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9524 Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant PD-1 antibodies. Methods: We systematically evaluated all melanoma patients who started adjuvant PD-1 antibody therapy at our center between March 2018 and September 2019 to identify predictive factors for outcome. The median follow-up time from start of adjuvant anti-PD-1 therapy was 22 months. Tumor and normal tissue of all stage IIIC/D/IV patients and of stage IIIA/B patients with relapse were sequenced using a 700 genes panel. Predictive factors for relapse and RFS were identified using univariate and multivariate logistic and Cox regression analysis. RFS was estimated by the Kaplan-Meier method. TMB high was defined as the top 20 % of the cohort, corresponding to TMB values ≥ 20 Var/Mb. Results: A total of 165 patients were included in this study. According to AJCC 8th the initial tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48 %), N = 85 stage IIIC/D/IV (52 %). 72/165 patients (44 %) suffered a relapse, 44/72 (61 %) with loco regional and 28/72 (39 %) with distant metastases. Sequencing results were available from 79 / 85 patients with stage IIIC/D/IV. Here we present the results of this cohort. TMB low (OR 17.46, 95%CI 4.03-75.55; p < 0.0001) or absence of BRAF V600E/K mutation (OR 4.13, 95%CI 1.36-12.53; p = 0.012) were statistically significant, independent predictive factors for relapse. Also, with regard to RFS, BRAF mutation status and TMB were statistically significant and independent predictive factors. In the table below we display results for the combined variables. Patients with BRAF V600E/K mutation and TMB high had the best outcome. Conclusions: We identified TMB high as positive predictive marker in stage IIIC/D/IVmelanoma patients with adjuvant PD-1 antibody therapy. In tumors with BRAF V600E/K mutation and concurrent low TMB, adjuvant targeted therapy with BRAF- and MEK-inhibitors may be an alternative. This is also supported by the data on adjuvant dabrafenib and trametinib, which showed a greater advantage in patients with low TMB, presumably due to less tumor heterogeneity.[Table: see text]

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. Patients and methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC)

The aim of the study was to evaluate if 18F-FDG-PET has the potential to detect complete responders to PD1-therapy in patients with unresectable metastasized melanoma two weeks after therapy initiation. Between September 2014 and May 2016, ten patients (four females; 65 ± 12 y) received a whole-body 18F-FDG-PET/MRI examination at three time points: Before therapy start (t0, base-line), two weeks (t1, study examination) and three months after treatment initiation (t2, reference standard). Therapy response was assessed with PET response criteria in solid tumors (PERCIST). Time to progression and overall survival (OS) were obtained for all patients. Three patients with partial metabolic response in PET at t1 turned out to have complete response at t2. No tumor relapse was observed in those patients so far (observation period: 265, 511 and 728 days, respectively). At t2, progressive metabolic disease (PMD) was seen in six patients from whom four showed PMD and two showed stable metabolic disease (SMD) at t1. OS in patients with PMD at t2 varied between 148 and 814 days. SMD at both t1 and t2 was seen in one patient, tumor progress was observed after 308 days. Our study indicates that whole-body 18F-FDG-PET might be able to reliably identify complete responders to PD1-therapy as early as two weeks after therapy initiation in stage IV melanoma patients. This might help to shorten therapy regimes and avoid unnecessary side effects in the future.

