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Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune “cold” signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028).Implications:CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment.

Kaplan-Meier (log-rank) analysis of MPP4 and SD3 showing the PFS and OS for stage III patients only. a. PFS for MPP4, **p=0.0017, b. OS for MPP4, *p=0.0117, c. PFS for SD3, ***p=0.0003 and d. OS for SD3, **p=0.0094.

Multiplex immunofluorescence staining quantification by Visiopharm Image Analytical System. DAPI nuclei were segmented defining the areas. Then each marker was quantified within this DAPI area. MPP4 low (MelR062) and MPP4 high (MelR166) phenotypes are represented.

Table S1. Patient Characteristics. AJCC: American Joint Committee on Cancer Table S2. Clinical information including histology, stage and survival. Table S3. Univariate analysis of clinico-pathological and CT features. Log-rank (Mantel-Cox) test to determine optimal cut-offs for low/high groups. Table S4. RNAseq immune genes for multiplex analysis.

The association between TMB and SD3/MPP4 is not statistically significant. A. MPP4, not significant, Fisher's exact. B. SD3, not significant, Fisher's exact.

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune “cold” signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028). Implications: CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment.

BackgroundThis study assessed and compared the morbidity of nodal dissection in the axilla and groin including sentinel lymph node biopsy (SLNB), completion lymph node dissection for a positive SLNB (CLND) and therapeutic lymph node dissection (TLND) with and without adjuvant radiotherapy (RT).

Background: Knowledge of variation in diagnosis and surgery in high-risk primary melanoma patients is limited. We assessed frequency and determinants of diagnostic procedures, wide local excision (WLE) and sentinel lymph node biopsy (SLNB).

Understanding recurrence patterns is vital for guiding treatment. This study describes recurrence patterns for patients with stage IIIB/C head and neck melanoma (HNM) after therapeutic lymph node dissection (TLND) ± adjuvant radiation therapy (RT). We also report outcomes for salvage therapy for patients with isolated regional relapse.A single-institution prospective database of 173 patients with American Joint Committee on Cancer (AJCC) stage IIIB/C HNM undergoing TLND between 1997 and 2012 was retrospectively reviewed. Timing and patterns of recurrence were reviewed. Univariable and multivariable analyses were undertaken using the Kaplan-Meier and Cox regression methods to determine factors predictive of recurrence. Median follow-up was 32 months.Adjuvant RT was administered to 66/173 (38 %) patients. Patients selected for RT had a higher AJCC stage and had more extracapsular invasion. The 5-year distant, cervical nodal and in-transit recurrence rates were 38, 10, and 13 %, respectively, following surgery alone compared with 60, 17, and 31 %, respectively, for the adjuvant RT group. The head and neck regional 5-year recurrence rate (combining in-basin nodal and in-transit) was 23 % for the entire cohort. Isolated cervical recurrence occurred in 19 patients: 17/19 underwent salvage surgery (10/17 patients received RT after salvage surgery) and 2/19 had RT alone. However, distant recurrence occurred in 12/19 salvage patients, with most occurring within 12 months, while 4/19 were disease free.Using a selective approach for adjuvant RT, isolated cervical recurrence after TLND is uncommon. Isolated cervical recurrence can be salvaged effectively with further local therapy; however, distant disease frequently follows.

ObjectiveThe aim of this paper is to determine levels of supportive care needs, anxiety, depression and symptoms amongst patients newly diagnosed with localised invasive primary melanoma and if these varied amongst patients who had a sentinel lymph node biopsy (SLNB). We also considered quality of life compared with general population norms.

Background: Current staging algorithms in melanoma patients undergoing therapeutic lymph node dissection (LND) fail to accurately distinguish long-term survivors from those at risk of rapid relapse. Our goal was to establish and validate nomograms for predicting both recurrence and survival after LND. Methods: A prospective cohort of stage IIIB and IIIC melanoma patients was ascertained from a tertiary hospital in Brisbane, Australia. Failure-time multivariate analysis identified key factors that, in adjusted combinations, generated nomograms to predict 2-year recurrence and 5-year melanoma-specific survival. The predictive value of these nomograms was further validated in a patient cohort from Rotterdam, The Netherlands. Results: In 494 Australian patients, number of positive lymph nodes, extra-capsular extension and nodular histopathological subtype were the main independent predictors of 2-year recurrence while age, number of positive nodes and extra-capsular extension were the independent predictors of survival. Predictive value was confirmed in The Netherlands cohort of 331 patients. The nomograms were able to classify patients according to their 2-year recurrence and 5-year survival rates even within each stage III sub-class. Conclusions: Models that include extra-capsular extension predict outcomes in patients with clinically involved lymph nodes. This tool may help tailor treatment and monitoring of this group of patients. (C) 2014 Elsevier Ltd. All rights reserved.

