Predictive indicators for revisional surgery in nasal reconstruction after Mohs surgery

Background: Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders of anatomical subunits. Reconstructive challenges can lead to multiple revisional surgeries to achieve the final aesthetic result. This study aimed to evaluate risk factors and predictors of revisional surgery in patients undergoing reconstruction after Mohs micrographic surgery for nasal tumours. Methods: This was a prospective cohort study from April 2, 2008 to February 26, 2019. The study population included all consecutive patients who underwent Mohs micrographic surgery for nasal skin cancer. Resection and reconstruction of nasal skin cancer was performed by the Mohs team. Results: A total of 988 cases met our study inclusion criteria with 64 (6.5%) cases requiring unplanned surgical revision. Revision rates were highest in the ala (9.0%, p < 0.05) and complex anatomical subunits (16.7%, p < 0.0001). In contrast, revision rates for dorsum lesions were lowest (1.8%, p < 0.001). In terms of reconstructive modalities, local flaps resulted in significantly higher rates of revision when compared to grafts (relative risk, 2.37; 95% CI, 1.15–5.0; p < 0.01). In terms of histological diagnosis, squamous cell carcinoma had significantly higher revision rates when compared to basal cell carcinoma (p < 0.05). Conclusions: To our knowledge, this is the first study to report the risk factors and predictors of revision surgery in patients undergoing MMS for nasal tumours. This study highlights that the reconstructive modality utilised affects the functional and cosmetic outcome of MMS. We note that ala complex subunit lesions, squamous cell carcinoma and flap reconstruction were associated with an increased risk of revision after Mohs reconstruction of nasal lesions. Level of evidence: Level III, risk/prognostic; therapeutic study. Trial registration number: (Ref: PLA-19-20_A03) 04/02/2020

Accuracy of SIAscopy for pigmented skin lesions encountered in primary care: development and validation of a new diagnostic algorithm.

BACKGROUND: Diagnosing pigmented skin lesions in general practice is challenging. SIAscopy has been shown to increase diagnostic accuracy for melanoma in referred populations. We aimed to develop and validate a scoring system for SIAscopic diagnosis of pigmented lesions in primary care. METHODS: This study was conducted in two consecutive settings in the UK and Australia, and occurred in three stages: 1) Development of the primary care scoring algorithm (PCSA) on a sub-set of lesions from the UK sample; 2) Validation of the PCSA on a different sub-set of lesions from the same UK sample; 3) Validation of the PCSA on a new set of lesions from an Australian primary care population. Patients presenting with a pigmented lesion were recruited from 6 general practices in the UK and 2 primary care skin cancer clinics in Australia. The following data were obtained for each lesion: clinical history; SIAscan; digital photograph; and digital dermoscopy. SIAscans were interpreted by an expert and validated against histopathology where possible, or expert clinical review of all available data for each lesion. RESULTS: A total of 858 patients with 1,211 lesions were recruited. Most lesions were benign naevi (64.8%) or seborrhoeic keratoses (22.1%); 1.2% were melanoma. The original SIAscopic diagnostic algorithm did not perform well because of the higher prevalence of seborrhoeic keratoses and haemangiomas seen in primary care. A primary care scoring algorithm (PCSA) was developed to account for this. In the UK sample the PCSA had the following characteristics for the diagnosis of 'suspicious': sensitivity 0.50 (0.18-0.81); specificity 0.84 (0.78-0.88); PPV 0.09 (0.03-0.22); NPV 0.98 (0.95-0.99). In the Australian sample the PCSA had the following characteristics for the diagnosis of 'suspicious': sensitivity 0.44 (0.32-0.58); specificity 0.95 (0.93-0.97); PPV 0.52 (0.38-0.66); NPV 0.95 (0.92-0.96). In an analysis of lesions for which histological diagnosis was available (n = 111), the PCSA had a significantly greater Area Under the Curve than the 7-point checklist for the diagnosis of melanoma (0.83; 95% CI 0.71-0.95 versus 0.61; 95% CI 0.44-0.78; p = 0.02 for difference). CONCLUSIONS: The PCSA could have a useful role in improving primary care management of pigmented skin lesions. Further work is needed to develop and validate the PCSA in other primary care populations and to evaluate the cost-effectiveness of GP management of pigmented lesions using SIAscopy.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

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 2008-2015, 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 hours (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 hours 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

Sequencing in management of in-transit melanoma metastasis: Diphencyprone versus isolate limb infusion

Background: In-transit metastases (ITMs) in melanoma are associated with poor prognosis, however a significant proportion of these patients survive for extended periods without further disease progression. We routinely use locoregional treatment e.g. Diphencyprone (DPCP) and/or isolated limb infusion (ILI) as long-term palliation. This study aimed to identify correct sequencing of these therapies based on disease burden and progression. Method: Retrospective evaluation of all melanoma patients with ITMs treated with DPCP/ILI/both from 2010-2017 at our Cancer Centre was performed. Patients were initially assessed in a multidisciplinary setting and empirically prescribed DPCP for low-disease burden, ILI for high-disease burden. Patient demographics, tumour characteristics, response to therapy, ITM progression and patient outcomes were analysed. Results: 78 patients (M:F=30:48), aged 47-95years (median 74years) treated with DPCP/ILI/both (n=44/21/13) were identified. Progression-free survival (PFS) was significantly increased in patients responsive to DPCP or ILI as initial treatment. Patients who failed on DPCP and subsequently treated with ILI had a significantly increased PFS compared to DPCP alone (p=0.026,HR=0.048). This was not the case with patients who were treated with DPCP following failed ILI. All patients who failed to respond to the initial therapy progressed within 6 months. Conclusion: Our study shows that careful stratification ITM patients according to disease burden is fundamental to optimal outcomes. High-disease burden patients benefit from initial ILI; low-disease burden patients should commence on DPCP. ILI can be considered in DPCP patients who fail early. Systemic therapy should be considered when locoregional therapies fail after 12 months or after rapid relapse following ILI

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

Mitochondrial oxidative phosphorylation in cutaneous melanoma

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease

PGC-1 alpha induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma

INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes’ expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma

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

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

PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma

Introduction: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. Methods: Primary melanoma cells, and MSCs derived from patients were obtained. Genes’ expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. Results: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. Conclusion: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma