We thank Yelamos et al. for their interest in our nicotinamide chemoprevention studies.1 Some of their comments are pertinent, while others are based on a flawed interpretation of our data. Zhao2 previously commented on (nonsignificant) numerical differences in the frequency of adverse-event term groupings (mucocutaneous infections) between the placebo and nicotinamide groups in our ONTRAC chemoprevention study (Oral Nicotinamide To Reduce Actinic Cancer).3 As stated previously, chance remains a highly plausible explanation for the numerically higher mucocutaneous infections in the nicotinamide arm and also, for example, for the numerically lower respiratory infections observed in the nicotinamide arm.4 This article is protected by copyright. All rights reserved.

Children and teenagers with a positive sentinel lymph node (SLN) after a prior diagnosis of an atypical spitzoid melanocytic tumor (ASMT) are usually cared for clinically in the same way as patients with melanoma. Little is known about long-term follow-up of these individuals to determine whether this practice is appropriate. To learn more about the biology of these tumors we retrospectively reviewed the clinical and pathologic findings of children and teenagers (<18 y of age at the time of diagnosis) with an ASMT, positive SLN and follow-up of at least 3 years. Their findings were compared with histologically unambiguous melanomas of children or teenagers, who had a positive SLN or died of metastatic melanoma. Eleven individuals, 6 girls and 5 boys, with primary ASMT and positive SLN were identified. The primary tumors ranged in thickness from 2.1 to 12 mm (median, 4.6 mm; mean, 5 mm). The tumor mitotic rate ranged from 1 to 10 mitoses/mm2 (median, 3/mm2, median, 3/mm2). The positive SLNs included 6 nodes with intranodal melanocytic aggregates measuring <1 mm in greatest dimension, and 5 nodes, in which the size of the melanocyte deposits was ≥1 mm. All the patients with ASMT and positive SLN remained free of disease with a median follow-up of 47 months (mean, 61 mo, range: 36 to 132 mo). In contrast, 2 of 5 patients <18 years of age with a histologically unambiguous melanoma and a positive SLN died of metastatic melanoma. The overall disease-specific mortality rate for all patients <18 years of age diagnosed with melanoma was 12%. Our findings confirm that children and teenagers with ASMTs and positive SLNs have a less aggressive clinical course than those with histologically unambiguous melanoma.

Radiation recall dermatitis (RRD) is a rare cutaneous reaction occurring within a previously irradiated field, precipitated by certain drugs. We report a case of RRD occurring after pre-sensitization with pegylated liposomal doxorubicin (PLD) in a woman with Stage IV breast cancer. The RRD occurred in one of the patient's four previous radiotherapy fields. We discuss the time/dose factors of radiation exposure and measure the corresponding skin dose. In our case the radiation dose was low and below previously reported thresholds, and illustrates that there is a more complex interaction between the radiotherapy and the trigger agent than has previously been considered.

Preliminary evidence indicates that it may be appropriate to expand the classification scheme of melanocytic neoplasms to include a third diagnostic category of melanocytic lesions of intermediate malignant potential that are capable of metastasis to regional lymph nodes but have limited potential for distant spread. We propose the term melanocytoma for this group of lesions. We believe that a nevus/melanocytoma/melanoma paradigm may provide a useful intellectual framework to understand, research, and clinically manage borderline melanocytic tumors.

Sydney Melanoma Unit and Melanoma Institute Australia, Mater Hospital and Royal Prince Alfred Hospital, Sydney, NSW, Australia; Discipline of Surgery, Faculty of Medicine, The University of Sydney, Sydney, NSW, Australia; Discipline of Pathology, Faculty of Medicine, The University of Sydney, Sydney, NSW, Australia; Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

TPS9091 Background: Significant advances have been made in the treatment of melanoma through the use of mitogen -activated protein kinase pathway (MAPK)-targeted therapies, with several agents now FDA-approved for patients (pts) with BRAF V600 mutations with stage IV or unresectable stage III disease. Based on the efficacy of BRAF inhibitors and combined BRAF/MEK inhibitors in patients with stage IV melanoma, these agents are being investigated as adjuvant therapy in patients with resectable stage III melanoma as part of multi-national phase 3 trials, where the current standard of care is upfront surgery. Mature results from these trials, however, will not be available for some time. A critical question to consider is whether neoadjuvant treatment with MAPK-targeted therapy will improve outcomes in a subset of these patients with significant burden of disease. Methods: Here we report 2 current phase II trials -- at MD Anderson Cancer Center (MD Anderson) and Melanoma Institute Australia (MIA) -- of neoadjuvant combined BRAF inhibition (dabrafenib, at 150 mg by mouth twice a day) and MEK inhibition (trametinib, at 2 mg by mouth once a day) for high risk resectable metastatic melanoma (stage IIIB-C; MIA and MD Anderson) and oligometastatic stage IV (MD Anderson)). Both trials incorporate serial biopsies during the course of treatment for translational research on molecular and immune biomarkers. At MD Anderson, eligible patients are randomized in a 2:1 fashion to neoadjuvant BRAF/MEK x 8 weeks with adjuvant BRAF/MEK x 44 weeks versus upfront surgery and SOC adjuvant therapy (target accrual 84 patients). Endpoints include RECIST response (RR), relapse-free survival (RFS), overall survival (OS), pathologic CR rate, and toxicity. At MIA, all patients receive neoadjuvant BRAF/MEK x 12 weeks, followed by adjuvant BRAF/MEK for 40 weeks (target accrual 35 patients). The primary endpoint is pathologic CR rate, secondary endpoints include RFS, OS, toxicity, and translational endpoints correlated with outcome. This neoadjuvant approach has the potential to establish a new treatment paradigm for patients with high-risk resectable metastatic melanoma harboring a BRAF mutation. Clinical trial information: NCT01972347, NCT02231775.

: Assessment of some of the quantitative parameters was highly reproducible between pathologists. However, evaluation of the location of tumor deposits within SLNs and assessment of extracapsular spread was less reproducible. Clearer definitions and training can be expected to improve the reproducibility of assessment. These results have important implications for reliability and reproducibility of these parameters in staging, prediction of outcome, and clinical management of melanoma patients. Cancer 2009. (c) 2009 American Cancer Society.

LBA9084 Background: Adjuvant radiotherapy (RT) is an option for patients with isolated regional recurrence of melanoma considered to be at high risk of further regional recurrence after lymphadenectomy. This is the first completed study to assess the effects of RT on regional recurrence, survival, morbidity and quality of life (QOL) in these patients. Methods: Multicenter randomized study of patients with isolated regional recurrence at increased risk (>25%) of regional recurrence. Eligibile patients included ≥1 parotid, ≥ 2 cervical or axillary or ≥ 3 groin nodes or extra nodal spread of tumor or maximum metastatic node diameter ≥3cm in neck or axilla or ≥4cm in the groin. Patients were randomized to observation or regional nodal basin RT (48Gy in 20 fractions) after lymphadenectomy. Regional recurrence was the primary end point and morbidity, QOL, patterns of relapse, disease free and overall survival were secondary end points. The target sample size was 220 patients, which would enable a difference in 3 year regional relapse (cumulative incidence) rates of 30% versus 15% to be detected with a power of 80% (using a two sided logrank test at the 5% level of significance). Results: 250 pts were randomized from 16 centers from March 2002 to September 2007. There were 123 in the RT group and 127 in OBS group. 2 pts withdrew consent and 31 were excluded from analysis of the main objective following an independent blinded review of eligibility compliance by two reviewers. 227 pts were available for analysis of the main objective (109 RT, 108 OBS). Median follow-up was 27 mo. There was a statistically significant improvement in lymph node field control with radiotherapy, 20 RT pts and 34 OBS pts relapsed (HR 1.77 1.02–3.08 p=0.041). Median survival times were 2.6 years (RT) and 3.9 years (OBS) p=0.14. Conclusions: Adjuvant RT improved regional control in melanoma patients at high risk of regional relapse after lymphadenectomy. An effect on survival was not demonstrated. No significant financial relationships to disclose.

e20033 Background: To date, little is known about how primary melanomas clonally evolve to distant metastases, including brain, and how driver mutations are selected during melanoma progression. To identify new driver and clonal evolution genetic events beyond the known mutations in BRAF/NRAS, we performed WEPS of same-pt PEB. Methods: DNA from tumor (T) and adjacent normal (AN) was extracted from macrodissected tissue slides. DNA libraries were captured using Agilent SureSelect Human All Exon v4 and sequenced at 2x48 bp. Variant calling was performed on T vs. matched AN using VARSCAN (default settings). Single nucleotide variations (SNV) were filtered using prior knowledge (COSMIC). We report only genes having probably or possibly damaging non-synonymous SNV (PolyPhen2 score > 0.45) by ANNOVAR analysis and nonsense mutations. Focused analysis for gene copy number alterations previously described in melanoma was performed using our previously published NGScopy package (Bioconductor). We considered analysis for gene copy number alterations if median coverage depth > 20X. We computed T/AN copy number ratio at the gene against the chromosome level. Results: To date, 4 pts with all four tissues (PEB-AN) have been analyzed. Mean coverage depth was 68X and read quality was 37. 85% of reads were uniquely mapped. The 10 most frequently mutated genes across all 12 T samples were APC, ARID1A, CDKN2A, EGFR, FBXW7, KIT, KMT2C, NF1, PTEN, and TET2 (FDR < 0.0001). NF1 mutations were present in all T from 4 pts. All T from 3 out of 4 pts had mutations in BRAF (2 with confirmed V600E), PTEN, IDH2, TET2, CCDC6, PCSK7, and members of the ARID and KMT2 gene family. Both metastatic T from 2 pts had mutations in TRIM27, NCOA1, BCL6, and BCL10 that were not present in primary. All T from 2 pts and all T from one pt had > 30% amplification of the KIT and KDR genes, respectively. Conclusions: Aggressive melanoma bears known mutations in signaling pathways that coexist with mutations in genes associated with chromatin modification, histone/nucleotide methylation, and metabolism. Identifying such mutations in primaries may predict future prognosis.

Results suggest that alterations in the Wnt pathway are important in the progression and in the epithelial and stromal interactions in PTs. They have important implications for understanding the pathogenesis of these uncommon but clinically important tumours.