To evaluate the influence of 18F-FDG-PET/CT on clinical decision making and outcome in advanced melanoma patients planned for radical metastasectomy. A cohort of 333 patients with mainly stage III/IV melanoma having a PET/CT for clinical reasons was prospectively enrolled in our oncologic PET/CT registry between 2013 and 2015. Referring physicians completed questionnaires regarding their intended management for each patient before and after PET/CT. Management changes after PET/CT were classified as major and minor changes. A subgroup of 107 patients (stage I, N = 5; stage II, N = 3; stage III, N = 42; stage IV, N = 57) was planned for complete metastasectomy initially, based on conventional imaging. Management changes and outcome were evaluated by linkage with the information obtained from patients’ medical records. In 28 of 107 patients (26%), the surgical treatment plan remained unchanged after PET/CT. In 24 patients (22%), minor changes were performed, such as enlargement or reduction of the surgical field. In 55 patients (51%, 95% CI 42%-61%) major changes of the intended treatment plan occurred; of those, 20 patients (19%) were classified to be tumor-free with PET/CT, 32 patients (30%) were found to have multiple previously unrecognized metastases and had to be treated by systemic therapy, three patients (3%) had to be changed to palliative radiotherapy or isolated extremity perfusion. The 1-year and 2-year overall survival (OS) in patients with complete metastasectomy (N = 52) was 90% and 79%, respectively. Systemically treated patients (N = 32) resulted in 1-year OS of 72% and 2-year OS of 61%. Eleven of 32 patients (34%) with systemic therapy experienced a complete response. Until December 2016, all 20 patients classified as tumor-free by PET/CT were alive. The study confirms the high impact of PET/CT on clinical management in patients with advanced melanoma planned for radical metastasectomy. PET/CT resulted in frequent management changes, preventing futile surgery in half of the patients.

The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy. Here, we can show that RSK activity is significantly increased in human melanoma cells with acquired resistance to the BRAFV600E/K inhibitor vemurafenib. Interestingly, inhibition of RSK signalling markedly impairs the viability of vemurafenib resistant melanoma cells and is effective both in two-dimensional and in three-dimensional culture systems, especially in a chronic, long-term application. The effect of RSK inhibition can be partly replicated by downregulation of the well-known RSK target, Y-box binding protein 1 (YB-1). Intriguingly, RSK inhibition also retains its efficacy in melanoma cells with combined resistance to vemurafenib and the MEK inhibitor trametinib. These data suggest that active RSK signalling might be an attractive novel therapeutic target in melanoma with acquired resistance to MAPK pathway inhibitors.

Purpose: Cancer immunotherapy depends on a systemic immune response, but the basic underlying mechanisms are still largely unknown. Despite the very successful and widespread use of checkpoint inhibitors in the clinic, the majority of cancer patients do not benefit from this type of treatment. In this translational study, we investigated whether noninvasive in vivo positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) is capable of detecting immunotherapy-associated metabolic changes in the primary and secondary lymphoid organs and whether this detection enables the prediction of a successful anti-cancer immune response. Methods: RIP1-Tag2 mice with progressed endogenous insular cell carcinomas underwent a combined cancer immunotherapy consisting of CD4+ T cells plus monoclonal antibodies (mAbs) against programmed death ligand-1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) or a sham treatment after radiation-mediated immune cell depletion. A second cohort of RIP1-Tag2 mice underwent exclusive checkpoint inhibitor therapy (CIT) using anti-PD-L1/LAG-3 mAbs or sham treatment without initial immune cell depletion to mimic the clinical situation. All mice were monitored by 18F-FDG-PET combined with anatomical magnetic resonance imaging (MRI). In addition, we retrospectively analyzed PET / computed tomography (CT) scans (PET/CT) regarding 18F-FDG uptake of CIT-treated metastatic melanoma patients in the spleen (n=23) and bone marrow (BM; n=20) as well as blood parameters (n=17-21). Results: RIP1-Tag2 mice with advanced insular cell carcinomas treated with combination immunotherapy exhibited significantly increased 18F-FDG uptake in the spleen compared to sham-treated mice. Histopathology of the spleens from treated mice revealed atrophy of the white pulp with fewer germinal centers and an expanded red pulp with hyperplasia of neutrophils than those of sham-treated mice. Immunohistochemistry and flow cytometry analyses of the spleens revealed a lower number of T cells and a higher number of neutrophils compared to those in the spleens of sham-treated mice. Flow cytometry of the BM showed enhanced activation of T cells following the treatment schemes that included checkpoint inhibitors. The ratio of 18F-FDG uptake at baseline to the uptake at follow-up in the spleens of exclusively CIT-treated RIP1-Tag2 mice was significantly enhanced, but the ratio was not enhanced in the spleens of the sham-treated littermates. Flow cytometry analysis confirmed a reduced number of T cells in the spleens of exclusively CIT-treated mice compared to that of sham-treated mice. A retrospective analysis of clinical 18F-FDG-PET/CT scans revealed enhanced 18F-FDG uptake in the spleens of some successfully CIT-treated patients with metastatic melanoma, but there were no significant differences between responders and non-responders. The analysis of the BM in clinical 18F-FDG-PET/CT scans with a computational segmentation tool revealed significantly higher baseline 18F-FDG uptake in patients who responded to CIT than in non-responders, and this relationship was independent of bone metastasis, even in the baseline scan. Conclusions: Thus, we are presenting the first translational study of solid tumors focusing on the metabolic patterns of primary and secondary lymphoid organs induced by the systemic immune response after CIT. We demonstrate that the widely available 18F-FDG-PET modality is an applicable translational tool that has high potential to stratify patients at an early time point.

