Risk Stratification of Sentinel Node Metastasis Disease Burden and Phenotype in Stage III Melanoma Patients.

BACKGROUND: Currently, all patients with American Joint Committee on Cancer (AJCC) pT2b-pT4b melanomas and a positive sentinel node biopsy are now considered for adjuvant systemic therapy without consideration of the burden of disease in the metastatic nodes. METHODS: This was a retrospective cohort analysis of 1377 pT1-pT4b melanoma patients treated at an academic cancer center. Standard variables regarding patient, primary tumor, and sentinel node characteristics, in addition to sentinel node metastasis maximum tumor deposit size (MTDS) in millimeters and extracapsular spread (ECS) status, were analyzed for predicting disease-specific survival (DSS). RESULTS: The incidence of SN+ was 17.3% (238/1377) and ECS was 10.5% (25/238). Increasing AJCC N stage was associated with worse DSS. There was no difference in DSS between the IIIB and IIIC groups. Subgroup analyses showed that the optimal MTDS cut-point was 0.7 mm for the pT1b-pT4a SN+ subgroups, but there was no cut-point for the pT4b SN+ subgroup. Patients with MTDS <0.7 mm and no ECS had similar survival outcomes as the N0 patients with the same T stage. Nodal risk categories were developed using the 0.7 mm MTDS cut-point and ECS status. The incidence of low-risk disease, according to the new nodal risk model, was 22.3% (53/238) in the stage III cohort, with 49% (26/53) in the pT2b-pT3a and pT3b-pT4a subgroups and none in the pT4b subgroup. Similar outcomes were observed for overall and distant metastasis-free survival. CONCLUSION: We propose a more granular classification system, based on tumor burden and ECS status in the sentinel node, that identifies low-risk patients in the AJCC IIIB and IIIC subgroups who may otherwise be observed.

Follow-up Schedule for Patients With Sentinel Node-negative Cutaneous Melanoma (The MELFO Study): An International Phase III Randomized Clinical Trial.

OBJECTIVES AND DESIGN: The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines. BACKGROUND: Evidence-based guidelines for the follow-up of sentinel node-negative melanoma patients are lacking. METHODS: Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared. RESULTS: At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P =0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P =0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P =0.99). CONCLUSIONS: A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high.

Effectiveness of SPECT/CT Imaging for Sentinel Node Biopsy Staging of Primary Cutaneous Melanoma and Patient Outcomes.

PURPOSE: Coregistered SPECT/CT can improve accuracy of sentinel node biopsy (SNB) for staging melanoma. This benefit has implications for pathology services and surgical practice with increased diagnostic and surgical workload. The purpose of this study was to investigate the effectiveness of SPECT/CT imaging. METHODS: SNB data were collected over a 10-year period. Preoperative SLN mapping was performed by using planar lymphoscintigraphy (LSG) for all patients (n = 1522) and after October 2015, patients underwent a second co-registered SPECT/CT scan (n = 559). The patients were stratified according to the imaging protocol. The number of nodes and nodal basins were assessed. The reasons for cancellation also were assessed. RESULTS: A total of 95% (1446/1522) of patients underwent a successful SNB procedure. Significantly more sentinel nodes were identified by the SPECT/CT protocol (3 vs. 2; p < 0.0001). More patients were cancelled in the SPECT/CT cohort (9.3% vs. 2.5%; p < 0.0001). Head & neck, lower limb, and AJCC IB primaries were significantly less likely to proceed to SNB. SPECT/CT identified significantly more positive SNBs (20.9% vs. 16.5%; p = 0.038). SPECT/CT imaging was associated with improved disease-free (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.54-1.0); p = 0.048) and disease-specific survival (HR = 0.48; 95% CI: 0.3-0.78; p = 0.003). Patients who did not proceed to SNB had a significantly increased nodal relapse rate (23.5% vs. 6.8%; HR = 3.4; 95% CI: 1.9-6.2; p < 0.0001) compared with those who underwent SNB. CONCLUSIONS: This large cohort study confirms the increased accuracy of SPECT/CT for identifying SLN metastases, which would appear to have a significant therapeutic benefit, although an increased risk of cancellation of the SNB procedure on the day of surgery.

