Tumor associated macrophages as key contributors and targets in current and future therapies for melanoma.

INTRODUCTION: Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis. AREAS COVERED: We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov. EXPERT OPINION: Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

Efficacy of Electrochemotherapy in Breast Cancer Patients of Different Receptor Status: The INSPECT Experience.

Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ (p = 0.0297) and HR+ (p = 0.0094), while overall survival was affected by time to local progression in all groups (p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions.

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma.

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4.

Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

Risk prediction models for head and neck cancer: A rapid review.

Background: Cancer risk assessment models are used to support prevention and early detection. However, few models have been developed for head and neck cancer (HNC). Methods: A rapid review of Embase and MEDLINE identified n = 3045 articles. Following dual screening, n = 14 studies were included. Quality appraisal using the PROBAST (risk of bias) instrument was conducted, and a narrative synthesis was performed to identify the best performing models in terms of risk factors and designs. Results: Six of the 14 models were assessed as "high" quality. Of these, three had high predictive performance achieving area under curve values over 0.8 (0.87-0.89). The common features of these models were their inclusion of predictors carefully tailored to the target population/anatomical subsite and development with external validation. Conclusions: Some existing models do possess the potential to identify and stratify those at risk of HNC but there is scope for improvement.

Head and neck cancer in the UK: what was the stage before COVID-19? UK cancer registries analysis (2011-2018).

Introduction People who present with more advanced stage head and neck cancer (HNC) are associated with poorer outcomes and survival. The burden and trends of advanced stage HNC are not fully known at the population level. The UK national cancer registries routinely collect data on HNC diagnoses.Aims To describe trends in stage of diagnosis of HNCs across the UK before the COVID-19 pandemic.Methods Aggregated HNC incidence data were requested from the national cancer registries of the four UK countries for the ten most recent years of available data by subsite and American Joint Commission on Cancer stage at diagnosis classification. Additionally, data for Scotland were available by age group, sex and area-based socioeconomic deprivation category.Results Across the UK, rates of advanced stage HNC had increased, with 59% of patients having advanced disease at diagnosis from 2016-2018. England had a lower proportion of advanced disease (58%) than Scotland, Wales or Northern Ireland (65-69%) where stage data were available. The completeness of stage data had improved over recent years (87% by 2018).Conclusion Prior to the COVID-19 pandemic, diagnoses of HNC at an advanced stage comprised the majority of HNCs in the UK, representing the major challenge for the cancer healthcare system.

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies.

The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PD-L1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment. Targeting the prominent myeloid compartment within the tumor microenvironment, and in particular the ever-abundant tumor-associated macrophages (TAMs), may be a promising strategy to complement existing therapies and enhance treatment success. TAMs are a highly diverse and plastic subset of cells whose pro-tumor properties can support melanoma growth, angiogenesis and invasion. Understanding of their diversity, plasticity and multifaceted roles in cancer forms the basis for new promising TAM-centered treatment strategies. There are multiple mechanisms by which macrophages can be targeted with antibodies in a therapeutic setting, including by depletion, inhibition of specific pro-tumor properties, differential polarization to pro-inflammatory states and enhancement of antitumor immune functions. Here, we discuss TAMs in melanoma, their interactions with checkpoint inhibitor antibodies and emerging mAbs targeting different aspects of TAM biology and their potential to be translated to the clinic.

Enriched circulating and tumor-resident TGF-ß+ regulatory B cells in patients with melanoma promote FOXP3+ Tregs.

