Publications by authors named "Kerwin Shannon"

76 Publications

Survival Outcomes of Salvage Metastasectomy After Failure of Modern-Era Systemic Therapy for Melanoma.

Ann Surg Oncol 2021 Aug 4. Epub 2021 Aug 4.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy.

Methods: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC.

Results: The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively.

Conclusions: Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy.
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http://dx.doi.org/10.1245/s10434-021-10489-xDOI Listing
August 2021

Histological regression in melanoma: impact on sentinel lymph node status and survival.

Mod Pathol 2021 Jul 10. Epub 2021 Jul 10.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20-0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51-0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58-0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.
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http://dx.doi.org/10.1038/s41379-021-00870-2DOI Listing
July 2021

Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies.

Eur J Cancer 2021 Aug 12;153:8-15. Epub 2021 Jun 12.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Mater Hospital, North Sydney, New South Wales, Australia; Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customised to individual patient and tumour factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.
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http://dx.doi.org/10.1016/j.ejca.2021.04.037DOI Listing
August 2021

Bilateral facial neuritis associated with dabrafenib and trametinib after failure of neoadjuvant immunotherapy for stage III melanoma.

ANZ J Surg 2021 Jun 14. Epub 2021 Jun 14.

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.16992DOI Listing
June 2021

The significance of regional metastasis location in head and neck cutaneous squamous cell carcinoma.

Head Neck 2021 09 21;43(9):2705-2711. Epub 2021 May 21.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.

Background: Regional metastasis of head and neck cutaneous squamous cell carcinoma (HNcSCC) can be seen in either parotid and/or cervical lymph nodes. The aim of this study was to assess whether there was a difference in prognosis between parotid and cervical nodal metastases.

Methods: Patients with regional metastasis from HNcSCC were identified from an institutional database. Disease-specific (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

Results: Five hundred and thirty-five patients were identified with median follow-up of 26.4 months (3-255 months). Two hundred and thirty-five patients had parotid metastasis, 96 patients had neck metastasis, and 204 patients had both. On multivariable analysis, any regional metastasis to the neck when compared to parotid alone conferred worse DSS (HR 1.8, p = 0.007) and OS (HR 1.3, p = 0.024).

Conclusion: Regional metastasis of HNcSCC to the neck confers worse outcomes compared to metastasis to the parotid alone.
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http://dx.doi.org/10.1002/hed.26744DOI Listing
September 2021

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Cancer Immunol Res 2021 Jun 5;9(6):612-623. Epub 2021 Mar 5.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4 or CD8 T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2 γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions..
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0817DOI Listing
June 2021

Clinical outcomes following surgical treatment of lentigo maligna of the head and neck.

Eur J Surg Oncol 2021 May 23;47(5):1145-1151. Epub 2020 Sep 23.

Sydney Medical School, The University of Sydney, Sydney, Australia; Institute of Academic Surgery, Royal Prince Alfred Hospital, Sydney, Australia; Department of Plastic and Reconstructive Surgery, Royal Prince Alfred Hospital, Sydney, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

Introduction: Lentigo maligna (LM), a subtype of melanoma in-situ commonly occurring in the head and neck region, often presents a treatment challenge due to anatomical constraints, particularly on the face of mostly elderly patients. This study sought to assess the clinical outcomes of wide local excision of head and neck LM, identify predictors of recurrence and define optimal excision margins.

Materials And Methods: Patients with LM treated between January 1997 and December 2012 were identified from the large institutional database of a tertiary center and their data were analyzed.

Results: In 379 patients, 382 lesions were eligible for analysis. Median maximal lesion diameter was 10.5 mm. The mean surgical excision and histopathological clearance margins were 6.2 mm and 4.0 mm, respectively. Median follow-up was 32 months. The LM recurrence rate was 9.9%, and subsequent invasive melanoma developed in 2.3% of cases (mean Breslow thickness 0.7 mm). The recurrence rate was 27.2% if the histological margin was <3.0 mm (median time to recurrence 46.5 months) compared with 2.6% if the margin was ≥3.0 mm. The mean surgical margin required to achieve a histological clearance of ≥3.0 mm was 6.5 mm.