Evaluation of the Indications for Sentinel Node Biopsy in Early-Stage Melanoma with the Advent of Adjuvant Systemic Therapy: An International, Multicenter Study.

BACKGROUND: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5-10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy METHODS: An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8-2.0 mm in Breslow thickness (pT1b-pT2a; AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. RESULTS: The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412; 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of >1/mm2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases (>1 mm maximum diameter). CONCLUSIONS: The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.

Extracapsular Spread in Melanoma Lymphadenopathy: Prognostic Implications, Classification, and Management.

BACKGROUND: Extracapsular spread (ECS) is recognized to be a high-risk factor in melanoma patients with macrometastatic (N+) nodal disease; however, ECS risk in sentinel lymph node (SLN) biopsy, micrometastatic stage III disease is ambiguous. OBJECTIVE: The aim of this study was to examine ECS incidence and its prognostic significance. METHODS: A two-center, retrospective analysis of all patients with micro/macrometastatic lymphadenopathy undergoing nodal surgery from 2008 to 2014 was performed. Patient demographics, tumor characteristics, nodal ECS status, and patient outcomes were collected. RESULTS: Overall, 515 patients with nodal disease were identified (males/females = 277/238); median age was 63 years (range 17-94). There was an increased frequency of ECS disease in N+ disease compared with SLN+ disease (52.4% vs. 16.2%; p < 0.0001). The absolute disease-specific survival (DSS) difference for SLN+ patients was approximately 30% at 10 years (66.2% vs. 37.2%; p < 0.0001), and the prognosis of SLN+/ECS+ patients was identical to N+/ECS- patients. Multivariate analysis demonstrated that ECS status was an independent prognostic indicator for DSS (hazard ratio 2.47, 95% confidence interval 1.87-3.26; p < 0.0001) in patients with SLN+ disease. There were significant differences in nodal burden according to ECS status between the SLN+ and N+ subgroups suggestive of differing biology in ECS+ tumors. CONCLUSION: We found that ECS is a significant DSS, progression-free survival, and overall survival indicator in SLN+ and N+ disease. We demonstrated that ECS upstages stage III disease, similar to ulceration in primary melanoma (stage I/II disease). A simplified staging system substituting ECS for N stage accurately stages patients according to prognosis.

Improved Perioperative Seroma and Complication Rates Following the Application of a 2-Layer Negative Pressure Wound Therapy System After Inguinal Lymphadenectomy for Metastatic Cutaneous Melanoma.

BACKGROUND: Perioperative complications following inguinal lymphadenectomy, including seroma formation, are frequent. We have employed a 2-layer negative pressure wound therapy (2-LNPWT) as a method to reduce seroma rate and perioperative complications. We present the outcome of our initial experience with 2-LNPWT and compare the outcomes of its use with traditional closed suction drains (CSDs). MATERIALS AND METHODS: A non-randomised retrospective case-control series was analysed. Surgeons performing inguinal lymphadenectomy for metastatic cutaneous melanoma utilised either the 2-LNPWT therapy or traditional CSDs according to their practice preference. RESULTS: The study included 111 patients. The cohorts were well matched for gender, disease burden, body mass index and comorbidities. The 2-LNPWT technique was associated with significantly better postoperative outcomes than CSD, in terms of incidence of seroma formation (26.9% vs 49.4%; p < 0.03), period of drainage (15 days vs 20 days; p = 0.005) and return to theatre rate (0% vs 15.3%; p = 0.03). The overall seroma rate was 44.1%. The only significant association with seroma initiation was the type of drainage system used (2-LNPWT 31.2% vs CSD 58.3%; p < 0.03; OR 3.0). The method of drainage did not alter the course of an established seroma. There was no significant difference in overall or disease-specific survival detected between the 2 groups. CONCLUSION: This retrospective non-randomised case control study has demonstrated the safe use of a novel application of negative pressure wound therapy that significantly reduced the incidence of seroma formation and postoperative complication rate for inguinal lymphadenectomy for melanoma.