B cells are emerging as key players of anti-tumor adaptive immune responses. We investigated regulatory and pro-inflammatory cytokine-expressing B cells in patients with melanoma by flow cytometric intracellular cytokine, CyTOF, transcriptomic, immunofluorescence, single-cell RNA-seq, and B:T cell co-culture analyses. We found enhanced circulating regulatory (TGF-ß+ and PD-L1+) and reduced pro-inflammatory TNF-α+ B cell populations in patients compared with healthy volunteers (HVs), including lower IFN-γ+:IL-4+ and higher TGF-ß+:TNF-α+ B cell ratios in patients. TGF-ß-expressing B cells in the melanoma tumor microenvironment assembled in clusters and interacted with T cells via lymphoid recruitment (SELL, CXCL13, CCL4, CD74) signals and with Tregs via CD47:SIRP-γ, and FOXP3-promoting Galectin-9:CD44. While reduced in tumors compared to blood, TNF-α-expressing B cells engaged in crosstalk with Tregs via TNF-α signaling and the ICOS/ICOSL axis. Patient-derived B cells promoted FOXP3+ Treg differentiation in a TGF-ß-dependent manner, while sustaining expression of IFN-γ and TNF-α by autologous T-helper cells and promoting T-helper cell proliferation ex vivo, an effect further enhanced with anti-PD-1 checkpoint blockade. Our findings reveal cytokine-expressing B cell compartments skewed toward regulatory phenotypes in patient circulation and melanoma lesions, intratumor spatial localization, and bidirectional crosstalk between B and T cell subsets with immunosuppressive attributes.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

Systematic overview of systematic reviews and clinical guidelines: assessment and prevention of behavioural risk factors associated with oral cancer to inform dental professionals in primary care dental practices.

Aims/objectives Tobacco and alcohol are recognised as the major modifiable risk factors for oral cancer, the incidence of which is rising globally and predicted to increase. This paper aimed to: 1) appraise and synthesise best practice evidence for assessing the major behavioural risk factors for oral cancer and delivering behaviour change interventions (for example, advice, counselling, signposting/referral to preventive services); and 2) assess appropriateness for implementation by dental professionals in primary care.Methods A systematic overview was undertaken of systematic reviews and international clinical guidelines. This involved: systematically searching and collating the international literature on assessing oral cancer risk and delivering preventive interventions within primary care; quality appraising and assessing the risk of bias using validated tools; synthesising the evidence for best practice; and assessing application of key findings to the dental setting.Results and conclusions There is clear evidence for the effectiveness of a 'brief', in-person, motivational intervention for sustained tobacco abstinence or reduced alcohol consumption, following risk factor assessment. Evidence for combined behavioural interventions is lacking. There is no firm conclusion with regards to optimal duration of brief interventions (range 5-20 minutes). For tobacco users, longer (10-20 minutes) and intensive (more than 20 minutes, with follow-up visits) interventions are more effective in increasing quit rates compared to no intervention; very brief (less than five minutes) interventions in a single session show comparable effectiveness to the longer/more intensive interventions. For alcohol users, 10-15-minute multi-contact interventions were most effective, compared to no intervention or very brief (less than five minutes) intervention or intensive intervention; brief interventions of five-minute duration were equally effective. There is limited direct evidence from the dental practice setting (one high-quality systematic review relating to tobacco prevention and none relating to alcohol). Thus, very brief, or brief advice of up to five minutes, should be trialled for tobacco and alcohol respectively in a dental practice setting, after risk assessment tailored to patient motivational status. Exploring delivery by the dental team is supported, as effectiveness was generally independent of primary care provider.

BRAF inhibitors and their immunological effects in malignant melanoma.

INTRODUCTION: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. AREAS COVERED: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. EXPERT OPINION: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing 'old friends' in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

A Whole-Grain Diet Increases Whole-Body Protein Balance Compared with a Macronutrient-Matched Refined-Grain Diet.

BACKGROUND: There are limited data from randomized control trials to support or refute the contention that whole-grains can enhance protein metabolism in humans. OBJECTIVES: To examine: 1) the clinical effects of a whole-grain diet on whole-body protein turnover; 2) the cellular effects of whole-grains on protein synthesis in skeletal muscle cells; and 3) the population effects of whole-grain intake on age-related muscle loss. METHODS: Adults with overweight/obesity (n = 14; age = 40 ± 7 y; BMI = 33 ± 5 kg/m2) were recruited into a crossover, randomized controlled trial (NCT01411540) in which isocaloric, macronutrient-matched whole-grain and refined-grain diets were fully provisioned for two 8-wk periods. Diets differed only in the presence of whole-grains (50 g/1000 kcal). Whole-body protein kinetics were assessed at baseline and after each diet in the fasted-state (13C-leucine) and integrated over 24 h (15N-glycine). In vitro studies using C2C12 cells assessed global protein synthesis by surface sensing of translation and anabolic signaling by Western blot. Complementary epidemiological assessments using the NHANES database assessed the effect of whole-grain intake on muscle function assessed by gait speed in older adults (n = 2783). RESULTS: Integrated 24-h net protein balance was 3-fold higher on a whole-grain diet compared with a refined-grain diet (P = 0.04). A whole-grain wheat extract increased submaximal rates of global protein synthesis (27%, P < 0.05) in vitro. In a large sample of older adults, whole-grain intake was associated with greater muscle function (OR = 0.92; 95% CI: 0.86, 0.98). CONCLUSIONS: Consuming 50 g/1000 kcal whole-grains per day promotes greater protein turnover and enhances net protein balance in adults. Whole-grains impact skeletal muscle at the cellular level, and are associated with greater muscle function in older adults. Collectively, these data point to a new mechanism whereby whole-grain consumption favorably enhances protein turnover and improves health outcomes.This clinical trial is registered on clinicaltrials.gov (identifier: NCT01411540).

