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Abstract Background Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). Methods One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. Results Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (≥2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. Conclusion Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease.

Introduction: Octreoscan (OS) is currently the gold standard for diagnosis of somatostatin receptor positive NET but it is limited by a lower spatial resolution and physiological uptake noises. DOTATATE is a somatostatin analogue, radiolabelled with 68Ga and adapted for PET imaging. Aim(s): To evaluate diagnostic performance and prognostic role of 68Ga-DOTATATE PET (DP) in NET. Materials and methods: Fifty-one patients with NET (40 sporadic, 17 MEN-I) of different origin were enrolled. DP was performed in all cases by acquiring whole body studies 40-60 min after the radioligand i.v. injection (74-111 MBq). OS was also performed in 27/51 patients using injection of Indium-111-DTPA-Phel-OSreotide (120-200 MBq). Examination results were rated considering histology, CT/MR examination and clinical follow-up. Results: DP had a patient based sensitivity and specificity of 77% and 100% and a lesion-based sensitivity and specificity of 64% and 85%, respectively. Positive and negative predictive values were 100% and 65%. The sensitivity was 100% in pancreas and gut, 75% in lung and thyroid, <50% in stomach. In the subgroup undergone both DP and OS, there was concordance in 21 and discordance in six cases (five DP positive/OS negative and one DP negative/OS positive). DP SUVmax was significantly higher in patients with stable than with progressive disease. Conclusion: In patients with NETs, DP shows higher diagnostic performance than OS and is believed to predict clinical behavior of the tumor. [ABSTRACT FROM AUTHOR]

Background: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen.Methods: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.Results: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b.Conclusions: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. [ABSTRACT FROM AUTHOR]

We previously demonstrated that patients with metastatic unresectable stage IIIb-IV melanoma receiving cetirizine (a second-generation H1 antagonist antihistamine) premedication with immunotherapy had better outcomes than those not receiving cetirizine. In this retrospective study, we searched for a gene signature potentially predictive of the response to the addition of cetirizine to checkpoint inhibition (nivolumab or pembrolizumab with or without previous ipilimumab). Transcriptomic analysis showed that inducible T cell costimulator ligand (ICOSLG) expression directly correlated with the disease control rate (DCR) when detected with a loading value > 0.3. A multivariable logistic regression model showed a positive association between the DCR and ICOSLG expression for progression-free survival and overall survival. ICOSLG expression was associated with CD64, a specific marker of M1 macrophages, at baseline in the patient samples who received cetirizine concomitantly with checkpoint inhibitors, but this association was not present in subjects who had not received cetirizine. In conclusion, our results show that the clinical advantage of concomitant treatment with cetirizine during checkpoint inhibition in patients with malignant melanoma is associated with high ICOSLG expression, which could predict the response to immune checkpoint inhibitor blockade.

Treatment duration with checkpoint inhibitors must be optimized to prevent unjustified toxicity, but evidence for the management of cutaneous squamous cell carcinoma is lacking. A retrospective study was performed to evaluate the survival of patients with cutaneous squamous cell carcinoma (CSCC) who discontinued cemiplimab due to different causes and without progression. Among 95 patients with CSCC who received cemiplimab, 22 (23%) patients discontinued immunotherapy due to causes other than progression, such as comorbidities, toxicity, complete response or lack of compliance (group that discontinued before censoring [DBC]), then 73 patients had standard treatment scheduled (STS). The overall survival was 25.2 months (95% CI: 8.9-29.4) in STS group and 28.3 months (95% CI: 12.7-28.3) in the DBC group; deaths for all causes were 11/22 (50%) in the DBC group and 34/73 (46.6%) in the STS group (p = 0.32). 10/22 (45.4%) subjects died due to CSCC in the DBC after discontinuation and 34/73 (46.6%) in the STS group, and the difference between groups was not significant (p = 0.230). Duration of treatment was significantly lower in subjects with stable disease versus those with complete or partial response (16.9, 30.6 and 34.9 months, respectively; p = 0.004). Among the 22 STS patients, 12 received cemiplimab for less than 12 months (10 [83%] died) and 10 for at least 12 months (1 [10%] died). Our observation, finding no outcome difference between DBC and STS groups, suggests that ICI treatment after one year might expose patients to further treatment related events without efficacy advantages., (© 2024. The Author(s).)

