SU-E-T-569: A Dosimetric Comparison of Helical Tomotherapy versus Intensity Modulated Proton for Lung Cancer.

PURPOSE: To evaluate the dosimetric difference between helical tomotherapy (HT) and intensity modulated proton therapy (IMPT) treatment for lung cancer patients. METHODS: Five patients treated by HT at University of Wisconsin Carbone Cancer Center were selected. HT plans were generated on TomoTherapy treatment planning station (TomoTherapy Inc., USA). The field widths were set to 2.5 cm for all patients in this study. The IMPT plans were generated using the same planning CT and contours with our in-house treatment planning system. Three to five field spot scanning IMPT were used to deliver uniform doses to the targets while minimizing the irradiated lung volume. The proton spots used has a Gaussian sigma of 6mm and are placed on a rectangular grid. The dose distribution of each proton spot is calculated using a pencil beam algorithm with tissue heterogeneity corrections. All the dosimetric analyses are performed using normalized total dose. Alpha/beta ratios were set to 3 for normal tissues and 10 for tumors. RESULTS: IMPT plans showed improvement of critical structure avoidance and target dose uniformity for all patients. Reductions in mean lung doses of between 81% to 27% were observed in the IMPT plans relative to the HT. The equivalent uniform dose of the target improved from 49.2 Gy in HT plan to 60.04 Gy in IMPT for patient #2, and equivalent for other cases. The maximum doses to cord were reduced by 20.5 Gy on average using IMPT. In two patient cases, the normal tissue complication probabilities were reduced by 53% and 14% with IMPT. CONCLUSION: IMPT provides improved dose homogeneity on the target and normal structure sparing compared with HT in the treatment of non-small cell carcinoma in lung. Significant reduction of mean lung dose was demonstrated, as well as toxicity to organs at risk adjacent to the target.

Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is rapidly increasing in incidence worldwide and approximately 5% of melanomas are hereditary. Deletions in chromosome 1p36 have been detected in melanoma but no candidate melanoma tumour suppressor gene has yet been found in this area. Recently, strong evidence has been reported that CHD5 is a tumour suppressor gene in this region. OBJECTIVES: To investigate CHD5 involvement in familial melanoma. METHODS: Peripheral blood DNA from 47 melanoma families who do not carry mutations in any of the three currently recognized melanoma genes, 398 patients with sporadic melanoma and 398 geographically matched nonmelanoma-bearing controls were studied. Linkage investigation, single nucleotide polymorphism (SNP) genotyping and mutation screening studies were carried out on the CHD5 locus. RESULTS: The CHD5 gene was not excluded by linkage analysis in any of the families. On SNP genotyping, the CHD5 rs7513548 SNP was found to be significantly associated with sporadic melanoma (odds ratio 1·53, 95% confidence interval 1·13-2·06). The AG genotype was found in 208 cases and 169 controls (cf. 141 and 175 cases and controls, respectively, for the AA genotype). On CHD5 mutation screening, a total of 50 single-base substitutions were detected. Of these, 39 were intronic and 11 were exonic. While 32 were previously recognized variants, 18 were newly identified. Three, in exons 4, 31 and 32, led to nonsynonymous substitutions. A p.Met1576Ile substitution was identified in a mother and daughter, both with invasive cutaneous melanoma. CONCLUSIONS: This study appears to be the first report of CHD5 variants in familial cutaneous melanoma. Such CHD5 variants could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. As only one of the 47 families studied has this variant, it appears to be a rare event and further screening of melanoma families is required to confirm whether or not CHD5 is involved in melanoma pathogenesis.

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Revised UK guidelines for the management of cutaneous melanoma 2010.

These guidelines for the management of cutaneous melanoma present an evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiology, diagnosis, investigation, and follow-up.

Epidemiology of invasive cutaneous melanoma.