Patients with primary melanoma of the scalp have been reported to have worse disease-related outcomes compared with other anatomical regions. There are few studies in the literature specifically addressing recurrence patterns and treatment outcomes for primary scalp melanoma as a discrete anatomical sub-region. We sought to identify key features adversely influencing disease control and survival and to clarify the role of resection plane, margin, and method of reconstruction in the management of this disease process.A retrospective clinical study of medical records was performed evaluating all patients with primary melanoma of the scalp treated at two hospitals in southeast Queensland between 2004 and 2014.A total of 107 patients were eligible for analysis. There were 46 recurrences in 38 patients in the cohort accounting for a recurrence rate of 35.5%. The local recurrence rate was 15.9% with 12 in-transit metastases after diagnosis. Regional and distant recurrence rates were 12.1% and 15%, respectively. At a median follow up of 30.5 months, disease-free survival was 47% and overall survival was also 47%. On multi-variate analysis, the deeper resection plane (sub-galeal) had a lower disease-free survival rate compared with the supra-galeal resection plane (P = 0.032).Our results support the hypothesis that primary scalp melanoma represents a unique aggressive subcategory with high rates of in-transit disease and poor disease-related and survival outcomes. There is a need for robust prospective comparative studies to address the significance of resection plane in the management of patients with scalp melanoma.

Patients with advanced nodal melanoma are typically managed with a regional nodal dissection; however, they have a high rate of distant relapse after surgery. This study assesses the role of preoperative radiotherapy to assist with the regional control in this subset of patients. Patients who had histologically confirmed stage III malignant melanoma and were treated with preoperative radiotherapy between 2004 and 2011 were eligible. All patients were staged with computer tomography and most with [F]-fluorodeoxyglucose (FDG) PET. Patients received preoperative radiotherapy, followed by a planned regional dissection at 12-14 weeks from completion with assessment of clinical, radiological and pathological responses. The primary outcome measure was the 1-year actuarial in-field control. There were 12 patients, with nine having disease of the axilla. All patients received radiotherapy up to a median dose of 48 Gy in 20 fractions, with seven patients achieving a partial clinical response. Ten patients proceeded to surgery, with four patients developing minor wound complications. The FDG-PET response did not appear to correlate with the pathological response. The 1-year in-field control rate was 92% (95% confidence interval 54-99) and the 1-year relapse-free survival was 54% (95% confidence interval 21-78). For selected patients with high-volume regional disease, we have successfully used preoperative radiotherapy, followed by a nodal dissection. Whether this type of protocol is of value in a more general group of patients with high-volume regional disease is currently under investigation.

Desmoplastic melanoma (DM) is a rare subtype of cutaneous malignant melanoma reported to have a high local recurrence rate with surgical excision alone. The incidence of regional and distant metastasis is considered to be lower than traditional cutaneous melanoma, warranting more aggressive treatment of local disease. We conducted a retrospective analysis of patients with DM treated through the Princess Alexandra Hospital Melanoma Clinic to address the role of radiotherapy in the local control of this tumour.A review of a clinical database identified 24 patients between January 1997 and March 2006 with histopathologically confirmed DM who had received surgical excision as initial treatment followed by postoperative radiotherapy. All histopathology reports and radiotherapy treatment plans were reviewed. The primary outcome measure was 3-year in-field relapse-free survival.There were 24 patients with 22 having a DM in the head and neck region. The median tumour thickness was 5.2 mm. The histopathological margin was less than 10 mm in 17 (71%) of patients. The 3-year in-field relapse-free survival was 91% (95% confidence interval 68.1-97.6%), the 3-year relapse-free survival was 86% (95% confidence interval 63.2-95.4%) with a 3-year overall survival of 83% (95% confidence interval 54.9-94.3%).In a selected series of patients with DM with a high risk of local recurrence, adjuvant radiotherapy may have been effective in reducing the rate of local recurrence after surgical resection. A randomized trial is currently being developed to confirm this possible benefit.

Purpose: Sentinel lymph node biopsy (SLNB) and completion lymph node dissection (CLND) following a positive SLNB have been proposed as less morbid alternatives to therapeutic lymph node dissection (TLND) for macroscopic lymphadenopathy. This study compares the morbidity of SLNB, CLND, and TLND performed in the axilla or groin. Methodology: Seven hundred and twenty patients (449 axilla, 271 groin) who underwent regional lymph node surgery from 1996 to 2008 were identified from a prospectively maintained database. Complications were analysed according to type, site, procedure and administration of adjuvant radiotherapy by Chi square and Fisher's exact tests. Results: Of the 720 patients, 421 (58%) patients underwent SLNB alone, 69 (10%) CLND, and 230 (32%) TLND. Following SLNB, 38/421 (9%) patients developed lymphoedema and this was significantly less than the rate following CLND (38/69 [55%] patients, p < 0.01) and TLND (129/230 [56%] patients, p < 0.01). Among SLNB patients, procedures in the groin (25/150 [17%] patients) were significantly more likely to develop lymphoedema than axilla (13/271 [5%] patients, p < 0.01). There was no significant difference between the incidence of lymphoedema following CLND and TLND. Lymphoedema was significantly more common after CLND or TLND in the groin (92/121 [76%] patients) compared with the axilla (76/178 [43%] patients, p < 0.01). Adjuvant radiotherapy was not associated with a significant increase in lymphoedema. Conclusion: SLNB is a low morbidity procedure. In contrast, both CLND and TLND carry similar high rates of lymphoedema, particularly in the groin. These data should be taken into consideration when counselling patients with positive SLNB.