Background: Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma., Methods: A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb-IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis., Results: The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ 2 , a marker of the N2 neutrophils with immunosuppressive activity., Conclusions: These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To explore the relationship between indices of hypoxia and vascular function from 18 F-fluoromisonidazole ([ 18 F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor-positive (ER +) breast cancer., Methods: Women aged  > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [ 18 F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [ 18 F]-FMISO influx rate constant, K i . Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables., Results: Of the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [ 18 F]-FMISO K i associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices., Conclusion: Hypoxia measured by [ 18 F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer., Key Points: • Hypoxia, measured by [ 18 F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. • Increased CAIX expression was associated with higher levels of hypoxia measured by [ 18 F]-FMISO-PET. • Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas., (© 2023. The Author(s).)

Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1 st -3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies., (© 2023. The Author(s).)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate., (© 2023. The Author(s).)

Background: Prognostic factors for initial response of advanced cutaneous squamous cell carcinoma to cemiplimab treatment are lacking. Il-6 has been found to affect immune cell populations which impact tumor development. The aim was to investigate the prognostic significance of IL-6 serum levels before and during treatment., Methods: Serum levels of IL-6 were correlated with clinical outcomes in a retrospective study., Results: Overall, 39 patients were enrolled. High serum levels of IL-6 (> 5.6 pg/ml) were associated with poorer survival (45.1% vs 0 deaths; OS: 16.1 ± 1.5 vs 20.8 ± 0 months, 95% CI 13,046 to 19,184) and shorter PFS (10.3 ± 1.9 vs 18.9 ± 1.5 months; 95% CI 3433 to 10,133) in patients with advanced CSCC treated with cemiplimab. In addition, patients whose IL-6 level increased after treatment with cemiplimab, independently of the basal level, had a poorer response to treatment than patients whose level was reduced or stable after immunotherapy., Conclusions: Serum levels of IL-6 at baseline and changes after cemiplimab immunotherapy may have a prognostic significance in patients with advanced cutaneous squamous cell carcinoma., (© 2023. The Author(s).)

Background: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF -mutated and wild-type melanoma., Methods: The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF -mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF -mutated patients will receive over 6 weeks (1) + (3); B) BRAF -mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks)., Discussion: Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival., Clinical Trial Registration: eudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17., Competing Interests: PA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer; Vanna Chiaron Sileni: Travel support for medical congress for Bristol Myers-Squibb, lectures fees and Advisory Board for Merck Sharp & Dohme, participation to advisory board for Novartis, Pierre Fabre; PiQ: speaker fees e advisory boards for BMS, MSD, Pierre-Fabre, Novartis, Roche; FS: Honoraria: BMS, Roche, Novartis, MSD, Sanofi, Merck, Sunpharma, Pierre-Fabre. Advisory Board: MSD, Novartis, Sunphama, Pierre Fabre; Massimo Guidoboni Consulting or Advisory Role: BMS, Novartis, Pierre Fabre Speakers’ Bureau: BMS, Novartis, Pierre Fabre Research Funding; MV: reports research finding to their institution for clinical studies from MSD and honoraria as consultant or advisor for Novartis, Bristol Myers Squibb, MSD, and Pierre Fabre; KP reports advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi; PaQ: advisory and consultant role for Roche, BMS, Merck, MSD, Novartis, Pierre Fabre, Sun Pharma, Sanofi; DM has received honoraria for professional services and consultancy for Novartis, Bayer HealthCare Pharmaceuticals Inc., Pierre-Fabre, Sanofi Genzyme, MSD Italia S.r.l., Roche, Skyline Dx B.V, Diatech Pharmacogenetics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ascierto, Cioli, Chiarion-Sileni, Quaglino, Spagnolo, Guidoboni, Del Vecchio, Peris, Queirolo, Fioretto, Caracò, Paone, Sorrentino, Capone, Giannarelli, Ferrara, Massi and Trojaniello.)