The MelFo Study UK: Effects of a Reduced-Frequency, Stage-Adjusted Follow-Up Schedule for Cutaneous Melanoma 1B to 2C Patients After 3-Years.

BACKGROUND: Evidence-based guidelines for follow-up treatment of American Joint Committee on Cancer (AJCC) stages 1B to 2C melanoma patients are lacking. The MELanoma FOllow-up study is an international phase 3 randomized trial, and the 3-year interim data were recently reported from the Netherlands. The study was undertaken concurrently with a British cohort for comparison and validation of the Dutch study. METHODS: The study enrolled and stratified 207 patients by AJCC stage. The conventional schedule group (CSG; n = 103) cohort was reviewed as per UK guidelines. The experimental schedule group (ESG; n = 104) cohort was reviewed in a reduced-frequency nurse-led, consultant-supervised clinic. Quality of life (QoL) was measured at baseline (T1), a 1 year (T2), and at 3 years (T3) using the State-Trait Anxiety Inventory, the Cancer Worry Scale, the Impact-of-Event Scale, and the Mental and Physical Component scales (PCS/MCS) of the RAND-36. RESULTS: Of the 207 QoL questionnaires, 170 (82.1%) were completed at T3. Both cohorts expressed high satisfaction (> 93%) with their regimens. At T3, no significant group effect was found on any patient-reported outcome measures scores, indicating no QoL difference between the follow-up protocols. Recurrence had developed in 33 patients Conventional follow-up (CFU), 16 [15.5%]; Experimental follow-up (EFU), 17 [16.3%]. Self-examination was the method of detection for 12 ESG patients (70.6%) and 11 CSG patients (68.8%). The melanoma-specific survival was identical. CONCLUSION: The UK 3-year data were consistent with the previous Dutch report. The reduced follow-up strategy was shown to be safe, with significant resource usage benefits for national cancer services. Patient anxiety levels were not increased by a less-intensive follow-up regimen, and acceptance was high. The study data indicate that patient self-examination is very effective for recurrence detection.

Challenging the Orthodoxy of Mandibular Reconstructions Comparing Functional Outcomes in Osseous versus Soft Tissue Reconstructions of the Posterolateral Mandible.

BACKGROUND: Appropriate reconstruction of the posterolateral mandible remains controversial. Both osseous and soft tissues are vital components for an overall successful outcome and are often combined in complex defects. Their respective effect on oromandibular function in the reconstruction of different degrees of mandibular defects has been less evaluated. This study aimed to compare patient-perceived oromandibular function in osseous and soft tissue-only reconstructions following posterolateral mandibular defects, defined as limited or extended. PATIENTS AND METHODS: A 10-year retrospective review of consecutive patients undergoing mandibular reconstructions of the posterolateral mandible were identified. Limited defects were defined as reaching from the ipsilateral parasymphysis to anterior of the coronoid (sparing insertion of muscles of mastication). Extended defects were defined as reaching from the ipsilateral parasymphysis to posterior of the coronoid (sacrificing the muscle insertions). Functional outcomes were assessed using the University of Washington Quality of Life questionnaire, version 4. RESULTS: A total of 163 patients were identified, of which 41 patients had the particular posterolateral mandibular resections sought after. In 23 limited resections, there was no difference in functional outcome between osseous and soft tissue-only reconstructions. In 18 patients undergoing extended resections, osseous reconstructions demonstrated significantly better outcomes (p = 0.011). There were no significant differences in patient demographics between the groups. CONCLUSION: Our study highlights the interest of soft tissue-only reconstructions of the posterolateral mandible. Limited resections seem not to benefit from complex osseous reconstruction for adequate function. Conversely, there is a noteworthy positive impact on functional outcomes in extended posterolateral mandibulectomies reconstructed with osseous tissue, compared with soft tissue only. Although a larger study is needed to identify a stronger relationship, these preliminary results could aid reconstructive decisions, particularly when considering patient morbidity.

Clinical Outcomes and Risk Stratification of Early-Stage Melanoma Micrometastases From an International Multicenter Study: Implications for the Management of American Joint Committee on Cancer IIIA Disease.

PURPOSE: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. METHODS: Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. RESULTS: Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension. CONCLUSION: Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.

Reconstructive burden and financial implications of wider excision margins for invasive primary cutaneous melanoma.

BACKGROUND: For invasive primary cutaneous melanoma, wider excision is advocated to reduce local recurrence risk and improve patient outcomes. Excision detail is controversial, especially in intermediate- and high-risk primary melanoma (AJCC pT2-pT4). Guidance varies from sizes 1 to 3 cm (translating into large defects of 2-6 cm). The aim of this study was to determine the reconstructive and resource burden of wider excision margins (EMs). METHODS: Data analysis from our prospective database (2008-2017) included 1184 patients (563F:621 M) with cutaneous melanoma (pT1b-pT4b). Procedure tariff data were sourced from our financial services department. RESULTS: Two hundred twenty-nine patients had a narrower EM (1 cm) and 995 (80.7%) had a wider EM (2-3 cm). Reconstructive requirement significantly increased with a wider EM collectively (11.3% vs 29.3%, odds ratio (OR) = 3.2; p < 0.0001), in the extremities (15.2% vs 42.0%; p < 0.0001), and in the head and neck (H&N) (23.5 % vs 64.7%; p < 0.0001). Reconstruction significantly increased hospitalisation rates (26.6% vs 63.0%, OR = 4.7; p < 0.0001) collectively, in the H&N (26.8 % vs 53.9%), and in the upper (18.9 % vs 42.3%) and lower extremities (34.8% vs 77.3%). Narrower EMs significantly reduced hospitalisation rates in the upper and lower extremities (7.1% vs 28.5%; p = 0.004, 37.9% vs 58.5%; p = 0.005, respectively). Overall procedure cost significantly increased by £180 (mean, p < 0.0001) and £346 (median, p = 0.0004) per patient when reconstruction was required. CONCLUSIONS: Our data suggest substantial impact of wider EM on patients, which more than doubled in the functionally and cosmetically sensitive extremities and the H&N region. Reconstructions add significant financial and healthcare service burden. Without randomised controlled trial (RCT) evidence demonstrating increased efficacy of wider EM, narrower EM is advocated whilst awaiting future planned RCT results specifically investigating on this.

Survival outcomes and interval between lymphoscintigraphy and SLNB in cutaneous melanoma- findings of a large prospective cohort study.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) in cutaneous melanoma (CM) is performed to identify patient at risk of regional and distant relapse. We hypothesized that timing of lymphoscintigraphy may influence the accuracy of SLNB and patient outcomes. METHODS: We reviewed prospective data on patients undergoing SLNB for CM at a large university cancer-center between 2008 and 2015, examining patient and tumor demographics and time between lymphoscintigraphy (LS) and SLNB. Kaplan-Meier survival analysis assessed disease-specific (DSS) and overall-survival (OS), stratified by timing of LS. Cox multivariate regression analysis assessed independent risk factors for survival. RESULTS: We identified 1015 patients. Median follow-up was 45 months (IQR 26-68 months). Univariate analysis showed a 6.8% absolute DSS (HR 1.6 [1.03-2.48], p = 0.04) benefit and a 10.7% absolute OS (HR 1.64 [1.13-2.38], p = 0.01) benefit for patients whose SLNB was performed < 12 h of LS (n = 363) compared to those performed >12 h (n = 652). Multivariate analysis identified timing of LS as an independent predictor of OS (p = 0.007) and DSS (p = 0.016) when competing with age, sex, Breslow thickness (BT) and SLN status. No difference in nodal relapse rates (5.2% v 4.6%; p = 0.67) was seen. Both groups were matched for age, sex, BT and SLN status. CONCLUSION: These data have significant implications for SLNB services, suggesting delaying SLNB >12 h after LS using a Tc99-labelled nanocolloid has a significant negative survival impact for patients and should be avoided. We hypothesise that temporal tracer migration is the underlying cause and advocate further trials investigating alternative, 'stable' tracer-agents.