Conclusions: Our data suggest that to minimize recurrence, a histological margin of ≥3.0 mm is required. To achieve this, a surgical margin of ≥6.5 mm was required. This is greater than the 5 mm margin recommended in some national guidelines. Careful long-term follow-up is required for all patients because of the risk of recurrence.
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http://dx.doi.org/10.1016/j.ejso.2020.09.028DOI Listing
May 2021

Soft Tissue Metastases in Head and Neck Cutaneous Squamous Cell Carcinoma.

Laryngoscope 2021 04 14;131(4):E1209-E1213. Epub 2020 Sep 14.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.

Objective: Soft tissue metastases (STM) in head and neck cutaneous squamous cell carcinoma (HNcSCC) are non-nodal based metastases to the parotid and cervical soft tissues of the head and neck. This is a unique subgroup of regional metastases amongst patients with cSCC and have been shown to be associated with poor prognosis. Detailed studies of this subgroup are lacking in the literature. A retrospective cohort analysis was performed to characterize the prognostic significance of STM in HNcSCC based on individual clinicopathological features.

Methods: Patients with HNcSCC with STM were identified from the Sydney Head and Neck Cancer Institute database. Clinicopathological characteristics were extracted from the histopathological reports. Recurrence and follow-up data were analyzed to determine disease-free and overall survival using the Kaplan-Meier method and Cox proportional hazards models.

Results: After excluding all patients with lymph node metastasis with no STM, there were 200 patients identified (161 parotid, 32 cervical, and seven with concurrent parotid and cervical STM) with a 5-year overall survival of 36%. In univariable analysis, age of patients, size of the deposits, location of the deposits, and patients that were not offered adjuvant radiotherapy have worse overall survival. However, on multivariable analysis, age and the number of STM deposits were independent factors that predict for worse survival.

Conclusion: The presence of STM in patients with HNcSCC is associated with poor prognosis. Increasing number of STM deposits, as well as involved margin of the regional excision, negatively impacted on the overall prognosis.

Level Of Evidence: Level III - retrospective cohort study. Laryngoscope, 131:E1209-E1213, 2021.
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http://dx.doi.org/10.1002/lary.29064DOI Listing
April 2021

Reappraisal of the prognostic significance of mitotic rate supports its reincorporation into the melanoma staging system.

Cancer 2020 11 11;126(21):4717-4725. Epub 2020 Aug 11.

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

Background: Mitotic rate is a strong, independent prognostic factor in patients with melanoma. However, incorporating it into the melanoma staging system has proved challenging.

Methods: The prognostic impact of mitotic rate was assessed in a melanoma cohort comprising 5050 patients from 2 geographically distinct populations. Computer-generated cut points for mitotic rate were constructed to determine its impact on melanoma-associated survival using Kaplan-Meier and multivariate regression analyses. The impact of mitotic rate also was assessed in randomly split training and validation sets.

Results: Mitotic rate had a nonlinear impact on survival, as evidenced by unequally spaced cut points. An index incorporating these cut points that was constructed from one population produced significantly more accurate predictions of survival in the other population than using the entire scale of mitotic rate. An index constructed from the combined cohort was found to be independently predictive of survival, with an impact comparable to that of ulceration. Optimal high-versus-low cut points for mitotic rate were generated separately for each T category (<2 mitoses/mm vs ≥2 mitoses/mm for T1 melanoma, <4 mitoses/mm vs ≥4 mitoses/mm for T2 melanoma, <6 mitoses/mm vs ≥6/mitoses/mm for T3 melanoma, and <7 mitoses/mm vs ≥7 mitoses/mm for T4 melanoma). Using Kaplan-Meier analysis, elevated mitotic rate was found to have an impact on survival comparable to that of ulceration within each T category. Application of the index for mitotic rate that was constructed from the training data set demonstrated an independent impact in the validation data set, with a significance similar to that of ulceration.

