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.

Machine-learning algorithm to predict multidisciplinary team treatment recommendations in the management of basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly occur on the nose and the management of these lesions is particularly complex, given the functional and complex implications of treatment. Multidisciplinary team (MDT) meetings are routinely held to integrate expertise from dermatologists, surgeons, oncologists, radiologists, pathologists and allied health professionals. The aim of this research was to develop a supervised machine-learning algorithm to predict MDT recommendations for nasal BCC to potentially reduce MDT caseload, provide automatic decision support and permit data audit in a health service context. METHODS: The study population included all consecutive patients who were discussed at skin cancer-specialised MDT (SSMDT) with a diagnosis of nasal BCC between January 1, 2015 and December 31, 2015. We conducted analyses for gender, age, anatomical location, histological subtype, tumour size, tumour recurrence, anticoagulation, pacemaker, immunosuppressants and therapeutic modalities (Mohs surgery, conventional excision or radiotherapy). We used S-statistic computing language to develop a supervised machine-learning algorithm. RESULTS: We found that 37.5% of patients could be reliably predicted to be triaged to Mohs micrographic surgery (MMS), based on tumour location and age. Similarly, the choice of conventional treatment (surgical excision or radiotherapy) by the MDT could be reliably predicted based on the patient's age, tumour phenotype and lesion size. Accordingly, the algorithm reliably predicted the MDT decision outcome of 45.1% of nasal BCCs. CONCLUSIONS: Our study suggests that the machine-learning approach is a potentially useful tool for predicting MDT decisions for MMS vs conventional surgery or radiotherapy for a significant group of patients. We suggest that utilising this algorithm gives the MDT more time to consider more complex patients, where multiple factors, including recurrence, financial costs and cosmetic outcome, contribute to the final decision, but cannot be reliably predicted to determine that outcome. This approach has the potential to reduce the burden and improve the efficiency of the specialist skin MDT and, in turn, improve patient care, reduce waiting times and reduce the financial burden. Such an algorithm would need to be updated regularly to take into account any changes in patient referral patterns, treatment options or local clinical expertise. CLINICAL TRIAL REGISTRATION: lPLAS_20-21_A08.

Quantitative and Spatial Analysis of CD8+/PD-1 Tumor-Infiltrating Lymphocytes as a Predictive Biomarker for Clinical Response of Melanoma In-Transit Metastases to Topical Immunotherapy.

BACKGROUND: Melanoma in-transit metastases (ITMs) are a challenge to treat and associated with systemic disease and poor prognosis. Topical diphencyprone (DPCP), a potent contact sensitizer, is an established treatment for melanoma ITMs. This exploratory study investigated the utility of BRAF mutation status, CD8, PD-1, PD-L1, and TILs distribution as biomarkers for response of ITMs to topical immunotherapy (DPCP). METHODS: The ITM deposits of 40 patients treated with DPCP were subjected to biomarker analysis for BRAF status, CD8 and PD-1 expression on tumor-infiltrating lymphocytes (TILs), and tumor PD-L1 expression. Response to DPCP and overall survival (OS) were compared by biomarker status. RESULTS: After 12 weeks, 10 patients (25%) had a complete response, 12 patients (30%) had a partial response, and 18 patients (45%) had no response. No significant association was found between any individual biomarker and response to DPCP or OS. The BRAF mutation rate was 25% (10/40). All the patients with a complete response had BRAF wild-type tumor. Peritumoral CD8+ T-cells were associated with complete response (P = 0.041). Both CD8+ and PD-1 expressions were highly correlated (P < 0.0001), and the highest levels of PD-1 expression were detected at the peritumoral interface (P = 0.0004). Only two cases were PD-L1-positive, and both had a complete response to DPCP (P = 0.043). CONCLUSION: Patients who have BRAF wild-type tumor are more likely to experience a complete response to DPCP. Peritumoral TILs and PD-1 expressions may predict a better response to DPCP. Expression of PD-L1 may be associated with a complete response to DPCP. A larger prospective study is required.

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.

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 to 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.

Neuropathic pain and quality of life after wide local excision and sentinel lymph node biopsy for melanoma: a multicentre study.