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

Background Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this Treatment strategy remain poorly understood. We Report on the Overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the Impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 Mutation (BRAFmut) status, types of RT and ST and their sequence. Patients and methods Data of 208 patients treated with SRS or whole brain Radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week- interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate- and multivariate Cox proportional hazard analyses were performed to determine prognostic Features associated with OS. Results The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAF mut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with to TT solely before RT (12.2 [95% confidence interval {CI} 9.3–15.1]; 9.8 [95% CI 6.9–12.6] versus 5.1 [95% CI 2.7–7.5]; P = .03). Conclusion SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and Warrant further studies.

Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Background Early detection is a key factor in improving survival from melanoma. Today, the clinical diagnosis of cutaneous melanoma is based mostly on visual inspection and dermoscopy. Preclinical studies in freshly excised or paraffin-embedded tissue have shown that the melanin fluorescence spectra after stepwise two-photon excitation, a process termed dermatofluoroscopy, differ between cutaneous melanoma and melanocytic naevi. However, confirmation from a larger prospective clinical study is lacking. Objectives The primary end point of this study was to determine the diagnostic accuracy of dermatofluoroscopy in melanoma detection. Secondary end points included the collection of data for improving the computer algorithm that classifies skin lesions based on melanin fluorescence and the assessment of safety aspects. Methods This was a prospective, blinded, multicentre clinical study in patients with pigmented skin lesions (PSLs) indicated for excision either to rule out or to confirm cutaneous melanoma. All included lesions underwent dermoscopy and dermatofluoroscopy in vivo before lesions were excised and subjected to histopathological examination. Results In total, 369 patients and 476 PSLs were included in the final analysis. In 101 of 476 lesions (21·2%) histopathology revealed melanoma. The observed sensitivity of dermatofluoroscopy was 89·1% (90 of 101 melanomas identified), with an observed specificity of 44·8%. The positive and negative predictive values were 30·3% and 93·9%, respectively. No adverse events occurred. Conclusions Dermatofluoroscopy is a safe and accurate diagnostic method to aid physicians in diagnosing cutaneous melanoma. Limitations arise from largely amelanotic or regressing lesions lacking sufficient melanin fluorescence.

We aimed to determine the prevalence and importance of fear of cancer progression (FoP) in melanoma patients with stage IA tumours to assess psychosocial and demographic factors associated with severity of FoP and to determine the relationship of FoP and quality of life (QoL). One hundred and thirty-six patients with stage IA melanoma completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS) and the EORTC-QLQ-C30. We found a mean FoP-Q-SF sum score of 30.2 points (±8.4 points SD). In this study, 33% of patients reported high FoP at or above the cutoff-value of 34 points. Higher FoP was found in women (p < 0.01), young (p = 0.03) and employed (p = 0.02) patients. Being confronted with a cancer diagnosis in closely related persons predicted higher FoP (p < 0.01). FoP correlated positively with the HADS anxiety (r = 0.50, p < 0.01) and depression scales (r = 0.26, p < 0.01) and negatively with the EORTC-QLQ-C30 global health state (r = -0.32, p < 0.01). FoP is considerably prevalent in low-risk melanoma patients and associated with reduced QoL, cancer in related persons, women sex and participation in working life. Considerably high levels of FoP, even in patients with low-risk malignancies, underline the need for psychosocial support and psychotherapeutic interventions for melanoma patients.

Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception. CA extern

BACKGROUND AND OBJECTIVES Automated computer-guided diagnostic procedures are increasingly being integrated into patient care. However, in contrast to the increasing application of automation, patient acceptance and trust in such technologies has rarely been studied. Automated diagnosis of melanoma with dermatofluoroscopy was recently approved by regulatory agencies. The objective of this study is to assess patient acceptance and trust in automated melanoma diagnosis with dermatofluoroscopy. PATIENTS AND METHODS We examined 140 pigmented skin lesions with dermatofluoroscopy as part of a prospective clinical study. Four weeks after their examination with dermatofluoroscopy, we contacted 100 patients with a 10-item questionnaire addressing their acceptance and trust in this technology on a five-point visual analogue scale. RESULTS A "high" to "very high" level of patient acceptance and trust in dermatofluoroscopy was found in 74 % of responders. Most patients agreed that computer-assisted diagnoses are trustworthy and may generally improve the diagnostic performance of physicians. However, all responders insisted on the interpretation of computer-assisted diagnoses by a physician and frequently rejected the idea of computers completely replacing physicians. CONCLUSION Patient acceptance and trust in dermatofluoroscopy was high. Patients clearly supported the use of automated, computer-assisted diagnostics as an adjunct to the physicians' examination.

Prognostic factors of melanoma patients with distant metastases remain poorly established. This study aimed to compare the prognostic impact of putative serum biomarkers, namely S100B, YKL-40 or CCL17, in stage IV melanoma patients. Serum concentrations were analyzed by ELISA. Disease-specific survival of 80 patients according to S100B, YKL-40 or CCL17 and clinical factors were calculated by univariate Kaplan–Meier survival and multivariate analysis. Low serum levels of S100B, high concentrations of CCL17 and female gender correlated with improved survival. A trend for favorable prognosis was observed for the M categories M1a/b versus M1c according to the AJCC classification. No correlation with survival was evident for YKL-40 serum levels and age. In multivariate analysis, S100B (HR 2.1; p = 0.005) and CCL17 (HR 1.8; p = 0.029) had independent prognostic impact. Patients with a combination of normal S100B and high CCL17 had a high chance for long-term survival, which was 43 % after 3 years. Serum levels of CCL17 and S100B represent independent prognostic markers for melanoma patients with distant metastases. These biomarkers were more powerful than the M category according to the AJCC classification to indicate overall survival. CCL17 represents a promising biomarker upon immune checkpoint blockade in melanoma.

The basis of radiation recall reactions (RRR) is a subclinical radiation damage that is uncovered later by treatment with anticancer agents. Several drugs have been associated with RRR, in particular taxanes and anthracyclines. Recently, a few cases were reported concerning radiation recall dermatitis caused by vemurafenib. Up to now, there have been no reports of RRR in the lung induced by vemurafenib. We describe the occurrence of RRR in three melanoma patients who had undergone radiotherapy for metastases followed by systemic treatment with the BRAF inhibitor vemurafenib. Two patients developed radiation recall pneumonitis (RRP) and one patient developed radiation recall dermatitis (RRD) 5-7 weeks after the radiation treatment was finished and 2-4 weeks after vemurafenib was started. The early application of systemic (RRP) and topical corticosteroids (RRD) enabled us to continue the treatment with vemurafenib without dose reduction. Caution is needed when vemurafenib is planned for patients who have undergone previous radiotherapy, and RRR of the skin and the lung have to be taken into account.