Data are presented on the current incidence of melanoma with recent and predicted future trends illustrating a likely continuing increase in incidence. Risk factors for developing melanoma are discussed, including current known melanoma susceptibility genes. Phenotypic markers of high-risk subjects include high counts of benign melanocytic naevi. Other risk factors considered include exposure to natural and artificial ultraviolet radiation, the effect of female sex hormones, socioeconomic status, occupation, exposure to pesticides and ingestion of therapeutic drugs including immunosuppressives and non-steroidal anti-inflammatory drugs. Aids to earlier diagnosis are considered, including public education, screening and use of equipment such as the dermatoscope. Finally, the current pattern of survival and mortality is described.

Utility of adjuvant systemic therapy in melanoma.

The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing.

An evidence base for reconsidering current follow-up guidelines for patients with cutaneous melanoma less than 0.5 mm thick at diagnosis.

BACKGROUND: Despite current guidelines, there is uncertainty about the required duration and frequency of follow-up visits for patients with invasive primary cutaneous melanoma < 0.5 mm thick. OBJECTIVES: To review patients with invasive melanoma thinner than 0.5 mm followed for at least 5 years to provide an evidence base for considering modification of guidelines. METHODS: A retrospective review of 430 patients diagnosed in the west of Scotland during 1992-2001 with melanoma < 0.5 mm was carried out. Recurrence, deaths from melanoma and second primary melanomas were all identified. RESULTS: From 1992 to 2001, 430 melanomas < 0.5 mm thick at diagnosis were diagnosed out of a total of 3036 primary cutaneous melanomas. To date there have been 593 deaths from melanoma (19%) in the whole group. Five of these deaths were reported in patients with melanomas < 0.5 mm, but on pathological review two were thicker than 0.5 mm at diagnosis (1.5 and > 3 mm), and the remaining three patients all developed thicker second primary melanomas (2.7, 12.0 and 19.0 mm) with a recurrence pattern and timing indicating that these thicker primaries were the cause of death. Fourteen further patients developed a second primary melanoma, and 13 are currently alive and disease free, one dying of other causes. CONCLUSIONS: Our data indicate that recurrence and subsequent death from melanomas < 0.5 mm is a very rare event, and that quarterly follow-up for 3 years will yield very few events. Modification of current guideline recommendations are suggested to include a period of patient education concentrating on recognition of second primary tumours followed by rapid access to an expert opinion if required.

Melanoma incidence and mortality in Scotland 1979-2003.

We studied 12,450 cases of invasive melanoma diagnosed in Scotland in 1979-2003, by thickness, pathological type, and body site at ages under 40, 40-59, and 60 years and over. Melanoma incidence trebled in males from 3.57 to 10.93/10(5) per year, and increased 2.3-fold in females from 5.60 to 12.96/10(5) per year. The rate of increase fell in each successive 5-year period. The greatest increase was in males aged 60 years and over at diagnosis. Significant incidence increases were seen in melanomas < 1 mm in all three age groups, but those > 4 mm only increased significantly at ages 60 years and over. All histological types increased significantly at ages 60 years and over, and in this age group the greatest increase was seen on the head and neck. Five-year disease-free survival improved steadily. Survival figures for 1994-1998 ranged from 93.6% for males and 95.8% for females with tumours < 1 mm, to 52.4 and 48.3%, respectively, for those with tumours > 4 mm. Over the 25 years, melanoma mortality doubled in males from 1.1 to 2.4/10(5) per year, but was unchanged in females at 1.5/10(5) per year. Public education on melanoma is required both for primary prevention and earlier diagnosis, particularly for older males.

Expression of p16, CD95, CD95L and Helix pomatia agglutinin in relapsing and nonrelapsing very thin melanoma.

