Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

BACKGROUND: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. METHODS: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. RESULTS: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641). CONCLUSIONS: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma.

Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas.

BACKGROUND: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA. METHODS: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively. RESULTS: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049). CONCLUSIONS: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

Cross-platform comparison of immune signatures in immunotherapy-treated patients with advanced melanoma using a rank-based scoring approach.

BACKGROUND: Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-sample scoring approach has been developed to alleviate instability of signature scores due to variations from sample composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms. METHODS: The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-sample rank-based scoring approach, singscore. We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction. RESULTS: singscore-derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-sample normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) [0.88, 0.92] and r2 IQR [0.77, 0.81]) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies. CONCLUSIONS: Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients' immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS.

Prognostic Significance and Management of Sentinel Nodes in the Triangular Intermuscular Space of Patients with Melanoma.

BACKGROUND: The clinical significance of sentinel nodes (SNs) in the triangular intermuscular space (TIS) of patients with melanoma is poorly understood. This study aimed to determine their incidence and positivity rate, and to report their management and patient outcomes. METHODS: This was a single-institution retrospective cohort study of patients with unilateral or bilateral TIS SNs on lymphoscintigraphy treated between 1992 and 2017. Recurrence-free survival was analyzed. RESULTS: Lymphoscintigraphy identified TIS SNs in 266 patients. They were bilateral in 17 patients. Of the 2296 patients with a melanoma on the upper back, 259 (11%) had TIS SNs. Procurement of SNs was not attempted in 122 (43%) of the 283 cases and failed in 11 cases (7%). An SN was successfully retrieved from the TIS in 145 patients (53%) and contained metastasis in 18 of 150 TIS SNs. This was the only positive SN in 12 patients (8%), upstaging all of them. Of the 18 patients with a positive SN in the TIS, 9 (50%) underwent completion axillary lymph node dissection, but no additional involved nodes were found in any of these patients. Recurrence in the TIS was observed in six patients (5%), none of whom had their TIS SN surgically pursued previously. CONCLUSIONS: Lymphoscintigraphy showed TIS SNs in 11% of patients with melanomas on their upper back. In such cases, retrieval of TIS SNs is required for accurate staging and to minimize the risk of TIS recurrence.

Adjuvant radiotherapy after salvage surgery for melanoma recurrence in a node field following a previous lymph node dissection.

BACKGROUND AND OBJECTIVES: Adjuvant radiotherapy (RT) can be given to melanoma patients following salvage surgery for node field recurrence after a previous regional node dissection, but the value of this treatment strategy is poorly documented. This study evaluated long-term node field control and survival of patients treated in this way in an era before effective adjuvant systemic therapy became available. METHODS: Data for 76 patients treated between 1990 and 2011 were extracted from an institutional database. Baseline patient characteristics, treatment details and oncological outcomes were analysed. RESULTS: Adjuvant RT with conventional fractionation (median dose 48 Gy in 20 fractions) was given to 43 patients (57%) and hypofractionated RT (median dose 33 Gy in 6 fractions) to 33 patients (43%). The 5-year node field control rate was 70%, 5-year recurrence-free survival 17%, 5-year melanoma-specific survival 26% and 5-year overall survival 25%. CONCLUSIONS: Salvage surgery with adjuvant RT achieved node field control in 70% of melanoma patients with node field recurrence following a prior node dissection. However, disease progression at distant sites was common and survival outcomes were poor. Prospective data will be required to assess outcomes for contemporary combinations of surgery, adjuvant RT and systemic therapy.

Whole-genome landscapes of major melanoma subtypes.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Multiplex melanoma families are enriched for polygenic risk.

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.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting.

BACKGROUND: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. OBJECTIVE: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. METHODS: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. RESULTS: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90). CONCLUSION: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

Clinicopathological Characteristics Predicting Further Recurrence and Survival Following Resection of In-Transit Melanoma Metastases.

BACKGROUND: In-transit metastases (ITMs) affect approximately 4% of patients with cutaneous melanoma. This study sought to identify clinical and pathological characteristics that predict further recurrence and survival following resection of ITMs. PATIENTS AND METHODS: Patients (n = 573) who underwent surgical resection of their first presentation of ITM following previous surgical treatment of an American Joint Committee on Cancer (AJCC) stage I-II melanoma between 1969 and 2017 were identified from an institutional database. Clinicopathological predictors of patterns of recurrence and survival following ITM resection were sought. RESULTS: The median time of ITM development was 2.4 years after primary melanoma resection. ITMs were most frequently located on the lower limb (51.0%). The most common melanoma subtype associated with ITM development was nodular melanoma (44.1%). After surgical resection of a first ITM, 65.4% of patients experienced recurrent disease. Most recurrences were locoregional (44.7%), with distant metastasis occurring in 23.9% of patients. Lower limb ITMs were more frequently associated with subsequent ITMs [odds ratio (OR) 2.41, p = 0.0002], and the lowest risk of distant metastasis (p < 0.0001) compared with other primary sites. Primary melanomas and ITM on head and neck, as well as the presence of ulceration, were associated with worse survival. CONCLUSIONS: Recurrence after surgical resection of a first ITM was common. Patterns of recurrence differed according to anatomical site; further ITM recurrences were more likely for lower limb ITMs, which were also associated with longer distant recurrence-free survival. Distant metastasis was more common for ITM on the head and neck, with worse survival.

Neoadjuvant Systemic Therapy (NAST) in Patients with Melanoma: Surgical Considerations by the International Neoadjuvant Melanoma Consortium (INMC).

Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.

The role of breast reconstruction choice on body image patient-reported outcomes at four years post-mastectomy for breast cancer: A longitudinal prospective cohort study.