Despite an increasing number of promising treatment options, only a limited number of studies concerning melanoma patients’ psycho-oncological distress have been carried out. However, multiple screening tools are in use to assess the need for psycho-oncological support. This study aimed first to identify parameters in melanoma patients that are associated with a higher risk for being psycho-oncologically distressed and second to compare patients’ self-evaluation concerning the need for psycho-oncological support with the results of established screening tools. We performed a cross-sectional study including 254 melanoma patients from the Center for Dermatooncology at the University of Tuebingen. The study was performed between June 2010 and February 2013. Several screening instruments were included: the Distress Thermometer (DT), Hospital Anxiety and Depression Scale and the patients’ subjective evaluation concerning psycho-oncological support. Binary logistic regression was performed to identify factors that indicate the need for psycho-oncological support. Patients’ subjective evaluation concerning the need for psycho-oncological support, female gender, and psychotherapeutic or psychiatric treatment at present or in the past had the highest impact on values above threshold in the DT. The odds ratio of patients’ self-evaluation (9.89) was even higher than somatic factors like female gender (1.85), duration of illness (0.99), or increasing age (0.97). Patients’ self-evaluation concerning the need for psycho-oncological support indicated a moderate correlation with the results of the screening tools included. In addition to the results obtained by screening tools like the DT, we could demonstrate that patients’ self-evaluation is an important instrument to identify patients who need psycho-oncological support.

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates. To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent. We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab. Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR. Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient’s convenience.

To evaluate the influence ofA cohort of 333 patients with mainly stage III/IV melanoma having a PET/CT for clinical reasons was prospectively enrolled in our oncologic PET/CT registry between 2013 and 2015. Referring physicians completed questionnaires regarding their intended management for each patient before and after PET/CT. Management changes after PET/CT were classified as major and minor changes. A subgroup of 107 patients (stage I, N = 5; stage II, N = 3; stage III, N = 42; stage IV, N = 57) was planned for complete metastasectomy initially, based on conventional imaging. Management changes and outcome were evaluated by linkage with the information obtained from patients' medical records.In 28 of 107 patients (26%), the surgical treatment plan remained unchanged after PET/CT. In 24 patients (22%), minor changes were performed, such as enlargement or reduction of the surgical field. In 55 patients (51%, 95% CI 42%-61%) major changes of the intended treatment plan occurred; of those, 20 patients (19%) were classified to be tumor-free with PET/CT, 32 patients (30%) were found to have multiple previously unrecognized metastases and had to be treated by systemic therapy, three patients (3%) had to be changed to palliative radiotherapy or isolated extremity perfusion. The 1-year and 2-year overall survival (OS) in patients with complete metastasectomy (N = 52) was 90% and 79%, respectively. Systemically treated patients (N = 32) resulted in 1-year OS of 72% and 2-year OS of 61%. Eleven of 32 patients (34%) with systemic therapy experienced a complete response. Until December 2016, all 20 patients classified as tumor-free by PET/CT were alive.The study confirms the high impact of PET/CT on clinical management in patients with advanced melanoma planned for radical metastasectomy. PET/CT resulted in frequent management changes, preventing futile surgery in half of the patients.

Background The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naive. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy. Patients and methods A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed. Results In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively. Conclusions Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naive patients.

During 2011 and 2014, new treatment modalities like tyrosine kinase inhibitors and checkpoint inhibitors were introduced into the therapy of metastatic melanoma. This study addresses the question whether overall survival (OS) of metastatic melanoma patients has already been improved in 441 patients diagnosed with metastatic melanoma between 2011 and 2014 in the real-world setting at the University Hospital Tuebingen. All patients were documented with their different therapies by the CMMR and followed up until March 2016. Survival probabilities were calculated by Kaplan–Meier estimators, and log-rank tests were used to evaluate significances. Hazard ratios were estimated by Cox regression analysis for survival probabilities and prognostic factors in stage IV melanoma. Best OS was observed in patients (n = 93) treated by metastasectomy as primary treatment with the intention to completely excise all metastases (3-year OS 61%). OS for patients with first-line systemic treatment (n = 258) was unfavorable in general (3-year OS 23%). Of those, the most favorable outcome was observed in patients without brain metastasis and treated with immunotherapy (mostly ipilimumab), as first-line treatment (median OS 35 months, 3-year OS 43%). In case of brain metastases, patients with targeted therapy had a better OS (median 14 months) than patients with ipilimumab treatment (median 7 months). Among all patients with first-line systemic treatment, outcome of patients diagnosed in the years 2013/2014, compared to 2011 and 2012, showed an improved survival. Three-year OS for patients that entered stage IV in 2013/2014 was 37% compared to those that entered stage IV in 2011 (18%) and 2012 (20%). The analysis of real-world data of treatment of metastatic melanoma showed an improvement of OS with both immunotherapy and targeted therapy. In case of cerebral metastasis, patients treated with targeted therapy showed a longer median OS than patients treated with ipilimumab.