Conclusions: The results of the current study demonstrated the comparable prognostic impact of mitotic rate and ulceration, providing support for its reincorporation into the T category.
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http://dx.doi.org/10.1002/cncr.33088DOI Listing
November 2020

Multiplex melanoma families are enriched for polygenic risk.

Hum Mol Genet 2020 10;29(17):2976-2985

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
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http://dx.doi.org/10.1093/hmg/ddaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566496PMC
October 2020

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

J Clin Oncol 2020 08 12;38(24):2719-2727. Epub 2020 Jun 12.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia.

Purpose: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity.

Patients And Methods: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496).

Results: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model ( < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%).

Conclusion: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.
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http://dx.doi.org/10.1200/JCO.19.02362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430218PMC
August 2020

Primary dermal melanoma: clinical behaviour, prognosis and treatment.

Eur J Surg Oncol 2020 11 1;46(11):2131-2139. Epub 2020 May 1.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Purpose: Primary dermal melanoma (PDM) is a subtype of cutaneous melanoma, confined to the dermis, which poses a challenging clinical dilemma. It may represent a true primary melanoma or a dermal cutaneous metastasis. This study aimed to delineate the histopathological characteristics and prognosis of PDM in a large patient cohort to guide appropriate treatment strategies.

Methods: A search of the Melanoma Research Database at Melanoma Institute Australia was conducted to identify all possible PDM patients at our institution diagnosed from 1978 to 2013. Overall, melanoma-specific and disease-free survival outcomes of the PDM group were compared to those of similar cohorts of Stage I-II and Stage IV M1a melanoma patients based on propensity score matching.

Results: Sixty-two PDM patients were identified from the MRD with a median follow-up of 6.3 years. Five-year survival was 87.1% and overall survival was 74.2%. PDMs had a significantly improved overall survival (p = 0.0002) and melanoma-specific survival (p = 0.001) compared to Stage I-II controls, however there was no difference in disease-free survival (p = 0.08). PDMs also demonstrated improved overall survival (p < 0.0001), melanoma-specific survival (p < 0.0001) and disease-free survival (p < 0.0001) compared to Stage IV M1a controls.

Conclusion: These findings demonstrate that PDMs have a more favorable prognosis compared to stage I-II cutaneous melanomas and suggest that these are in fact true primary lesions. This study thus provides evidence to justify a treatment approach, by way of a wide local excision and possibly sentinel lymph node biopsy, as for early stage primary cutaneous melanomas.
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http://dx.doi.org/10.1016/j.ejso.2020.04.043DOI Listing
November 2020

Cumulative Incidence and Predictors of CNS Metastasis for Patients With American Joint Committee on Cancer 8th Edition Stage III Melanoma.

J Clin Oncol 2020 05 28;38(13):1429-1441. Epub 2020 Jan 28.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma.

Patients And Methods: Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis.

Results: At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined.

Conclusion: Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.
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http://dx.doi.org/10.1200/JCO.19.01508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193747PMC
May 2020

Surgical management of the neck in patients with metastatic melanoma in parotid lymph nodes.

J Surg Oncol 2019 Dec 25;120(8):1462-1469. Epub 2019 Oct 25.

Department of Head and Neck Surgery, Chris O'Brien Lifehouse Cancer Centre, Sydney, Australia.

Background: The role and extent of neck dissection in patients with parotid metastatic cutaneous head and neck melanoma remain unclear. The aims of this study were to determine the incidence and patterns of cervical node involvement in patients with parotid metastatic melanoma, and to determine if a limited lymphadenectomy of the clinically negative neck is appropriate.

Methods: Patients who underwent parotidectomy and neck dissection for clinically apparent parotid metastatic melanoma, irrespective of neck status, were identified from two prospectively maintained databases.

Results: A total of 276 patients fulfilled the study criteria. Median follow-up was 23 months. A total of 185 necks were clinically negative, 82 were clinically positive. A total of 36 elective neck-dissection specimens harbored occult metastases; these were found in levels I (16.7%), II (58.3%), III (36.1%), IV (13.9%), and V (30.6%). Regional recurrence occurred in 32 patients with a clinically negative neck, the majority being in-transit metastases (n = 15). Only one case of recurrence could have potentially been avoided by a comprehensive lymphadenectomy.

Conclusions: In patients with clinically apparent parotid melanoma metastases, elective comprehensive neck dissection reduces failure rates in cervical nodes, and provides more accurate staging and prognostic information. However, our findings support the emerging trend for more limited elective neck dissection. Levels I and IV can probably be safely omitted.
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http://dx.doi.org/10.1002/jso.25732DOI Listing
December 2019

Sentinel Node Biopsy in 105 High-Risk Cutaneous SCCs of the Head and Neck: Results of a Multicenter Prospective Study.

Ann Surg Oncol 2019 Dec 3;26(13):4481-4488. Epub 2019 Oct 3.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.

Background: Regional nodal metastases from cutaneous squamous cell carcinoma (cSCC) is strongly associated with a poor prognosis, but these metastases are difficult to predict clinically. Sentinel node biopsy (SNB) has been used for a wide range of malignancies to assess for regional nodal metastasis, but is not widely used for cSCC.

Methods: Patients presenting with high-risk cSCC of the head and neck with clinically N0 necks were offered SNB at the time of primary cSCC excision or secondary wide local excision. Patients with positive sentinel nodes were offered completion lymph node dissection, and all the patients were followed up at regular intervals for up to 5 years.

Results: In this study, 105 lesions underwent SNB, and 10 sentinel nodes (9.5%) were positive. In an additional five patients, regional recurrence developed after a negative sentinel node, with a total subclinical nodal metastasis rate of 14.3%. Nodal metastases were significantly associated with reduced disease-specific survival. The significant predictors of metastasis were four or more high-risk features or tumors with a concurrent invasion deeper than 5 mm and PNI.

Conclusion: For high-risk cSCC, SNB is a safe and feasible staging technique. The total number of high risk features and certain combinations of high-risk features predicted metastasis better than individual high-risk features.
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http://dx.doi.org/10.1245/s10434-019-07865-zDOI Listing
December 2019

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Nat Commun 2019 07 18;10(1):3163. Epub 2019 Jul 18.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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http://dx.doi.org/10.1038/s41467-019-11107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639323PMC
July 2019

Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

J Clin Pathol 2020 Jan 12;73(1):17-22. Epub 2019 Jul 12.

Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.

Methods: Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.

Results: High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20-89) with the two patients <45 years of age showing highest intratumour heterogeneity. was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance ( S821F, T670I, mutations at codons 12 and 13).

Conclusion: We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.
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http://dx.doi.org/10.1136/jclinpath-2019-206038DOI Listing
January 2020

Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial.

Lancet Oncol 2019 07 3;20(7):961-971. Epub 2019 Jun 3.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia.

Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.

Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAF-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing.

Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29-63) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%; 95% CI 5-30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31-66) patients had a complete pathological response and 18 (51%; 95% CI 34-69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.

Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.

Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.
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http://dx.doi.org/10.1016/S1470-2045(19)30331-6DOI Listing
July 2019

Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial.

Lancet Oncol 2019 07 31;20(7):948-960. Epub 2019 May 31.

Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.

Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.

Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C.

Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(19)30151-2DOI Listing
July 2019

Recurrent hotspot SF3B1 mutations at codon 625 in vulvovaginal mucosal melanoma identified in a study of 27 Australian mucosal melanomas.

Oncotarget 2019 Jan 29;10(9):930-941. Epub 2019 Jan 29.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

Introduction: Clinical outcomes for mucosal melanomas are often poor due to a lack of effective systemic drug therapies. Identifying driver genes in mucosal melanoma may enhance the understanding of disease pathogenesis and provide novel opportunities to develop effective therapies.