Background: Nivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes., Methods: In this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient's genetic profile plays a role in this association., Results: We observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways., Conclusions: In conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells., Competing Interests: Competing interests: PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. SW is employee and stockholder in NanoString Technologies. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The clinical observation showed a potential additive effect of anti-PD-1 agents and cetirizine in patients with advanced melanoma., Methods: Clinical outcomes of concomitant cetirizine/anti-PD-1 treatment of patients with stage IIIb-IV melanoma were retrospectively collected, and a transcriptomic analysis was performed on blood samples obtained at baseline and after 3 months of treatment., Results: Patients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28-0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29-0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p < 0.05). The expression of FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p < 0.0001), IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005)., Conclusions: This retrospective study suggests that M1 macrophage polarization may be induced by cetirizine through the interferon-gamma pathway. This effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents., (© 2022. The Author(s).)

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients., (© 2022. The Author(s).)

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.

Interval metastasis is a particular metastatic category of metastatic localizations in the lymph nodes in patients with melanoma. Interval nodes are generally located at nonregional lymphatic stations placed along the pathway of the spread of melanoma, such as the epitrochlear lymph node station, the popliteal fossa, and the retroareolar station. Imaging techniques for evaluation of patients with interval metastasis from melanoma diseases include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), lymphoscintigraphy (LS), and positron emission tomography (PET). A literature review was conducted through a methodical search on the Pubmed and Embase databases. The evaluation of lymph node metastases represents a critical phase in the staging and follow-up of melanoma patients. Therefore, a thorough knowledge of the imaging methods available and the interactions between the clinician and the radiologist are essential for making the correct choice for individual patients, for a better management, and to improve treatment and survival.

Background: The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients., Methods: A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model., Results: The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P < 0.0001), male gender (P = 0.04), increasing Breslow thickness (P < 0.0001), presence of ulceration (P = 0.004), SNTB size (P < 0.0001) and metastatic NSN (P < 0.0001) were independent negative predictors of OS., Conclusion: The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization., (© 2022. The Author(s).)