Wide local excision and sentinel lymph node biopsy is the mainstay of treatment for patients with melanoma. As survival outcomes improve, longer term quality of life questions become more pertinent and this study aims to assess the factors which may play a role following surgery. A total of, 221 patients who underwent wide local excision and sentinel lymph node biopsy for melanoma (AJCC stage I and II) were recruited from three UK centres. These patients completed a patient outcome questionnaire, which included demographic and treatment data as well as quality of life and pain questionnaires. Pain was the only significant factor influencing the quality of life with a negative correlation seen between pain and quality of life scores (P<0.001). In total, 34% of patients reported pain at their surgical site and four (1.8%) patients scored as high risk for neuropathic pain. Patients experiencing pain were significantly younger that those not reporting pain (median 55.0 vs. 63.5 years, P<0.001). Length of time since surgery did not correlate with pain nor quality of life scores. Our results suggest that following this common procedure a sizeable proportion of patients experience pain and poorer quality of life which does not improve with time. The level of pain experienced is clinically significant and merits evaluation and treatment in this group of patients who are increasingly surviving their melanoma diagnosis. Further investigation into potential prophylactic measures is suggested.

A UK feasibility and validation study of the VE1 monoclonal antibody immunohistochemistry stain for BRAF-V600E mutations in metastatic melanoma.

BACKGROUND: Determining the BRAF mutation status of patients with advanced metastatic melanoma is essential in order to assess patients' eligibility for targeted BRAF inhibitor therapy. The aim of this study was to validate the utility of immunohistochemistry (IHC) to rapidly obtain the BRAF status in the UK cancer centre setting. METHODS: All samples sent for molecular testing for detection of the BRAF mutation over a 26-month period were prospectively tested using the VE1 monoclonal antibody IHC stain. RESULTS: Two-hundred and nineteen samples from 214 patients were identified. All patients were AJCC stage III/IV, except one. There was an overall 95.0% (208/219) concordance rate, with a sensitivity of 94.4% (84/89) and a specificity of 95.4% (124/130) when using genomic assays as the gold standard. Discordance resulted from the inability of the molecular technique to detect the V600E2 mutation and an inability of the IHC staining technique to detect non-V600E mutations. Molecular testing on smaller tumour deposits was also unreliable. CONCLUSIONS: IHC staining has good sensitivity and excellent specificity for BRAF V600E mutations. BRAF IHC can be incorporated into a BRAF mutation testing algorithm for UK cancer centres to as a feasible first-line assay and identify a subset of cases that require subsequent genomic testing. It has the additional major advantages of reduced cost and rapid turnaround time.

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.

Cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an EORTC Melanoma Module.

Melanoma is an increasingly common skin cancer worldwide. Recent treatment advances have provided patients and healthcare professionals (HCPs) with choices where quality of life (QoL) and toxicity are important considerations. A melanoma-specific QoL questionnaire is being developed in a cross-cultural setting using a four phase process developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group. In phase 1, a literature search identified a list of pertinent QoL issues; this was shown to HCPs and patients in eight countries and rated for importance and relevance. Questions were constructed for the highest-rated issues (phase 2) and piloted in another patient sample (phase 3). Using EORTC Quality of Life Group criteria and sequential use of factor and Rasch analysis, scales were hypothesized for field testing (phase 4). Seven QoL domains (disease symptoms, treatment issues, financial issues, access/quality of information, satisfaction with care, psychosocial issues and support), comprising 73 QoL issues, were rated by 46 HCPs and 78 patients. Fifty-six issues were rephrased as questions and piloted with 132 patients. A 38-item questionnaire (QLQ-MEL38) is available for field testing in conjunction with the EORTC QLQ-C30. This study has shown that melanoma patients have important QoL issues that have been incorporated into a new cross-culturally validated instrument. Future testing of this EORTC module is planned and will be an important step forward in providing reliable QoL data to aid future decision-making in the management and clinical trials of this complex group of patients.

Incontinentia pigmenti associated with cerebral palsy and cerebral leukomalacia: a case report and literature review.

Incontinentia pigmenti (IP) is a multisystem disorder with characteristic cutaneous signs. After the skin, the central nervous system is the next most affected system. We report a child with IP and left-sided hemiparesis and cerebral periventricular leukomalacia on magnetic resonance imaging (MRI). The MRI findings would support ischemia sustained perinatally.