OBJECTIVES: To examine the impact of breast reconstruction on women's perceptions of body image over time and to assess the influence of sociodemographic variables on body image. METHODS: A prospective, longitudinal cohort study, using validated breast cancer-specific questionnaires, to compare patient-reported outcomes in women choosing immediate (n = 61), delayed (n = 16) or no (n = 23) breast reconstruction. RESULTS: One hundred women completed baseline questionnaires that included items on body image; 30 women completed all four annual follow-up sets, while 20 women completed baseline only. The three groups were well matched at baseline and similar trajectories in body image measures were identified over 48 months in all groups. At 12 months post-mastectomy, significant changes were seen in eight of the 10 subscales; this reduced to seven subscales at 24 months and four at 36 months. By 48 months, only three subscales remained significantly different to baseline scores: women remained less vulnerable and had fewer limitations (improved outcomes); the one worse outcome was persistently higher levels of arm concern. Three of the sociodemographic variables (health insurance, age and employment status) showed significant inter-group differences at some time points. CONCLUSION: These findings suggest women recover from the negative impact of mastectomy on body image within four years of surgery, whether they have immediate, delayed or no reconstruction. Our results provide some indirect evidence that having a choice of BR options is important, regardless of the choice made. Four years appears to be a suitable follow-up period for future studies in this area.

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

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.

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

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.

A survey of surgical management of the sentinel node positive melanoma patient in the post-MSLT2 era.

BACKGROUND: The evidence-based management of melanoma patients with a positive sentinel lymph node biopsy (SLNB) has undergone a dramatic shift following publication of practice-changing surgical trials demonstrating no melanoma-specific survival advantage for completion lymph node dissection (CLND) in this scenario. We aimed to survey how surgeons' clinical practice had shifted in response to new evidence from these trials, and at a time when there was starting to become available systemic adjuvant treatments for AJCC Stage III melanoma patients. METHODS: A web-based survey consisting of practice-based questions and hypothetical clinical scenarios about current melanoma practice with regard to positive sentinel node biopsy was developed and sent to the surgical members of a Melanoma and Skin Cancer (MASC) Trials group in December 2018. Responses were analysed using descriptive statistics. RESULTS: There were 212 invitations sent and 65 respondents (31%). Respondents were from 17 countries, 94% of whom practice in specialist melanoma centres or at referral centres. Of these 97% were familiar with the MSLT2 and DeCOG-SLT clinical trials. At survey, 5% of respondents reported routinely recommending CLND and 55% recommend CLND in selected cases. Respondents were most likely to recommend CLND when multiple SLNs were positive. Important factors for surgical decision-making mentioned included size of SLN deposit, number of positive SLNs and likely compliance with the recommended surveillance regimen. CONCLUSION: In line with rapid adoption of published evidence, surgical management of Stage III melanoma has altered significantly, with few surgeons within the cohort now performing routine CLNDs after positive SLNB.

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

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/mm2 vs ≥2 mitoses/mm2 for T1 melanoma, <4 mitoses/mm2 vs ≥4 mitoses/mm2 for T2 melanoma, <6 mitoses/mm2 vs ≥6/mitoses/mm2 for T3 melanoma, and <7 mitoses/mm2 vs ≥7 mitoses/mm2 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.

The Landmark Series: Neoadjuvant Systemic Therapy (NAST) for Stage 3 Melanoma Patients - A Potential Paradigm Shift in Management.

Since the advent of effective systemic therapy, quantum changes have occurred in the multidisciplinary management strategies used for patients with American Joint Committee on Cancer stages 3 and 4 melanoma. For high-risk stage 3 patients, neoadjuvant immune checkpoint blockade (ICB) and targeted therapies present a promising novel approach to improving survival outcomes. In particular, patients who respond to ICB have an excellent prognosis, and clinical trials are ongoing to investigate whether those with a pathologic complete response (pCR) or near-pCR in a single node may avoid therapeutic lymph node dissection and adjuvant therapy. Toxicities currently are acceptably low, but when toxic events occur, they can have an enduring impact on a patient's quality of life. To date, nearly all patients evaluated after treatment with neoadjuvant dabrafenib plus trametinib have some clinical and pathologic response. Patients who achieve pCR have improved prognosis, but pCR is not as reliable a predictor of improved outcome as pCR or near-pCR after neoadjuvant ICB. Ongoing studies should ideally be coordinated through the International Neoadjuvant Melanoma Consortium to ensure maximal efficiency at improving outcomes for melanoma patients.

Principles of patient-centred care and barriers to their implementation: a case study of breast reconstruction in Australia.

PURPOSE: "Patient-centred care" is widely promoted as an ideal goal of health care systems, but is often difficult to achieve in practice. This article has three aims: to develop an original set of generalisable patient-centred care principles (PCCPs); to identify barriers to the implementation of these principles in a real-world setting, using breast reconstruction (BR) services in Australia as a case study; and to document examples of successful patient-centred care in relation to BR. METHODS: Semi-structured interviews (n = 90) were conducted with 31 breast and plastic reconstructive surgeons, 37 breast cancer health professionals and 22 women who underwent mastectomy as part of their breast cancer treatment and were dissatisfied with their BR experiences. RESULTS: Ten broad PCCPs were derived from our participant interviews. These principles comprised the following: maximising patient choice, access to services, patient and family support and appropriateness of information; minimising patient costs and physical and psychosocial morbidity; and facilitating informed decision-making, interdisciplinary patient management and evidence-informed practice. While the major barriers to the implementation of these PCCPs in relation to BR were resource driven, surgeon-related factors were also identified. CONCLUSIONS: These PCCPs highlight areas of need but also provide examples of high quality patient-centred care. They may help to guide a national discussion about minimum standards of BR practice, while allowing for some necessary regional and cultural variation. They also have the potential to be applied more widely to the provision of a range of health services within Australia or internationally.