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts., Competing Interests: Competing interests: PAA—received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, Sanofi; had a consultant role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna; participated to Advisory Board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. PB—Advisory board or conference honoraria: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol Myers Squibb, GSK, Nestlè. CC—Participation to scientific meetings provided by Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; Advisory board participation Novartis, MSD. VCS—Participation to scientific meetings provided by Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; Advisory board participation Merck-Serono, Pierre-Fabre, Novartis; Invited speaker: Pierre-Fabre, Novartis, Bristol Meyers Squibb. APDT—Advisory Boards Bayer, Roche, Novartis, PharmaMar. NF—Personal financial interest Advisory board: AAA, Merck, MSD, Novartis, Pfizer; Public speaking: AAA, Ipsen. Institutional financial interest Grant: Ipsen, AAA, Merck. Clinical trials (local PI): 4SC, Astellas, Beigene, Fibrogen, Incyte, Ipsen, MSD, Nucana. GG—Participation to board: Merck, Glaxo, Pharmamar, Novartis, Bayer, EISAI. MM—Honoraria for serving as a speaker from MSD, Roche, Bristol Myers Squibb (BMS), Sanofi, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GlaxoSmithKline (GSK), Sciclone, Alfasigma, and Merck Serono; Personal fees for advisory boards from Merck Sharp & Dohme Corp., Roche, BMS, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, Sanofi, GSK, Alfasigma, and Merck Serono; Stockholder in Epigen Therapeutics and Theravance. PQua—Invited speaker and advisory board participation: BMS, Merck, MSD; Novartis, Pierre Fabre, Sanofi, Roche. PQue—Advisory board participation: Roche, Novartis, Pierre Fabre, Merk Sharp and Dome, BMS, Sanofi, Sun Pharma, Merck. FS—Personal financial interests Advisory board, public speaking: Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, Merck, Hutchison Medipharma Limited—Institutional financial interests Clinical trials (PI): GETNE, Incyte, MSD, Hutchison Medipharma Limited—Non financial interests AIOM: coordinator of neuroendocrine neoplasms guidelines, ITANET: executive board member ESMO: member of the NETs and endocrine tumors faculty Panelists MB reports honoraria for consulting, advisory role, speakers’ bureau, travel, accommodation, expenses from MSD, Roche/Genertech, AstraZeneca, Thermo Fisher Scientific, Illumina. FB reports participation to Advisory Klox Technologies, Smith And Nephew, Acelity 3m, Urgo Medical, Decomed, Mimedx. RB reports donors to the Hospital and/or participation to Advisory Boards AZ, BI, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, Eisai. AB reports advisory board: Janssen, IPSEN, Novartis AAA, AMGEN - Public speaking: Novartis AAA, AMGEN. DC reports consultant/advisory role for Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, Merck. FC reports advisory board or conference honoraria for BMS, MSD, Pierre Fabre, Novartis. RD reports participation as advisor and speaker for BMS, Novartis, MSD, Sanofi, Pierre Fabre. AMDG has served as a consultant and/or advisor to Incyte, Pierre Fabre, Glaxo Smith Kline, Bristol Myers Squibb, Merck Sharp Dohme, and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre and Sanofi. GF reports AbbVie Srl, Ag Global Event, Allmiral, Amgen, Atenapoli, Bb & C. Srl, Boehringer Ingelheim Italia Spa, Casa Di Cura Ruesh Spa, Collage Spa, Cosmetica Srl, Defhaforum Srl, Dialecticon Srl, Dynamico Education Srl, Editamed Srl, Edizioni Minerva Medica, Effetti Srl, Eli Lilly Italy Spa, F.C. Congressi Srl, Galderma Italia Spa, General Topica Srl, Havas Life Italy Srl, Havas Pr Milan Srl, Health Publishing, Healthware Group, Hippocrates Sintech Srl, Hps Health Publishing & Service Srl, Icim International Srl, Infomedica Srl, Intramed Comunication, Iqvia Solution Srl, Janssen Cilag Srl, La Fonderie, Ldv Srl, Leo Pharma Spa, Maghia Srl, Medica Editoria, Medicoop Vesevo, Mertz Pharma Italia Spa, Micom Srl, Non Solo Meeting Srl, Novartis Pharma Ag, Palazzo Della Salute Srl, Perrigo Italia Srl, Pierre Fabre Dermo Cosmetique, Plannig Congressi, Prex Srl, Qbggroup Srl, Sidemast Srl, Sifarma Spa con socio unico, Sifarma Spa, Sintesi Infomedica Srl, Tecniche Nuove Spa, Thenewway Srl, Triumph Italy Srl, Uvet Gbt Spa, Valetudo Srl, Vyvalife Srl, Vyvamed Srl, Winch ‐ Srl. MCF has served on advisory boards and received honoraria for lectures from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi and Sun Pharma. MTF reports participation to scientific meetings provided by Novartis, Pierre-Fabre, Bristol Meyers, Lilly, AbbVie. FG received honoraria for speaker/advisory role from Servier, Eli Lilly, Iqvia, Merck Serono, Amgen and Bristol Myers Squibb. DG reports Pfizer, Ipsen, Merck. PG reports lecture fees and Advisory Board: AstraZeneca, Roche, Pfizer, MSD, Novartis, Eli Lilly, Boehringer Ingelheim, AMGEN. MG reports participation to scientific meetings provided by Merck Sharp & Dohme, Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; advisory board participation for Pierre-Fabre, Novartis, Merck Sharp & Dohme, Bristol Meyers Squibb; invited speaker: Pierre-Fabre, Novartis, Merck Sharp & Dohme, Bristol Meyers Squibb. DM reports honoraria or Advisory Board for Novartis, Bayer HealthCare Pharmaceuticals, Pierre-Fabre, Sanofi Genzyme, MSD Italia S.r.l., Roche, Skyline Dx B.V. LM reports participation to board Astellas and Ipsen. AMM reports Novartis, BMS, MSD, Pierre Fabre, Gilead, Sunpharma, Merck’s, Sanofi. FM reports consultant in events organized by Bristol Meyers Squibb, MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre, honoraria for participation to events MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre, participation to meetings: Pharmar, BMS, Novartis - Advisory Board Bristol Meyers Squibb, MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre. GP reports invited speaker and advisory board participation: BMS, MSD, Incyte, Novartis, Pierre Fabre, Roche, Sanofi. GP reports AbbVie; Almirall; Janssen Cilag; Leo-Pharma; Merck Serono, Novartis, Pfizer, Pierre Fabre, Sanofi Genzyme. JP reports participation to advisory board BMS, MSD. NP reports Kyowa Kirin, Merck Serono, MSD, Novartis, Pierre Fabre, Recordati Rare Diseases, Sanofi, Takeda. FS reports lecture fees: BMS, Novartis, MSD, Pierre Fabre, Sun Pharma, Sanofi, Merck, advisory board: MSD, Novartis, Philogen, Sun Pharma. LT reports financial support with the following subjects with commercial interests in the health sector: Elekta, Igea Medical, Sun Farma, Sanofi, Roche, Molipharma, Nanobiotix AB, HNS GEC-ESTRO WG, AIRO. IZ reports Advisory Board or speakers fee from Novartis, Sanofi Genzyme, Sunpharma, Philogen, MSD, La Roche Posay, Biogena. GCAC, LA, GB, AB, PB, LB, VB, FB, AC, VF, FF, MG, CG, RM, PM, RP, FP, PP, LR, GR, PR, GR, ET, MCT, MT, MV, BV have declared no significant conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate., (© 2022. The Author(s).)

