The effect of a single dose of nivolumab prior to isolated limb perfusion for patients with in-transit melanoma metastases: An interim analysis of a phase Ib/II randomized double-blind placebo-controlled trial (NivoILP trial).

OBJECTIVE: ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). METHODS: In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). RESULTS: A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. CONCLUSION: For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study.

PURPOSE: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Sentinel lymph node localization and staging with a low-dose of superparamagnetic iron oxide (SPIO) enhanced MRI and magnetometer in patients with cutaneous melanoma of the extremity - The MAGMEN feasibility study.

BACKGROUND: In patients with melanoma, sentinel lymph node (SLN) status is pivotal for treatment decisions. Current routine for SLN detection combines Technetium99m (Tc99) lymphoscintigraphy and blue dye (BD). The primary aim of this study was to examine the feasibility of using a low dose of superparamagnetic iron oxide (SPIO) injected intracutaneously to detect and identify the SLN, and the secondary aim was to investigate if a low dose of SPIO would enable a preoperative MRI-evaluation of SLN status. METHODS: Patients with melanoma of the extremities were eligible. Before surgery, a baseline MRI of the nodal basin was followed by an injection of a low dose (0.02-0.5 mL) of SPIO and then a second MRI (SPIO-MRI). Tc99 and BD was used in parallel and all nodes with a superparamagnetic and/or radioactive signal were harvested and analyzed. RESULTS: Fifteen patients were included and the SLNB procedure was successful in all patients (27 SLNs removed). All superparamagnetic SLNs were visualized by MRI corresponding to the same nodes on scintigraphy. Micrometastatic deposits were identified in four SLNs taken from three patients, and SPIO-MRI correctly predicted two of the metastases. There was an association between MRI artefacts in the lymph node and the dose SPIO given. DISCUSSION: It is feasible to detect SLN in patients with melanoma using a low dose of SPIO injected intracutaneously compared with the standard dual technique. A low dose of SPIO reduces the lymph node MRI artefacts, opening up for a non-invasive assessment of SLN status in patients with cancer.

Health-related quality of life using the FACT-M questionnaire in patients with malignant melanoma: A systematic review.

BACKGROUND: Since there are no formal definition of health-related quality of life (HRQOL) there may be a lack of coherence and understanding of how to interpret HRQOL-data. The aim of this study is to summarize HRQOL-results that have used the FACT-M questionnaire in patients with melanoma, and specifically to summarize FACT-M between tumor stage. METHODS: This review was conducted in accordance with the PRISMA guidelines. INCLUSION CRITERIA: original studies on cutaneous melanoma between 2005 and 2020, written in English, containing "Functional Assessment of Cancer Therapy Melanoma" OR "Functional Assessment of Cancer Therapy M" OR FACT-M OR FACT/M OR FACTM OR "FACT M" OR FACT-melanoma OR "FACT Melanoma" together with FACT-M numbered data and basic patient characteristics, using the databases Scopus, Web of Science, PubMed and PsycINFO. RESULTS: 16 articles describing 14 patient cohorts published 2008-2020 were included. The majority of the studies did not report subscale scores in accordance with FACT-M guidelines. The results did indicate that FACT-M total scores were inversely correlated with AJCC stage. Subscale analysis demonstrated varying degrees of correlation with AJCC stage. The Melanoma Surgery Subscale score was lowest in stage III patients, probably reflecting more advanced surgical procedures in this group of patients. CONCLUSIONS: Though this review is based on a questionnaire limited to the assessment of melanoma patients, it highlights the universal need for clinical studies to describe their selected HRQOL-questionnaires, its definition of HRQOL and its dimensions, as well as comply with the questionnaire's guidelines when reporting HRQOL-data.

Meta-Analysis of Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion as a Treatment for Uveal Melanoma Liver Metastases.

