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Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, intralesionally administered in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. Ten patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events (AEs), and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35-97) years with a median follow-up of 11.6months. Of these 10 patients, 5 had a complete response (CR), 3 had a partial response, 1 had stable disease and 1 showed progressive disease (PD) as their best response. Best overall response rate (ORR) was 80%. Median progression-free survival was 10.8 months (95% confidence interval, 2.2-19.4). Grade 1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 50% achieving a CR. This realworld data demonstrates promising results and suggests T-VEC can be an alternative to systemic therapy in this select, mostly elderly patient population.

Nearly 10% of patients with high-risk early-stage melanoma will develop satellite or in-transit metastases (ITM), classified as stage III disease similar to lymph node metastases. The pivotal registration trials of the CTLA-4 antibody ipilimumab, and the PD-1 antibodies nivolumab and pembrolizumab, also included patients with unresectable stage III disease. However, there has been no analysis of patients with ITM, and anecdotal retrospective small series have indicated a potential lesser effect. This study aimed to identify patients with unresectable ITM within the randomized trials, and to determine response, progression-free survival and overall survival. The pivotal phase III randomized intervention trials that included melanoma patients with ITM, with or without nodal metastasis, and were treated with ipilimumab, nivolumab or pembrolizumab was identified. The datasets from each trial were then searched to identify the specific details of the investigated patient population for a pooled analysis. The primary endpoint was complete response rate. Seven trials that included stage III patients, and with accessible datasets, were identified. There was a total of 4711 patients, however, no patients with ITM could be identified, as this data was not captured by the case report forms. Evidence from prospective clinical trials on the use of immunotherapy in patients with ITM is lacking. We recommend pooling data from multiple institutions to examine efficacy of available drug therapies in this patient population, but more importantly, prospective clinical trials of locoregional treatments with or without systemic drug therapies are required.

Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.

Now effective adjuvant therapy has arrived in melanoma, accurate staging and patient selection to optimize its risk/benefit ratio is crucial. The American Joint Committee on Cancer staging system is the most widely used and validated melanoma staging system, which recently released its 8th edition. We aimed to externally validate the prognostic and discriminatory ability for survival of the 8th edition compared to the 7th edition and evaluate prognostic factors. Prospective database of stage III melanoma (2000-2016). Prognostic factors for melanoma-specific survival and distant metastasis-free survival were analyzed. Survival differentiation of the 7th and 8th edition was assessed with log-rank tests and Cox proportional hazards models. Discriminatory ability was compared using the receiver operating characteristic and Akaike's Information Criterion. Six hundred forty patients were included (median follow-up 59 months). Median melanoma-specific survival was 138 months, distant metastasis-free survival 96 months. Age, Breslow thickness, ulceration of the primary tumor and number of positive lymph nodes (N) were independent prognostic parameters for distant metastasis-free survival and melanoma-specific survival. The 8th edition performed slightly better than the 7th edition in terms of survival discrimination but showed slightly worse distant metastasis-free survival and melanoma-specific survival differentiation between stage IIIA and IIIB. Sentinel node (SN) metastasis size cutoff of 1 mm differentiated survival in both 7th and 8th edition stage IIIA, showing excellent distant metastasis-free survival and melanoma-specific survival for patients with a SN metastasis size

The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (≥ vs.35%: hazard ratio=1.44, 95% confidence interval: 1.23-1.69) and number of positive LNs appeared to be of independent strong prognostic importance. Dissection sites impacted the optimal LNR cutoff: 35% for axillary, 40% for inguinal, and 50% for neck dissections. Combining these into one 'high versus low LNR' resulted in a highly significant multivariately adjusted hazard ratio of 1.48 (95% confidence interval: 1.26-1.74). In subgroup analyses, LNR was only significant in advanced disease (American Joint Committee on Cancer stage N2b, N3; IIIC). LNR was most significant for inguinal dissections, followed by axillary dissections, but seemed less useful in neck dissections. LNR is an independent significant prognostic factor in stage III melanoma patients. Our study showed higher than previously reported cutoffs that differed per dissection site. However, because of conflicting results compared with other studies and apparent limited prognostic impact confined to subgroups, the practical use of LNR seems limited.

In resected high-risk melanoma (stage IIB/C-III) the risk of locoregional and/or distant recurrence is substantial and so far adjuvant therapies have been fairly unsuccessful. Interferon showed slight improvements in recurrence-free survival (RFS) but failed to convincingly improve overall survival (OS). In these patients, adjuvant therapy with treatments that show promising results in stage IV disease is arising. Studies using immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 agents reveal convincing RFS benefits. OS rates, however, are not mature yet in most studies. Only ipilimumab has shown an OS benefit but at a high cost of toxicity. Also in studies with adjuvant targeted therapy using BRAF and MEK inhibitors, ensuring results are reported regarding RFS. As possible toxicity cannot be ignored, it is crucial to identify patients who would benefit most from these adjuvant therapies. In patients with clinically detectable lymph node metastases, studies using neoadjuvant schedules of immunotherapy and targeted therapy have been performed. In phase I and II studies the most optimal schedule of combination immunotherapy was identified and further research on this front will follow in the coming years. Concluding, after decades of scarce options for patients with high-risk melanoma, recent developments in adjuvant therapy have changed the standard of care for these patients.