Health related quality of life (HRQoL) is an important recognized health outcome for cancer treatments, but also disease course with slower recovery and increased morbidity. These issues are of implication in melanoma, which maintains a risk of disease progression for many years after diagnosis. This study aimed to explore and weigh factors in the perception of the quality of life and possible relationships with demographic-clinical characteristics in people with melanoma via a machine learning approach. In this observational study, patients with melanoma, without metastatic disease, were recruited from January 2020 to December 2021 with a follow-up of at least one year. Demographic variables and clinics were collected, and the 12-Item Short-Form Health Survey (SF-12) was adopted as the physical and mental aspects of the Health-Related Quality of Life (HRQoL) measure. All the variables were processed in a random forest model to weigh at each node of each tree of this machine learning regression model, their actual weight in SF-12 score. We included 203 melanoma patients, mean aged 59.25 ± 15.1 years: 56 (27%) affecting the upper limbs and 147 (73%) affecting the trunk. The model of 142 patients with no missing value, generating 92 trees (MSE = 0.45, R2 of 0.78), reported that the lesion site was the most influencing variable on HRQoL based on the decrease in Gini impurity in variable weighing at each node intersection in forest generation. In this scenario, we built two distinct models for lesion sites and demonstrated that the variable that most influenced the quality of life in upper limb melanoma was lymphedema, while BMI was in the trunk. Given these results, random forest regressions could play a crucial role in the clinical and rehabilitation approach. The machine-learning model for detecting the HRQoL predictor in melanoma patients indicates that the experienced lymphedema and BMI may influence the HRQoL perception. This study suggests that the prevention and treatment of lymphedema and bodyweight reduction might improve the quality of life in melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinto, Marotta, Caracò, Simeone, Ammendolia and de Sire.)

Molecular imaging techniques have rapidly progressed over recent decades providing unprecedented in vivo characterization of metabolic pathways and molecular biomarkers. Many of these new techniques have been successfully applied in the field of neuro-oncological imaging to probe tumor biology. Targeting specific signaling or metabolic pathways could help to address several unmet clinical needs that hamper the management of patients with brain tumors. This review aims to provide an overview of the recent advances in brain tumor imaging using molecular targeting with positron emission tomography and magnetic resonance imaging, as well as the role in patient management and possible therapeutic implications., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR)., Methods: Melanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors., Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by anti-PD-1 (HR=0.25), globally immunotherapy was significantly associated with improved survival, either for anti-CTLA4 monotherapy or combined with anti-PD-1 (HR=0.47 and 0.26, respectively) and BRAFI+MEKI (HR=0.62)., Conclusions: The nivolumab/pembrolizumab in combination of ipilimumab and the addition of ant-MEK to the BRAFi can be considered the best therapies to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment., Competing Interests: PA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Pfizer. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array and travel support from MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Crispo, Corradin, Giulioni, Vecchiato, Del Fiore, Queirolo, Spagnolo, Vanella, Caracò, Tosti, Pennacchioli, Giudice, Nacchiero, Quaglino, Ribero, Giordano, Marussi, Barruscotti, Guida, De Giorgi, Occelli, Grosso, Cairo, Gatti, Massa, Atzori, Calvani, Fabrizio, Mastrangelo, Toffolutti, Celentano, Budroni, Gandini, Rossi, Testori, Palmieri, Ascierto and the Clinical National Melanoma Registry Study Group at the Italian Melanoma Intergroup.)