BACKGROUND: Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous hepatic perfusion (PHP), a minimally invasive technique, is available as well. PHP benefits from the fact that the procedure can be repeated and therefore possibly offers better survival. We conducted a systematic review and meta-analysis comparing both techniques. METHODS: A systematic literature search was performed using the electronic databases of Scopus, MEDLINE, Web of Science, PubMed and Cochrane CENTRAL. A total of nine articles reporting on eight studies were included in the analysis. Individual survival data were extracted from each study. RESULTS: The median overall survival (OS) was 17.1 months for IHP and 17.3 months for PHP. The median progression-free survival (PFS) was 7.2 months for IHP and 9.6 months for PHP. The median hepatic progression-free survival was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. CONCLUSION: There was no difference in OS or PFS between IHP and PHP for patients with uveal melanoma liver metastases, but patients have significantly less of a risk for complications and mortality following PHP.

The Intricate Relationship between Melatonin and Breast Cancer: A Short Review.

Melatonin is a relatively recently isolated hormone, produced by the pineal gland. Its implication in several cell functions has augmented interest from scientists worldwide. There is ongoing research investigating the deterrent relationship between melatonin and malignancies and in particular breast cancer. The aim of this article is to review some of the most important findings concerning the effect of melatonin on cancer biology, from both preclinical and clinical studies providing an insight to the complex biological actions of this molecule, as well as their potential significance. The last part concentrates on the oncostatic activities of melatonin on breast cancer and special attention is given on the interplay between melatonin and estrogen. Epidemiological, experimental and clinical evidence indicates that this area is worth further investigation.

The Effect of Beta-Adrenergic Blocking Agents in Cutaneous Melanoma-A Nation-Wide Swedish Population-Based Retrospective Register Study.

Previous studies have demonstrated an anti-tumoral effect of beta-adrenergic blocking agents on cutaneous melanoma (CM). The aim of this study was to investigate if beta-adrenergic blocking agents have an impact on survival in Swedish patients with melanoma. A population-based retrospective registry study including all patients diagnosed with a primary invasive melanoma between 2009 and 2013 was performed. Data from the Swedish Melanoma Register were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Register. Cox regression analyses including competing risk assessments were performed. There were 12,738 patients included, out of which 3702 were exposed to beta-blockers vs. 9036 non-exposed patients. Age, male sex, Breslow thickness, ulceration, and nodal status were independent negative prognostic factors for melanoma-specific survival (MSS). Adding beta-blockers to the analysis did not add any prognostic value to the model (HR 1.00, p = 0.98), neither when adjusting for competing risks (HR 0.97, p = 0.61). When specifically analyzing the use of non-selective beta-blockers, the results were still without statistical significance (HR 0.76, p = 0.21). In conclusion, this population-based registry study could not verify that the use of beta-adrenergic blocking agents improve survival in patients with melanoma.

Reply to Comment on Katsarelias, D., et al. "The Effect of Beta-Adrenergic Blocking Agents in Cutaneous Melanoma-A Nation-Wide Swedish Population-Based Retrospective Register Study." Cancers 2020, 12, 3228.

We thank De Giorgi et al for their interest in our study, and for raising important and relevant questions [...].

Is blood a necessary component of the perfusate during isolated limb perfusion - a randomized controlled trial.

Background: Isolated limb perfusion (ILP) is a treatment option for malignancies localized to an extremity and is performed by surgical isolation of the limb which is connected to an extracorporeal circulation system. A high concentration of a chemotherapeutic agent is perfused through the limb, while systemic toxicity is avoided. Currently, the use of packed red blood cells in the priming solution is the norm during ILP. The aim of this study was to investigate the possibility to replace an erythrocyte-based prime solution with a crystalloid-based prime solution while maintaining the regional metabolic oxygen demand during ILP. Methods: In a single-center, randomized controlled, non-blinded, non-inferiority clinical trial, 21 patients scheduled for treatment with ILP were included and randomized 1:1 to either an erythrocyte-based prime solution (control) or a crystalloid-based prime solution (intervention). Results: There was a significant difference in lactate level (mmol/L) during the perfusion between the intervention group and the control group (1.6 ± 0.4 vs. 3.6 ± 0.7, p = .001). No significant differences in oxygen extraction (%) (22 ± 11 vs. 14 ± 4, p = .06), oxygen delivery (ml/min) (90 ± 49 vs. 108 ± 38, p = .39), oxygen consumption (ml/min) (14 ± 2 vs. 14 ± 5, p = .85), regional central venous saturation (%) (83 ± 10 vs. 91 ± 4, p = .07) or INVOS (%) (76 ± 14 vs. 81 ± 11, p = .42) were found between the intervention group and the control group. Conclusion: This study showed no significant improvement with the addition of packed red blood cells into the prime solution in ensuring the metabolic oxygen demand in the treated extremity during ILP, and we, therefore, recommend that a crystalloid-based prime solution should be used.

Surgery for gastrointestinal metastases of malignant melanoma - a retrospective exploratory study.

BACKGROUND: Cutaneous melanoma has a rapidly increasing incidence in Sweden, and it has more than doubled in the last two decades. In recent years, new systemic treatments for patients with metastatic disease have increased overall survival. The role of surgery in the metastatic setting has been unclear, and no randomized data exist. Many surgeons still perform metastasectomies; however, the exact role probably has to be redefined. The aim of this single-institution study was to retrospectively examine the safety and efficacy of surgery in abdominal melanoma metastases and to identify prognostic and predictive factors. METHODS: Retrospective analysis of a consecutive series of all patients with stage IV melanoma with gastrointestinal metastases that underwent abdominal surgery at a single center between January 2010 and December 2018. Fifteen patients who underwent in total 18 abdominal procedures, both acute and elective, were identified and included in the study. RESULTS: Out of 18 laparotomies, six (33%) were emergency procedures due to ileus (n = 4), small bowel perforation (n = 1), and abdominal abscess (n = 1). Twelve procedures (66%) were elective with the most common indication being persistent anemia (58%, n = 7), abdominal pain and anemia (33%, n = 4), and abdominal pain (8%, n = 1). All procedures were performed by laparotomy. There were 19 small bowel resections, 3 partial colon resections, and 2 omental resections. Radical resection was possible in 56% (n = 10) of cases and 67% (n = 8) when only considering elective procedures. In 17 of 18 procedures (94%), there were mild or no surgical complications (Clavien-Dindo grades 0-I). The median overall survival was 14 months with a 5-year survival of 23%. CONCLUSIONS: Patients with abdominal melanoma metastases can safely undergo resection with a high grade of radical procedures when performed in the elective setting. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03879395 . Registered 15 March 2019.

A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with Stage III Cutaneous Malignant Melanoma in Sweden.

BACKGROUND: Cutaneous melanoma is steadily increasing worldwide. The new AJCC 8th edition was recently launched and introduced several changes in melanoma staging, particularly for stage III. We conducted a population-based registry study with the purpose to evaluate the impact and prognostic accuracy of the new classification in Sweden. METHODS: Consecutive patients diagnosed with stage III melanoma between January 2005 and September 2017 were identified by the Swedish Melanoma Registry (SMR) and included for analyses. Patients with multiple primary melanomas were excluded. Patients were classified according to the AJCC 7th as well as the 8th edition. Melanoma-specific survival (MSS) was retrieved from the Swedish Cause of Death Registry. RESULTS: A total of 2067 eligible patients were identified from the SMR; 1150 patients (57%) changed stage III subgroup when reclassified according to the AJCC 8th edition. The median 5- and 10-year MSS for the whole cohort of stage III melanoma patients was 59% and 51% respectively. The MSS for substage IIIA, B, and C were all improved when patients were reclassified by using to the AJCC 8th edition. The newly defined substage IIID had the worst prognosis with a 10-year MSS of 16%. CONCLUSIONS: A high proportion of patients diagnosed with stage III melanoma in Sweden between 2005 and 2017 was restaged to another subgroup, when they were reclassified according to the AJCC 8th of staging manual. We established an improved MSS for all substages compared with the former AJCC 7th edition. This may have implications on decisions about adjuvant treatment.