Intraoperative use of Mohs' surgery for the resection of major cutaneous head and neck cancer under general anaesthetic: Initial experiences, efficiency and outcomes.

BACKGROUND: Complete excision of high-risk extensive non-melanoma skin cancers in the head and neck is paramount to achieving loco-regional control. However, achieving clear margins still remains a significant challenge. Mohs' micrographic surgery (MMS) provides the most accurate method of intraoperative mapping and histological assessment of tumour margins. We have developed a technique combining MMS with reconstruction as a single-stage procedure performed under general anaesthetic. We present our experience and results. MATERIALS AND METHODS: Following regional skin cancer multidisciplinary team (MDT) discussion, patients considered appropriate for management as a single-stage combined procedure were referred for assessment. At surgery, a two-team approach was employed consisting of an MMS resection team and a reconstructive team, allowing simultaneous resection and elevation of any free tissue required for reconstruction. Outcome data were retrieved from a prospectively collated MMS database. RESULTS: Twenty-six cases were performed between January 2010 and January 2013. Fifty-eight percent of cases were basal cell carcinomas. Clear margins were achieved in 50% of cases following the first Mohs' layer. Free tissue reconstruction was required in 13 cases. Mean anaesthetic time was 445 min. Loco-regional control was achieved in 96% of patients, at a mean follow-up period of 29 months (range 11-50 months). CONCLUSIONS: This study shows that the combined single-stage MMS and reconstruction surgical model is safe, results in a low recurrence rate and improved patient care. It is a model that can be replicated in other tertiary skin cancer units.

Inhibition of keratinocyte-driven contraction of tissue-engineered skin in vitro by calcium chelation and early restraint but not submerged culture.

Skin graft contracture remains a significant cause of patient morbidity with reduction in joint mobility and cosmetic deformity. Despite recent advances, its mechanism is largely unknown. The authors have previously demonstrated the importance of the keratinocyte in the contraction of tissue-engineered skin in vitro. In this study, they investigate the effect of reducing keratinocyte differentiation on contraction by adding 0.8 mM ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetra acetic acid (EGTA) to the culture medium and by culturing tissue-engineered skin submerged in medium rather than at air-liquid interface. They also simulate the effect of early mechanical splinting in vitro to study its effect on contraction. Here the study shows that removal of the epidermis after 16 days culture at air-liquid interface results in immediate dermal relaxation with a return to the original dermal surface area. Lowering extracellular calcium concentration with EGTA reduces keratinocyte differentiation and reduces the rate of contraction. Submerged culture does not significantly reduce differentiation of tissue-engineered skin and does not reduce contraction. However, following an initial short period of mechanical constraint, the rate of contraction of tissue-engineered skin is reduced. Reducing keratinocyte differentiation by lowering extracellular calcium with EGTA, reduces contraction. However, submerged culture of tissue-engineered skin is ineffective. A short period of splinting of meshed skin grafts during the initial phase of epithelialization and keratinocyte differentiation may be most effective in the prevention of subsequent contractures in vivo but additional studies are needed to establish this.

Use of an in vitro model of tissue-engineered human skin to study keratinocyte attachment and migration in the process of reepithelialization.

To produce a stable epidermis, keratinocytes need to be firmly attached to the basement membrane. However, following wounding, keratinocytes are required to develop a migratory phenotype in order to reepithelialize the wound. To investigate some of the issues underlying reepithelialization, we have developed a three-dimensional in vitro model of tissue-engineered skin, comprising sterilized human dermis seeded with human keratinocytes and dermal fibroblasts. Using this model, we have shown that the inclusion of fibroblasts within the model increases the stability of keratinocyte attachment. We have also demonstrated that keratinocyte migration occurs most effectively in the absence of a basement membrane and following the inclusion of fibroblasts in the model. In addition, subjecting the keratinocyte layer to mechanical trauma induces a migratory phenotype. We conclude that this three-dimensional in vitro wound model can be used to increase our understanding of the factors that enhance keratinocyte migration and hence wound healing in vivo.