Kato and colleagues ([1][1]) reported 4 cancer patients with metastatic disease, hyperprogression under treatment with anti-PD-1/PD-L1 monotherapy, and a cooccurring MDM2/4 amplification in the cancer cells. They defined hyperprogression as time-to-treatment failure 50% increase in tumor

Radiotherapy has become an effective treatment in the management of melanoma patients. It has its place beneath surgical treatment options in a tumor entity that has only limited response to systemic medical therapies. New therapies, such as ipilimumab and vemurafenib, may prolong survival for several months but will cure only a few patients. Radiotherapy will still be required in adjuvant settings to reduce the local recurrence rate and in palliative situations, particularly in brain and bone metastasis. We review several indications for radiotherapy in the management of malignant melanoma with an effect on the guidelines in our clinical practice.

Background Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Conclusion Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

This study identified sex differences in clinical presentation and survival for primary cutaneous melanoma without clinical evidence of metastasis at diagnosis from 1976 to 2008 in southern Germany. Melanoma-specific survival curves and estimated survival probabilities were generated using the Kaplan-Meier method. Multivariate survival analyses were carried out using the Cox modeling. Male patients had significantly thicker and more frequently ulcerated tumors and a lower 10-year disease-specific survival (DSS) and recurrence-free survival probability compared with females among patients of 43 years old or younger (DSS: 86.1 vs. 93.2%, P

Primare Ziele der Nachsorge des malignen Melanoms der Haut sind die fruhzeitige Diagnose von Zweitmelanomen und Tumorrezidiven. Die Fruherkennung der Rezidive ist fur die Patienten prognoserelevant. Durch ein strukturiertes stadienadaptiertes Nachsorgeschema werden mehr als 80% der Rezidive hauptsachlich in Nachsorgeuntersuchungen erkannt. Durch die korperliche Untersuchung werden die meisten Rezidive detektiert und durch die Lymphknotensonographie wird eine Fruherkennung lokoregionarer Rezidive ermoglicht, bevor diese tastbar werden. Daruber hinaus sollten bildgebende Verfahren stadien- und risikoadaptiert eingesetzt werden, bei Melanomen im Primartumorstadium sind diese verzichtbar. Somit kann bei diesen Melanomen (besonders bei Tumordicken ≤1,0 mm) der Umfang der Untersuchungen im Vergleich zu bisherigen Empfehlungen deutlich reduziert werden. Dadurch konnen die Kosten fur die Nachsorgeuntersuchungen erheblich verringert werden, ohne das Risiko fur die Patienten deutlich zu erhohen. Im Stadium III wird eine Intensivierung der Nachsorgeuntersuchungen durch bildgebende Verfahren zur Verbesserung der Fruherkennung von Rezidiven empfohlen.