Leakage through the bone-marrow during isolated limb perfusion in the lower extremity.

Isolated limb perfusion (ILP) is used for melanoma in-transit metastases of the extremities. The use of Melphalan and TNF-alpha, necessitates monitoring of possible systemic leakage throughout the perfusion. It has been suspected that leakage through bone marrow is possible. We present the case of a patient with in-transit melanoma metastases in the lower extremity, who underwent minimally invasive ILP, according to our new protocol through percutaneous insertion of the catheters under fluoroscopy. Following cannulation of the vessels a high leakage rate was recorded. The procedure was converted to open with clamping of the artery and vein, however the leakage was not possible to control, and venography showed that this was due to bone marrow veins. To the best of our knowledge this is the first case of a verified leakage during ILP through bone marrow veins. We believe that some minor leakages registered under ILP could be attributed to this leakage route.

BRAF status as a predictive factor for response in isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. METHODS: Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. RESULTS: Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. CONCLUSION: In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.

Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma.

BACKGROUND: Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP. METHOD: Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo). RESULTS: The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02). CONCLUSION: As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Sentinel node for malignant melanoma: An observational study of a consecutive single centre experience.

INTRODUCTION: Sentinel node biopsy (SNB) for melanoma gives prognostic information, however the success is dependent on several factors. The aim of this study was to describe outcome data after the introduction of the technique at our centre, including analysis of false negative rate (FNR), predictive factors for positive sentinel node (SN) and non-sentinel node (NSN), as well as prognostic factors for melanoma-specific survival (MSS). MATERIALS AND METHODS: This is a retrospective observational study of a prospectively kept database at Sahlgrenska University Hospital. Between March 2000 and December 2013, 769 consecutive patients with cutaneous malignant melanoma undergoing SNB were included. The median follow-up time was 55 months (2-179 months). Tumour load in the SN was categorized according to the largest tumour deposit, low when ≤1 mm and high when >1 mm. RESULTS: The FNR was 20% and the SN positivity rate was 14% with a decrease in both FNR and SN positivity rate during the study period. In multivariate analysis the only predictive factor for a positive SN was Breslow thickness. The 5-year melanoma specific survival (MSS) was 81% and in multivariate analysis the prognostic factors were SN-status (low metastatic load HR = 2.6, p = 0.001; high metastatic load HR = 2.7, p = 0.004) followed by Breslow thickness and ulceration. CONCLUSIONS: In this study Breslow thickness was the only independent predictive factor for a positive SN, no predictive factors were identified for NSN. Independent prognostic factors for MSS were SN status, Breslow thickness and ulceration. Interestingly, there was no survival difference depending on SN tumour burden when using 1 mm as cut-off.

Minimally invasive isolated limb perfusion - technical details and initial outcome of a new treatment method for limb malignancies.

OBJECTIVE: Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are treatment options for patients with locally advanced melanomas and sarcomas of the extremities. ILP potentially have higher response rates, but requires open surgery for vascular access, whereas ILI is minimally invasive and easier to perform. We now present the technical details and outcome of a new approach to ILP by a minimally invasive vascular access (MI-ILP). METHODS: Six patients, five with melanoma in-transit metastases and one with squamous cell carcinoma, were included in a phase I feasibility trial. Percutaneous vascular access of the extremity vessels was performed and the inserted catheters were then connected to a perfusion system. RESULTS: All six treated patients underwent the procedure without the need for conversion to open surgery. The median operating time was 164 min and the median leakage rate was 0.1%. The complete response rate was 67%. Four patients (67%) had a Wieberdink grade II reaction and two patients (33%) had a grade III reaction. CONCLUSIONS: MI-ILP is feasible and gives the same treatment characteristics as open ILP, but with the advantage of a minimally invasive vascular access.