BACKGROUND: The incidence of malignant melanoma is increasing worldwide and patients are being diagnosed earlier with thinner primary lesions. Most patients with very thin melanoma (Breslow thickness < 0.76 mm) are cured by surgery but 2-18% relapse locally or with distant metastases. OBJECTIVES: The objective of this study was to establish potential new prognostic markers in very thin melanoma. METHODS: We identified a group of subjects with relapsing very thin primary cutaneous melanoma and a matched control group who had not relapsed. We investigated the expression of p16, Helix pomatia agglutinin (HPA), CD95 and CD95 ligand (CD95L) by immunohistochemistry on paraffin-embedded tissue sections from the subject group, their subsequent metastases and the control group. RESULTS: Reduced p16 expression was significantly associated with relapse in very thin melanoma (P = 0.0129). Loss of p16 expression was also found in 76% of metastases. There was no significant association between HPA, CD95 or CD95L expression and subsequent relapse. CONCLUSIONS: This work is the first to show a significant loss of p16 in relapsing very thin melanoma.

Management of basal cell carcinoma by surveyed dermatologists in Scotland.

BACKGROUND: The British Association of Dermatologists (BAD) has produced guidelines for management of basal cell carcinoma (BCC) in the UK. OBJECTIVES: Our primary objectives were to assess the management of BCCs in Scotland and to compare it with BAD guidelines. Our secondary objectives were to audit waiting times and referral patterns. METHODS: In phase I of the audit, dermatologists in 14 centres across Scotland prospectively registered demographic and clinical data of all lesions suspected to be BCCs over a 6-week period between October and December 2000. In phase II, details of management of these lesions were evaluated by case note review. RESULTS: Of the 48 consultant dermatologists contacted, 42 took part in the survey. There were 524 clinically suspected BCCs seen in 470 patients; 164 lesions in 146 patients showed pathology other than BCC and were excluded from analysis, thus leaving 360 lesions available for analysis. There was wide variation in waiting times among Scottish dermatology centres. BCCs were equally distributed between the sexes, and lesions most commonly presented in those aged 71-80 years. A diagnostic biopsy was taken in 22% of lesions, and the rest were treated definitively after a clinical diagnosis of BCC, of which 90% were confirmed on histology. Nodulocystic lesions were the most common type of tumour, comprising 48% of lesions, and most BCCs were located on the head and neck region. Correlation of the histological type of BCC and treatment received showed that nodulocystic and morpheic BCCs were managed as recommended. There were more superficial BCCs treated with surgical excision than expected (22 of 34 lesions). Four of 21 recurrent tumours and 9 of 81 tumours on high-risk areas of the face were managed with curettage and cautery or cryotherapy, rather than surgical excision. Of the 297 excised tumours, 25 (9%) were incompletely excised. All the high-risk tumours and incompletely excised tumours were offered follow-up in the dermatology clinics. CONCLUSIONS: In general, BCCs are managed according to BAD guidelines in Scotland, but waiting times vary considerably.

The unexpected sites of melanoma regional recurrences.

UNLABELLED: Sentinel node biopsy is a means of identifying nodal involvement in melanoma and lymphoscintigraphy identifies unpredictable sites of melanoma sentinel nodes in up to 25% of cases. Whilst there is a dearth of recent publications in this area, it nevertheless remains an interesting observation that unpredictable sites of sentinel nodes are so common as to be accepted as normal. This study was performed to determine if this high rate of unpredictable lymphatic drainage was reflected in clinical practice, where therapeutic lymph node dissections were performed for pathologically confirmed regional disease. METHODS: Patients undergoing regional lymph node dissections for histologically proven malignant melanoma were identified from a computer database. Patient details were analysed from case records. RESULTS: Two hundred and forty-three case records were examined and 237 were suitable for analysis. The site of the primary was the head and neck in 50 (21%), trunk in 73 (31%), upper limb in 27 (11%) and lower limb in 87 (37%). In 15 cases (6%), the first site of regional disease was unpredictable. In these 15 cases, the site of the primary was the head and neck in two, trunk in 11, upper limb in one and lower limb in one. In 37 cases (16%), a subsequent site of nodal recurrence was unpredictable. Clinicians should be aware that patients with melanomas, particularly of the trunk, especially those in whom a therapeutic nodal dissection has been performed, may have nodal disease at unpredictable sites. However, unexpected sites of regional disease are not as common as sentinel node biopsy would suggest. Guidelines for lymph node examination in cutaneous melanoma are suggested based on these findings.

CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families.

BACKGROUND: Up to 5% of patients with melanoma have a family history of a first-degree relative also being affected. OBJECTIVES: To study such families for germline mutations, to help clarify the gene-environment interaction in melanoma aetiology. METHODS: Thirty-two families in Scotland with melanoma in two or more first-degree relatives are reported for the first time. Peripheral blood DNA was extracted, and denaturing high-performance liquid chromatography analysis performed on exons 1alpha and 2 of the CDKN2A gene and their splice junctions. The coding sequences and splice junctions of these exons were sequenced in all samples as confirmation of the chromatographic pattern observed. RESULTS: Seven of the 32 melanoma families (22%) have CDKN2A mutations. One mutation, H83N, which has not previously been described in melanoma families, was found in one family. In addition, two families have R112G mutations, one family has a G67R mutation, one has an exon 1alpha 24-bp duplication where bases 9-32 are duplicated between bases 32 and 33, and two families have M53I mutations, bringing the total of known Scottish families with the M53I mutation to six. CONCLUSIONS: This study brings the total of Scottish families investigated for germline mutations to 48, and strongly suggests that the M53I mutation originated in Scotland.

Outcomes and pathological review of a cohort of children with melanoma.

BACKGROUND: Prepubertal malignant melanoma is rare, pathological criteria are difficult and follow-up data on patients are lacking in the literature. OBJECTIVES: To review prepubertal cases of melanoma diagnosed in the West of Scotland 1979-2002. METHODS: Twenty cases were identified in whom melanoma was diagnosed before the age of 15. Pathological review was possible for 13 of 20 cases, and current follow-up information is available for all 20. Three pathologists not responsible for the original diagnosis reviewed the slides independently, in every case without knowledge of the outcome. RESULTS: Of the 13 cases reviewed, there was concordance of diagnosis between the three pathologists in 12 cases. Eight of the 13 cases reviewed were considered to be unusual naevi rather than melanoma. One child has died of melanoma and all three pathologists agreed with the original pathological diagnosis. One patient has experienced nodal metastases but is alive and disease-free 12 years later. The remaining 18 cases have had no recurrence since primary surgery 2-21 years ago. CONCLUSIONS: There may be a tendency to overdiagnose prepubertal melanoma. Good communication between clinician and pathologist and the use of an expert pathology panel is recommended before making the diagnosis.

Differential susceptibility of macrophage cell lines to Bacillus anthracis-Vollum 1B.

Bacillus anthracis (BA) is a spore forming bacterium and the causative agent of anthrax disease. Macrophages (Mphis) play a central role in anthrax disease. An important step in disease progression is the ability of BA to secrete lethal toxin (LeTx) that kills Mphis. LeTx is a heterodimer composed of protective antigen (PA) and lethal factor (LF). Researchers have shown that Mphi cell lines demonstrate differential susceptibility to purified LeTx; for example RAW264.7 and J774A.1 Mphis are sensitive to LeTx whereas IC-21 Mphis are resistant. Research has also suggested that exogenous factors, including other BA proteins, can influence the activity of LeTx. For this reason, the objective of the current work was to examine if RAW264.7, J774A.1, and IC-21 Mphis demonstrated differential susceptibility when cultured with a LeTx-producing strain of BA. Here, we co-cultured Mphis with LeTx+ Vollum 1B (V1B) spores for >15 h and assayed for Mphi cell death by morphology, trypan blue (TB) staining, neutral red (NR) activity, and lactate dehydrogenase (LDH) activity in the culture media. Following the addition of V1B spores, necrosis (approximately 50% mortality) was observed in RAW264.7 and J774A.1 Mphis at 7.5 and 10 h, respectively. By 15 h, both RAW264.7 and J774A.1 Mphis demonstrated 100% mortality. In contrast, IC-21 Mphis, under identical culture conditions, remained viable (98%) and activated throughout the course of the experiment (>24 h). The mechanism of RAW264.7 cell death appeared to involve LeTx because the V1B-induced cytotoxicity was dose-dependently reversed by the addition of anti-PA antibody to the culture media. These observations suggest there is differential susceptibility of Mphi cell lines to the LeTx+ V1B strain of BA. Further development of this in vitro model may be useful to further characterize the interactions between Mphis and BA spores.