Results: Somatic variant analysis identified (6 of 27: 22%) as the most commonly mutated gene, followed by (3 of 27: 11%). Other less frequently mutated genes (4% otherwise stated) included (7%), (7%), , , , , , , and . Recurrent SF3B1 p.R625 hotspot mutations were exclusively detected in vulvovaginal (5 of 19: 26%) and anorectal melanomas (3 of 5:60%). The only other SF3B1 mutation was a p.C1123Y mutation that occurred in a conjunctival mucosal melanoma.-mutated patients were associated with shorter overall survival (OS; 34.9 months) and progression-free survival (PFS; 16.9 months) compared to non--mutated patients (OS: 79.7 months, log-rank = 0.1172; PFS: 35.7 months, log-rank = 0.0963).

Conclusion: Molecular subgroups of mucosal melanoma with mutations occurred predominantly in the vulvovaginal region. mutations may have a negative prognostic impact.

Methods: Formalin-fixed biopsies were collected from 27 pathologically-confirmed mucosal melanomas. Genomic DNA was isolated from the tumor tissue and sequenced using a novel dual-strand amplicon sequencing technique to determine the frequency and types of mutations across 45 target genes.
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http://dx.doi.org/10.18632/oncotarget.26584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398173PMC
January 2019

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2019 07 23;139(7):1449-1458.e1. Epub 2019 Jan 23.

Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia; Children's Cancer Institute, Kensington, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Sydney, Australia.

Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTC-binding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.jid.2019.01.008DOI Listing
July 2019

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility.

Int J Cancer 2019 03 21;144(5):1049-1060. Epub 2018 Nov 21.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.
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http://dx.doi.org/10.1002/ijc.31791DOI Listing
March 2019

Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma.

Mod Pathol 2018 02 6;31(2):275-287. Epub 2017 Oct 6.

Central Clinical School, The University of Sydney, Sydney, Australia.

Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases; APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.
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http://dx.doi.org/10.1038/modpathol.2017.128DOI Listing
February 2018

Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center.

Mod Pathol 2017 11 21;30(11):1538-1550. Epub 2017 Jul 21.

Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia.

Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins ≥8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence.
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http://dx.doi.org/10.1038/modpathol.2017.76DOI Listing
November 2017

Bone resection for facial cutaneous malignancies.

J Surg Oncol 2017 Sep 19;116(4):545-549. Epub 2017 Jun 19.

Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.

Background And Objectives: The aim of this study is to analyze the clinical outcomes of patients who underwent bone resection for cutaneous malignancy of the face and scalp.

Methods: We retrospectively collected patient data from 62 patients who underwent bone resection for craniofacial cutaneous malignancy of the face and scalp over the last 10 years. We investigated risk factors for disease progression and assessed the utility of pre-operative imaging to predict bone, dura, and brain infiltration.

Results: Out of all factors analyzed, brain invasion, surgical margin involvement, and dural margin involvement were found to significantly reduce survival. CT and MRI correctly predicted bone infiltration in 88% and 89% of cases. MRI correctly predicted dura invasion in 89% but grossly underestimated the amount of dural invasion in 23% of reports.

Conclusions: Our data indicate that the resection of bone is a reasonable surgical option in the treatment of patients with advanced cutaneous malignancies of the face and scalp. Brain invasion and positive margins reduced the probability of survival.
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http://dx.doi.org/10.1002/jso.24693DOI Listing
September 2017

Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis.

Int J Rheum Dis 2017 Sep 8;20(9):1277-1285. Epub 2017 May 8.

University of Sydney, Sydney, New South Wales, Australia.

Aim: Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis.

Methods: Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy.

Results: Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6 CCR4 CXCR3 CCR10 ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy.

Conclusion: Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.
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http://dx.doi.org/10.1111/1756-185X.13076DOI Listing
September 2017

Conditional Survival: An Assessment of the Prognosis of Patients at Time Points After Initial Diagnosis and Treatment of Locoregional Melanoma Metastasis.

J Clin Oncol 2017 May 4;35(15):1721-1729. Epub 2017 Apr 4.