Although the majority of patients with metastatic melanoma achieve a prolongation of overall survival by using checkpoint inhibitor based immunotherapy (CIT), there is still a larger number of patients who do not benefit from this therapy. As a CIT-induced systemic immune response is required to promote the anti-tumor effect we analyzed the glucose metabolism in secondary lymphoid organs such as the spleen by 18F-FDG-Positron Emission Tomography (PET). In preclinical studies, we were able to distinguish responders from non responders by focusing on the spleen 18F-FDG-uptake of mice with CIT in experimental tumor models. Thus, we aimed to gain deeper insights into impact of CIT on the metabolism in secondary lymphatic organs to identify responders and to stratify patients for differential treatment strategies. We retrospectively analyzed 18F-FDG-PET/CT scans (baseline and post-therapy) of 38 patients with metastatic melanoma with CTLA-4 or PD-1 Ab treatment as third line therapy (21 responder: 5x nivolumab; 7x pembrolizumab; 9x ipilimumab; 17 non-responder: 2x nivolumab; 11x pembrolizumab; 4x ipilimumab). Spleen regions of interest (ROI) were defined in the CT data, copied to the coregistered PET and analyzed semiquantitatively. Total lesion glycolysis (TLG) was calculated by multiplication of the spleen volume and the SUVmean. We determined in the baseline 18F-FDG-PET/CT-scans (prior to CIT), no significant differences in spleen volume (221±18 cm3 vs. 209 ±22 cm3) and in the spleen 18F-FDG-uptake (SUVmean: 1,74±0,06vs.1,72±0,05; TLG: 384±37 vs. 359±36) between responders and non-responders. In the follow up 18F-FDG-PET/CT-scans 110±68 days after onset of CIT we measured a similar increase in spleen volume in responders (+8±6%) and non-responders (+7±5%). 15 out of 21 responders revealed an enhanced spleen 18F-FDG uptake when compared to the baseline 18F-FDG-PET/CT-scans. The mean standard uptake values in the spleen of responders increased by +10±9% SUVmean. In sharp contrast, we determined hardly any change in the spleen 18F-FDG uptake of non-responders (SUVmean -1,3±2,6%). Additionally, the total lesion glycolysis (TLG) in the CIT-responders increased stronger (+25±22%) than in non-responders (+6±6%). Our results suggest that CIT-induced metabolic changes in secondary lymphatic organs are associated with therapy responds. Thus, non invasive 18F-FDG-PET/CT investigations might represent a powerful tool to monitor CIT-induced systemic immune responses in patients. Consequently, preclinical research is prerequisite to uncover the exact mode of action of CIT-induced systemic immune response in secondary lymphatic organs. Moreover, prospective clinical studies are essential to evaluate the prognostic value of our method. Citation Format: Johannes Schwenck, Barbara Schörg, Francesco Fiz, Kilian Wistuba-Hamprecht, Andrea Forschner, Thomas Eigentler, Benjamin Weide, Claus Garbe, Martin Röcken, Christina Pfannenberg, Bernd J. Pichler, Christian la Fougere, Manfred Kneilling. 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3034.

e21557Background: Next-generation sequencing will gain more and more importance for melanoma patients. Detection of genetic alterations in tumor tissue may help to understand mechanisms of resistan...

e21588Background: Immune checkpoint inhibitors are standard of care for most patients (pts) with MM, yet only a minority has durable disease control. CTX has limited activity when used first-line, ...

The ongoing increase in melanoma incidence throughout Caucasian populations worldwide raises the question of an economic and efficient management of primary melanoma and follow-up. The primary treatment of a cutaneous melanoma is surgical excision. An excision biopsy is recommended, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for a higher tumor thickness should be applied at the primary excision or in a two-step procedure. When dealing with facial, acral, or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. Whereas the treatment for primary melanoma is accepted world wide, follow-up strategies for melanoma patients are discussed controversially, and so far, no international consensus has been reached.

Melanoma is highly resistant to chemotherapy. In melanoma, the PI3K-AKT-mTOR signaling pathway is constitutively activated through multiple mechanisms. Several experimental studies suggest that targeting the PI3K-AKT-mTOR signaling pathway is a promising strategy to overcome chemoresistance. This is the first report describing a chemosensitizing effect of mTOR inhibition in patients with melanoma. We report two cases of patients with metastatic melanoma who showed significant remission after combination of carboplatin and paclitaxel with the mTOR inhibitor sirolimus. Our case report, together with the literature discussed, suggests that mTOR inhibition possibly enhances the sensitivity of melanoma cells to chemotherapy and should prompt in-depth and clinical investigation.