AJCC stage IIIB and IIIC melanoma patients are at risk for disease relapse or progression. The advent of effective systemic therapies has made curative treatment of progressive disease a possibility. As resection of oligometastatic disease can confer a survival benefit and as immunotherapy is possibly most effective in a low tumor load setting, there is a likely benefit to early detection of progression. The aim of this pilot study was to evaluate a PET/computed tomography (CT) surveillance schedule for resected stage IIIB and IIIC melanoma. From 1-2015, stage IIIB and IIIC melanoma patients at our institution underwent 6-monthly surveillance with PET/CT, together with 3-monthly S100B assessment. When symptoms or elevated S100B were detected, an additional PET/CT was performed. Descriptive statistics were used to evaluate outcomes for this surveillance schedule. Fifty-one patients were followed up, 27 patients developed a recurrence before surveillance imaging, five were detected by an elevated S100B, and one patient was not scanned according to protocol. Eighteen patients were included. Thirty-two scans were acquired. Eleven relapses were suspected on PET/CT. Ten scans were true positive, one case was false positive, and one case was false negative. All recurrences detected by PET/CT were asymptomatic at that time, with a normal range of S100B. The number of scans needed to find one asymptomatic relapse was 3.6. PET/CT surveillance imaging seems to be an effective strategy for detecting asymptomatic recurrence in stage IIIB and IIIC melanoma patients in the first year after complete surgical resection.

We report on the case of a 41-year-old man with a recently diagnosed amelanotic ulcerated melanoma, with a Breslow thickness of 3.5 mm and Clark level IV. He had a pre-existing mass in the axilla, which had grown in parallel to the developing tumor. A large regional lymph node was clinically suspected. Ultrasound (US) examination of the axilla showed a large benign lipoma but also a very atypical peripheral perfusion. At the same time, a sentinel node showed a peripheral perfusion on US. Fine-needle aspiration cytology was performed of the different lesions and showed a melanoma metastasis in the sentinel node. Thereafter, a lymph node dissection was performed. The lipoma was seen in histopathology and even the peripheral perfusion was confirmed. US and US-guided fine-needle aspiration cytology can be easily applied in the diagnosis of lymph node metastases in melanoma patients and can help determine a benign or a malignant involvement.

In a recent article by Lam et al. describing the experience of the Sydney Melanoma Unit, a novel term called 'multimodality approach' to the sentinel node (SN) was applied. However, the timing of the use of the tools available in the presented cases should be discussed. An algorithm of which time to use, which tool to detect the correct SN by preoperative ultrasound (US) in combination with an US-guided fine needle aspiration cytology (FNAC) will be proposed and demonstrated using five clinical examples. All examples prove the advantage of a combined strategy to track down the correct and involved SN. A sensitive US power mode, for the amplification of even the slightest changes in vascularization, is the most important tool in our diagnostic preoperative approach. First, reliable US criteria, as recently published must consequently be applied. Second, a FNAC should be performed early enough, even when only early signs are visible. Third, a swift overnight cytology before sentinel lymph node biopsy should be available. US is a method for the early detection of clinically nonevident metastases. Using the proposed algorithm when to perform which part of the multimodality approach, we demonstrated the enormous information out of additionally performed US. In the case of a suspicious US finding, we always perform a FNAC of the node. In the event of a negative finding, the SLND will take place as scheduled. In the case of a positive finding, the patient can directly undergo completion lymph node dissection. Melanoma Res 21:450-456 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The prognosis of sentinel node (SN)-positive melanoma patients is predicted by a number of characteristics such as size and site of the metastases in the SN. The pathway and prognosis of strong pigmentation of melanoma metastases in the SN is unclear. The aim of this study is to evaluate the role of pigmentation and growth pattern of metastases in the SN with respect to survival. A total of 389 patients underwent an SN procedure (1997-2011). Ninety-five patients had a positive SN and material from 75 patients was available for review. The median follow-up time was 75 months (range 6-164). Pigmentation was scored from 0 to 2 using the following scale: 0=absent, 1=slight, and 2=strong. Growth pattern was scored as either eccentric (1) or infiltrative (2). SN tumor burden was measured according to the Rotterdam criteria. The primary melanoma had a median Breslow thickness of 2.90 mm (0.8-12.00 mm). Ulceration was present in 34 patients (45.3%). There was a median SN tumor burden of 0.5 mm (0.05-7.00 mm). In a total of 75 patients, 59 patients (79%) had no pigmentation, 13 patients (17%) had slight pigmentation, and three patients (4%) had strong pigmentation in the SN. Because of the small numbers, the classification was modified to either absent 59 (79%) or present 16 (21%) pigmentation, respectively. The SN tumor burden was significantly higher (P=0.031) for patients with pigmentation. Patients with pigmentation had a 5-year melanoma-specific survival (MSS) of 47% and a 10-year MSS of 33%. Patients without pigmentation had a 5-year MSS of 70% and a 10-year MSS of 59% (P=0.06). There was no difference in MSS for patients with an eccentric or an infiltrative growth pattern, nor did it correlate with other prognostic factors. Multivariate analysis for MSS showed five significant factors associated with worse prognosis: male sex (P=0.036), nodular melanoma (P=0.001), truncal site (P=0.0001), SN tumor burden more than 1.0 mm (P=0.022), and positive completion lymph node dissection (P=0.004). The 5-year MSS for SN tumor burden is 94% for 0.1 mm or less, 66% for 0.1-1.0 mm, and 41% for more than >1.0 mm (P

With great interest we read the article by Lam et al. from the Sydney Melanoma Unit on the multimodality approach to the sentinel node (SN). This study is the first to describe in a detailed manner that in melanoma the obstruction of lymphatic drainage by the tumor can also lead to a false-negative SN biopsy, which might have easily been avoided, if an ultrasound (US) was performed preoperatively. [...]