The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.

Anorectal malignant melanoma (AMM) is a rare malignant tumor. Surgery remains the gold standard but new adjuvant treatments to allow local sphincter-saving are warranted. Electrochemotherapy (ECT) is an alternative to surgery in selected cohorts of patients. To evaluate safety and efficacy of ECT in a retrospective series of patients with primary or recurrent AMM in terms of local disease control, local progression free and overall survival. Seven primary and one recurrent AMM underwent ECT. Patients were followed at 1 and 2 months and at the longest available follow-up with clinical examination and/or ultrasound. One month after ECT 6/8 (75%) patients showed complete response, 1/8 partial response (12.5%) and 1/8 stable disease (12.5%), confirmed at 2 months. Bleeding stopped in all patients, and pain was absent or mild/moderate in all patients. No serious adverse events were observed. At 1 year of follow-up seven out of eight patients were alive (87.5%), four were disease-free and three were alive with disease. At the longest available follow-up (mean 4.9 ± 2.0 years) five out of eight (62.5%) of patients were still alive. Our study showed that ECT is well tolerated and effective in the treatment of patients with anal melanoma with good local control of disease., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry., Methods: Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated., Results: Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure., Conclusions: Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

Objectives: Hypoxia is associated with poor prognosis and treatment resistance in breast cancer. However, the temporally variant nature of hypoxia can complicate interpretation of imaging findings. We explored the relationship between hypoxia and vascular function in breast tumours through combined 18 F-fluoromisonidazole ( 18 F-FMISO) PET/MRI, with simultaneous assessment circumventing the effect of temporal variation in hypoxia and perfusion., Methods: Women with histologically confirmed, primary breast cancer underwent a simultaneous 18 F-FMISO-PET/MR examination. Tumour hypoxia was assessed using influx rate constant K i and hypoxic fractions (%HF), while parameters of vascular function (K trans , k ep , v e , v p ) and cellularity (ADC) were derived from dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI, respectively. Additional correlates included histological subtype, grade and size. Relationships between imaging variables were assessed using Pearson correlation (r)., Results: Twenty-nine women with 32 lesions were assessed. Hypoxic fractions > 1% were observed in 6/32 (19%) cancers, while 18/32 (56%) tumours showed a %HF of zero. The presence of hypoxia in lesions was independent of histological subtype or grade. Mean tumour K trans correlated negatively with K i (r = - 0.38, p = 0.04) and %HF (r = - 0.33, p = 0.04), though parametric maps exhibited intratumoural heterogeneity with hypoxic regions colocalising with both hypo- and hyperperfused areas. No correlation was observed between ADC and DCE-MRI or PET parameters. %HF correlated positively with lesion size (r = 0.63, p = 0.001)., Conclusion: Hypoxia measured by 18 F-FMISO-PET correlated negatively with K trans from DCE-MRI, supporting the hypothesis of perfusion-driven hypoxia in breast cancer. Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that combined assessment may be needed for disease characterisation, which could be achieved using simultaneous multimodality imaging., Key Points: • At the tumour level, hypoxia measured by 18 F-FMISO-PET was negatively correlated with perfusion measured by DCE-MRI, which supports the hypothesis of perfusion-driven hypoxia in breast cancer. • No associations were observed between 18F-FMISO-PET parameters and tumour histology or grade, but tumour hypoxic fractions increased with lesion size. • Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that the combined hypoxia-perfusion status of tumours may need to be considered for disease characterisation, which can be achieved via simultaneous multimodality imaging as reported here.

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report.