Occupational socioeconomic risk associations for head and neck cancer in Europe and South America: individual participant data analysis of pooled case-control studies within the INHANCE Consortium.

BACKGROUND: The association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures. METHODS: Pooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige-Treiman's Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position-International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs. RESULTS: For the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94). CONCLUSIONS: These findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action.

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.

Is the 'never event' concept a useful safety management strategy in complex primary healthcare systems?

WHY IS THE AREA IMPORTANT?: A sub-group of rare but serious patient safety incidents, known as 'never events,' is judged to be 'avoidable.' There is growing interest in this concept in international care settings, including UK primary care. However, issues have been raised regarding the well-intentioned coupling of 'preventable harm' with zero tolerance 'never events,' especially around the lack of evidence for such harm ever being totally preventable. WHAT IS ALREADY KNOWN AND GAPS IN KNOWLEDGE?: We consider whether the ideal of reducing preventable harm to 'never' is better for patient safety than, for example, the goal of managing risk materializing into harm to 'as low as reasonably practicable,' which is well-established in other complex socio-technical systems and is demonstrably achievable.We reflect on the 'never event' concept in the primary care context specifically, although the issues and the polarized opinion highlighted are widely applicable. Recent developments to validate primary care 'never event' lists are summarized and alternative safety management strategies considered, e.g. Safety-I and Safety-II. FUTURE AREAS FOR ADVANCING RESEARCH AND PRACTICE: Despite their rarity, if there is to be a policy focus on 'never events,' then specialist training for key workforce members is necessary to enable examination of the complex system interactions and design issues, which contribute to such events. The 'never event' term is well intentioned but largely aspirational-however, it is important to question prevailing assumptions about how patient safety can be understood and improved by offering alternative ways of thinking about related complexities.

Bleomycin electrochemotherapy for the management of locally advanced metastatic melanoma: Two notable clinical cases potentially indicating a greater therapeutic role in the era of targeted and immuno-therapy.

Bleomycin electrochemotherapy (ECT) has emerged as a treatment modality for locally advanced metastatic melanoma over the past decade. The phenomenon of reversible electroporation enhances cell permeability when a pulsed electrical current is applied to tissues. This facilitates enhanced cytotoxicity of bleomycin with minimal systemic side effects. We present two case analyses of patients with advanced metastatic melanoma of lower limb which did not respond to alternative therapies, including immunotherapy and isolated limb perfusion, but had a positive clinical response to bleomycin ECT. Locoregional control of the tumour was gained along with positive functional outcomes for the patients including increased mobility and reduced malodour. Bleomycin ECT is an exciting new therapeutic modality in the armamentarium of the plastic surgeon. Operating parameters have been developed and refined which facilitate its safe use along with incorporation into international melanoma guidelines. Evidence in the literature supports its use in select cases, however, it is vital that we share our experiences in its use so that its role can be better defined. Particularly in the era of rapidly developing systemic treatments which are decreasing mortality and thereby increasing the number of patients requiring locoregional disease managment.

Correction to: Low-phytate wholegrain bread instead of high-phytate wholegrain bread in a total diet context did not improve iron status of healthy Swedish females: a 12 week, randomized, parallel-design intervention study.

ue to author error the paper was published wit.