies conducted at higher latitudes presented higher risks for a history of sunburns. Role of country, inclusion of controls with dermatological diseases and other study features seemed to suggest that "well conducted" studies supported the intermittent sun exposure hypothesis: a positive association for intermittent sun exposure and an inverse association with a high continuous pattern of sun exposure.    

Indoor tanning by adolescents: prevalence, practices and policies.
Journal: Eur J Cancer. 2005 Jan;41(1):20-7.
Lazovich D and Forster J.  

Despite known acute and chronic health effects from the use of indoor tanning, including the potential for all forms of skin cancer, the practice is popular in the United States (US) and Europe . A review of the scientific literature that examines adolescents and indoor tanning use was undertaken, summarising what is known about prevalence and practices among adolescents, characteristics associated with adolescent use, and policies that regulate adolescent access to indoor tanning facilities. The prevalence of indoor tanning is consistently found to be higher among girls than boys and to increase with age in both Europe and the US . An examination of other demographic characteristics, skin cancer risk factors, knowledge, attitudes and social factors points to higher prevalence of the behaviour among adolescents with positive attitudes towards tans and whose friends or parents also tan indoors. Adolescent access to indoor tanning is rarely regulated in the US or Europe , and where regulations exist, business compliance is low. In addition, businesses actively market their product to adolescents as they organise to limit further regulations prohibiting adolescent access. Pricing, licensure, advertising restrictions and media campaigns, in combination with adolescent-targeted interventions, are possible strategies that could be tested for their effectiveness to reduce adolescent indoor tanning use. Harm reduction policies, such as eye protection, that reduce risk for adolescents who choose to tan indoors, are also important.  

Diagnosis of melanoma in the elderly and surgical implications.
Journal: Surg Oncol. 2004 Dec;13(4):211-21.
Testori A et al

The diagnosis of primary melanoma is mainly related to the precocity on which a patient is referred to the specialist, but in elderly patients this may present some peculiar characteristics, one is anatomical, a typical melanoma of the face, the lentigo maligna melanoma and the second is attitudinal, the fact that elderly patients often do not refer a changing cutaneous lesion to a doctor until becoming symptomatic. The therapeutic approach has to be discussed with an anaesthesiologist if the procedure has to be conducted under general anaesthesia or with a cardiologist if under local anaesthesia. Once there are no contraindications medically, a similar oncological approach should be proposed without any reduction in radicality due to the elderly age.    

Management of metastatic cutaneous melanoma.
Journal: Oncology ( Williston Park ). 2004 Oct;18(11):1443-50; discussion 1457-9. Buzaid AC 

The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination chemotherapy, from 10% to 30%. However, these responses are usually not durable. Immunotherapy, particularly high-dose interleukin (IL)-2 (Proleukin), has also shown a low response rate of approximately 15%, although it is often long-lasting. In fact, a small but finite cure rate of about 5% has been reported with high-dose IL-2. Phase II studies of the combination of cisplatin-based chemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy, have shown overall response rates ranging from 40% to 60%, with durable complete remissions in approximately 8% to 10% of patients. Although the results of the phase II single-institution studies were encouraging, phase III multicenter studies have reported conflicting results, which overall have been predominantly negative. Various factors probably explain these discrepancies including different biochemotherapy regimens, patient selection, and, most importantly, "physician selection." Novel strategies are clearly needed, and the most encouraging ones for the near future include high-dose IL-2 in combination with adoptive transfer of selected tumor-reactive T cells after nonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy, and the combination of chemotherapeutic agents and biochemotherapy with oblimersen sodium (Genasense).      

Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria.
Journal: JAMA. 2004 Dec 8;292(22):2771-6.
Abbasi NR et al.  

CONTEXT: The incidence of cutaneous melanoma has increased over the past several decades, making its early diagnosis a continuing public health priority. The ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) acronym for the appraisal of cutaneous pigmented lesions was devised in 1985 and has been widely adopted but requires reexamination in light of recent data regarding the existence of small-diameter (< or =6 mm) melanomas. EVIDENCE ACQUISITION: Cochrane Library and PubMed searches for the period 1980-2004 were conducted using search terms ABCD and melanoma and small-diameter melanoma. Bibliographies of retrieved articles were also used to identify additional relevant information. EVIDENCE SYNTHESIS: Available data do not support the utility of lowering the diameter criterion of ABCD from the current greater than 6 mm guideline. However, the data support expansion to ABCDE to emphasize the significance of evolving pigmented lesions in the natural history of melanoma. Physicians and patients with nevi should be attentive to changes (evolving) of size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color. CONCLUSIONS: The ABCD criteria for the gross inspection of pigmented skin lesions and early diagnosis of cutaneous melanoma should be expanded to ABCDE (to include "evolving"). No change to the existing diameter criterion is required at this time.

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