Awareness, knowledge and attitudes to basal cell carcinoma and actinic keratoses among the general public within Europe.

OBJECTIVE: As the incidence of non-melanoma skin cancer (NMSC) is reported to be increasing in Europe, the objective of this survey was to establish the general population's awareness and knowledge of basal cell carcinoma (BCC) and actinic keratoses (AK) within five European countries. METHODS: A total of 1500 individuals from the United Kingdom, France, Italy, Germany and Spain were randomly selected to participate in the study. In a 10-minute structured telephone interview respondents answered questions on skin cancer and BCC and AK. RESULTS: Overall, 46% of respondents were concerned about skin cancer. Even though the majority of respondents believed there was a correlation between skin cancer and the sun or overexposure to sunlight, nearly a third of the surveyed population rarely or never used sunscreen when outdoors. In general there was a low level of awareness about BCC and AK, with only 22% and 6% of respondents, respectively, being aware of the conditions. CONCLUSION: There is a need to increase the awareness of skin cancer and safe sun practices among the European population.

Hormone replacement therapy after surgery for stage 1 or 2 cutaneous melanoma.

A total of 206 women were followed for a minimum of 5 years after primary melanoma surgery to establish if hormone replacement therapy (HRT) adversely affected prognosis. In all, 123 had no HRT and 22 have died of melanoma; 83 had HRT for varying periods and one has died of melanoma. After controlling for known prognostic factors, we conclude that HRT after melanoma does not adversely affect prognosis.

Diagnostic and neural analysis of skin cancer (DANAOS). A multicentre study for collection and computer-aided analysis of data from pigmented skin lesions using digital dermoscopy.

BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important step towards a reduction in mortality. Computer-aided analysis of digital images obtained by dermoscopy has been reported to be an accurate, practical and time-saving tool for the evaluation of pigmented skin lesions (PSLs). A prototype for the computer-aided diagnosis of PSLs using artificial neural networks (NNs) has recently been developed: diagnostic and neural analysis of skin cancer (DANAOS). OBJECTIVES: To demonstrate the accuracy of PSL diagnosis by the DANAOS expert system, a multicentre study on a diverse multinational population was conducted. METHODS: A calibrated camera system was developed and used to collect images of PSLs in a multicentre study in 13 dermatology centres in nine European countries. The dataset was used to train an NN expert system for the computer-aided diagnosis of melanoma. We analysed different aspects of the data collection and its influence on the performance of the expert system. The NN expert system was trained with a dataset of 2218 dermoscopic images of PSLs. RESULTS: The resulting expert system showed a performance similar to that of dermatologists as published in the literature. The performance depended on the size and quality of the database and its selection. CONCLUSIONS: The need for a large database, the usefulness of multicentre data collection, as well as the benefit of a representative collection of cases from clinical practice, were demonstrated in this trial. Images that were difficult to classify using the NN expert system were not identical to those found difficult to classify by clinicians. We suggest therefore that the combination of clinician and computer may potentially increase the accuracy of PSL diagnosis. This may result in improved detection of melanoma and a reduction in unnecessary excisions.