ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Multicenter Selective Lymphadenectomy Trial-I confirms the central role of sentinel node biopsy in contemporary melanoma management: response to 'No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report'.

Sentinel lymph node (SLN) biopsy has become a standard procedure for many patients with melanoma and is recommended in numerous national and professional melanoma guidelines. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) confirms earlier large database studies and prospective clinical trials in demonstrating the independent and unequalled prognostic value of the SLN. It also demonstrates the ability of biopsy-directed management to provide effective regional disease control with the least possible morbidity. These benefits are not in question and provide ample justification for the procedure, even without evidence of a survival benefit. However, MSLT-1 also provides strong evidence of a substantial reduction in the risk of melanoma death for patients with intermediate thickness melanomas who harbour occult nodal metastases at the time of presentation. Denying appropriately selected patients with melanoma the opportunity to undergo SLN biopsy is no longer reasonable or acceptable.

Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development.

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.

Calcium ionophore activation of chronic myelogenous leukemia progenitor cells into dendritic cells is mediated by calcineurin phosphatase.

We have previously demonstrated that Ph+ myeloid progenitor cells of patients with chronic myeloid leukemia (CML) can acquire characteristics of mature dendritic cells (DC) following calcium mobilization with calcium ionophore (A23187, CI). In this study we characterize the intracellular signaling pathway by which CI induces the acquisition of DC features in these leukemic cells. CI-induced activation of CML cells is attenuated by the calcineurin phosphatase inhibitor cyclosporin A (CsA) as well as the calmodulin (CaM) antagonist W-7. These cause ablation of both the CI-induced immunophenotypic expression of DC markers and immunostimulatory properties in mixed leukocyte responses (MLR). Minimal blocking effect was observed when Ca(2+)/CaM kinase II (281-301) inhibitor was added to the cultures. These findings suggest a Ca(2+)-dependent mechanism for the CI-induced activation of CML cells into antigen-presenting cells (APC), which is primarily mediated through the CaM/calcineurin pathway.

Granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12 synergize with calcium ionophore to enhance dendritic cell function.

The authors previously showed that monocytes treated with calcium ionophore (CI) acquire characteristics of mature dendritic cells (DC) in part through a calcineurin-dependent pathway. In this study, the authors evaluated the ability of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2), and interleukin-12 (IL-12) alone or in combination with CI to induce DC characteristics in peripheral blood monocytes. Monocytes obtained by leukapheresis and countercurrent centrifugal elutriation were cultured with calcium, cytokines, or both, profiled by flow cytometry, and assessed for antigen uptake and sensitization of autologous CD8+ T cells to antigen. Monocytes treated with the combination of GM-CSF, IL-2, and IL-12 resulted in immunophenotypic and antigen uptake profiles typical of immature DC, including loss of surface CD14 expression, de novo low-level expression of B7.1, negligible CD83 expression, marked enhancement of CD40 and ICAM-1, and high major histocompatibility complex class I and II levels. A high level of antigen uptake by macro-pinocytosis was observed. In contrast, CI treatment significantly up-regulates B7.1, B7.2, CD40, CD54, and CD83 and substantially down-regulates CD14 and macro-pinocytosis, a profile consistent with mature DC. Many CI-induced modulations, but none resulting from cytokine treatment alone, were inhibited by the calcineurin phosphatase inhibitor cyclosporin A. Compared with monocytes treated with CI alone, combined treatment of monocytes with GM-CSF, IL-2, IL-12, and CI augmented B7.1 and CD83 expression and enhanced sensitization of autologous CD8+ T cells to melanoma-antigen-derived peptides. These results suggest that several independent pathways of DC activation can cooperatively enhance the function of monocyte-derived DC.

Incidence of sentinel node metastasis in patients with thin primary melanoma (< or = 1 mm) with vertical growth phase.

BACKGROUND: Patients with thin primary melanomas (< or = 1 mm) generally have an excellent prognosis. However, the presence of a vertical growth phase (VGP) adversely impacts the survival rate. We report on the rate of occurrence of nodal metastasis in patients with thin primary melanomas with a VGP who are offered sentinel lymph node (SLN) biopsy. METHODS: Among 235 patients with clinically localized cutaneous melanomas who underwent successful SLN biopsy, 71 had lesions 1 mm or smaller with a VGP. The SLN was localized by using blue dye and a radiotracer. If negative for tumor by using hematoxylin and eosin staining, the SLN was further examined by immunohistochemistry. RESULTS: The rate of occurrence of SLN metastasis was 15.2% in patients with melanomas deeper than 1 mm and 5.6% in patients with thin melanomas. Three patients with thin melanomas and a positive SLN had low-risk lesions, based on a highly accurate six-variable multivariate logistic regression model for predicting 8-year survival in stage I/II melanomas. The fourth patient had a low- to intermediate-risk lesion based on this model. At the time of the lymphadenectomy, one patient had two additional nodes with metastasis. CONCLUSIONS: VGP in a melanoma 1 mm or smaller seems to be a risk factor for nodal metastasis. The risk of nodal disease may not be accurately predicted by the use of a multivariate logistic regression model that incorporates thickness, mitotic rate, regression, tumor-infiltrating lymphocytes, sex, and anatomical site. Patients with thin lesions having VGP should be evaluated for SLN biopsy and trials of adjuvant therapy when stage III disease is found.

Active macromolecule uptake by lymph node antigen-presenting cells: a novel mechanism in determining sentinel lymph node status.

BACKGROUND: Although sentinel lymph node (SLN) biopsy is a powerful staging tool for patients with melanoma and breast cancer, controversy remains regarding specific aspects of technique. We examined particle uptake by antigen-presenting cells (APCs) to determine if this mechanism is responsible for the differential retention of radioactivity in SLNs relative to nonsentinel lymph nodes (NSLNs). METHODS: Mapping was conducted in pigs injected with vital blue dye, fluoroscein isothiocyanate-labeled human serum albumin (FITC-HSA), and one of two 99mtechnetium-labeled tracers, i.e., human serum albumin, a small macromolecule, or unfiltered sulfur colloid, a mixture of small and large particles. Macromolecule uptake by APCs was studied in vitro by using FITC-HSA and measured by fluorescence-activated cell sorting (FACS). SLNs and NSLNs were analyzed by fluorescence microscopy or FACS, with counterstaining for leukocyte cell surface markers. RESULTS: Both radiotracers were effective. Cultured APCs rapidly took up FITC-HSA. Microscopy showed FITC-HSA in the subcapsular sinus of SLNs shortly after injection and subsequent distribution to interfollicular areas. FACS revealed increasing amounts of FITC-HSA in SLNs over time. Cells responsible for uptake were APCs, expressing major histocompatibility (locus) class II. CONCLUSIONS: This report establishes active macromolecule uptake as a mechanism that determines SLN status. This mechanism has important implications for performing SLN biopsy.

Use of gastrostomy and combined gastrojejunostomy tubes for enteral feeding.

Recent economic changes in health care delivery have led to more frequent feeding by tube enterostomy. Over the last two decades percutaneous endoscopic gastrostomy (PEG) has been established as the standard method for long-term enteral access for nutrition, though operative gastrostomy remains indicated in a few conditions. Additionally, the combined gastrojejunostomy tube is indicated in selected patients in need of concomitant access to the jejunum and gastric decompression. This report reviews data regarding the safety and efficacy of the PEG tube and the indications for operative gastrostomy. Complications of feeding tubes and strategies to avoid or remedy them are also discussed. More recent techniques, including laparoscopic gastrostomy and jejunal access via the stomach, are reviewed as are some ethical concerns regarding the appropriateness of feeding enterostomies in certain patients.