Lauren E. Haydu, Richard A. Scolyer, Serigne Lo, Robyn P.M. Saw, Kerwin F. Shannon, Andrew J. Spillane, Jonathan R. Stretch, and John F. Thompson: The University of Sydney, Sydney; Richard A. Scolyer, Robyn P.M. Saw, and John F. Thompson, Royal Prince Alfred Hospital, Camperdown; Michael J. Quinn, The University of Wollongong, Wollongong, NSW, Australia; and Lauren E. Haydu, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose Standard cancer staging and prognostic estimates are determined at the time of the patient's initial disease presentation. Conditional survival is an alternative, dynamic assessment from follow-up time points after the initial disease diagnosis and is based on the condition of survivorship. Estimates of conditional survival can provide critical prognostic information for patients and clinicians, guide subsequent cancer follow-up schedules, and influence decisions regarding treatments. The current study presents conditional survival estimates developed from a cohort of 4,540 patients diagnosed with stage III melanoma treated at a single institution. Methods Patients with stage III disease at first melanoma diagnosis (initial; n = 2,042), or who developed locoregional metastasis as a first recurrence some time after primary diagnosis (recurrent; n = 2,498), were assessed. Conditional melanoma-specific survival (MSS) estimates up to 5 years after diagnosis were adjusted for age, sex, and 8th edition American Joint Committee on Cancer (AJCC) stage. Results Older age at diagnosis of stage III disease conveyed a worse prognosis at each conditional survival time point. Males had significantly worse MSS outcomes for up to 2 years of conditional survival, after which males and females had similar MSS. For patients with AJCC stage IIIB and stage IIIC disease, MSS outcomes were similar to those of patients with stage IIIA disease after 3 and 5 years of survivorship, respectively. Conclusion Adjuvant systemic treatments may have the greatest benefit when administered within the first 2 years of stage III melanoma diagnosis, during which period prognosis is significantly worse for male patients of increasing age and AJCC substage. Conditional survival estimates illustrate improved survival prospects for patients with cancer returning for follow-up and may define a finite period of increased risk after diagnosis.
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http://dx.doi.org/10.1200/JCO.2016.71.9393DOI Listing
May 2017

Quality of Life Following Sentinel Node Biopsy for Primary Cutaneous Melanoma: Health Economic Implications.

Ann Surg Oncol 2017 Aug 20;24(8):2071-2079. Epub 2017 Mar 20.

Division of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: Sentinel node biopsy (SNB) is commonly performed in contemporary melanoma management, however there is a paucity of long-term quality of life (QoL) estimates required for economic evaluation of this treatment.

Methods: A single-center, prospective, cross-sectional study of adults with American Joint Committee on Cancer stage I/II/IIIA melanoma of the limbs, trunk, or neck who had undergone wide excision and SNB, but not complete regional node dissection, was undertaken. Limb volume was measured using perometry, with lymphedema defined as a ≥10% volume increase in the ipsilateral limb compared with the contralateral limb. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire measured QoL. Associations between patient and treatment characteristics were assessed using linear regression.

Results: Among 694 patients (median time from SNB of 37 months), 14 (2%) had objectively measured lymphedema (i.e. an increase in limb volume of ≥10%). Of 687 stage I/II patients with complete QoL data, the mean weighted QoL was 0.745 (standard deviation 0.04) on a 0-1 scale (i.e. death to full health). In multivariable analysis, weighted QoL was 0.0004 higher for each year of increasing age (p = 0.001); 0.011 lower for females (p = 0.001), 0.018 lower following post-SNB limb trauma (p = 0.002); 0.252 lower for patients who perceived a large increase in limb size (p = 0.015); and 0.027 lower with self-reported difficulty in walking, running, or climbing stairs (p = 0.043).

Conclusions: Our data suggest that very few patients treated at our institution had lymphedema in the long-term following SNB, with weighted QoL strongly associated with perceived rather than actual changes in limb size.
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http://dx.doi.org/10.1245/s10434-017-5842-2DOI Listing
August 2017
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