The update of the G-DRG system for the year 2009 has been successfully negotiated. Like in the past years, changes are minimal and not dramatic, but they significantly enhance the quality of the DRG system. Once again, the German DRG system demonstrates its versatility and reliability for clinical reimbursement purposes. In the field of dermatology, several improvements or enhancements can be identified; the average case mix index that declined in the past years should now rise by 0.5 percent for 2009. Oncology cases are affected especially by this increase. Some refinements advanced for several years by the German Dermatologic Society (DDG) have been recognized --complex therapies like vacuum wound therapy, isolation due to multi-resistant infections and multiple primary tumors now have better cost weights. Although there still remain some minor problems like reimbursement of cost-intensive treatments, German dermatology is in summary very well prepared for the year 2009.

Just as in the year before, the structure and regulations of the new GDRG version 2007 was successfully agreed on a mutual basis by the national self-governing bodies in the German health care system. Although some problems in high-specialized medicine or day clinic care will remain, the current developments demonstrate once more the learning aptitude of the G-DRG-system. Some beneficial and major changes have been made in 2007, but most of them do not touch dermatology. Additional procedure-based payments have been introduced in 2007 including the parenteral administration of such expensive agents as etanercept and itraconazole. A statistical analysis of cost weights of the year 2006 versus 2007 for two university clinics suggests that in dermatology, the increasing complexity of the G-DRG system partly leads to lower cost weights. Overall in 2007 a remarkable increase of complexity and differentiation throughout the DRG-system can be identified as well as a careful expansion of procedure-based payments.

Background: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. Methods: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. Results: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. Conclusion: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

9514 Background: There is limited data about the impact of melanoma on the psychological burden of patients. Despite some known predictors for distress like female gender or younger age, melanoma stages have not been found being related to distress in melanoma patients and there is no data concerning distress in melanoma patients under systemic treatment for metastases. Methods: Between July and September 2016, 820 melanoma patients at the outpatient clinic at the Department of Dermatology at the University of Tuebingen underwent psycho-oncological screening. The patients routinely completed the distress thermometer (DT), supplemented by a problem list, before consulting the physician. DT scores ≥ 5 are above-threshold, indicating the need for psycho-oncological support. We matched psycho-oncological data with tumor and patient specific data to examine tumor or patient specific influence on distress using logistic regression. Results: 406 (49.5%) men and 414 (50.5%) women were included, mean age was 62.35 years (IQR 52-75), mean time since primary diagnosis of melanoma was 54.84 months (IQR 15-76). 359 (44%) of the patients suffered from advanced melanoma (stage III n = 182, stage IV n = 177). 120 patients (14.6%) received systemic treatment for metastases: 90/120 (75%) checkpoint inhibitors, 27/120 (22.5%) targeted therapy and 3/120 (2.5%) chemotherapy. 338/820 (41.2%) of the patients met the cut-off score for distress. Significant influencing factors (p < 0.05) for DT values of ≥ 5 were: female gender, younger age, melanoma stage III and IV. Interestingly we found a lower risk for values above-threshold for patients under systemic treatment, although this was not significant (p = 0.252). Conclusions: This is the first analysis to demonstrate the impact of advanced melanoma stages on DT scores above-threshold. Our study is also the first to indicate a lower risk for distress in patients under systemic treatment. This might be due to the closer contact between these patients and their physicians. Nevertheless, more than 40% of our patients needed psycho-oncological support. Departments that care for melanoma patients should therefore be fitted by a sufficient number of psycho-oncologists.

e21615 Fear of progression in patients with low-risk malignant melanoma Fear of cancer progression (FoP) is one of the problems most commonly reported by cancer patients and is among the most prevalent cancer-related worries in cancer survivors. FCR is highly variable in different cancer entities. Background: This study aimed to elicit the prevalence and significance of FCR in melanoma patients with low risk tumors and further to assess psychosocial and demographic factors predicting severity of FoP as well as to determine the impact of FoP on quality of life (QoL). Methods: In total, 133 patients with low-risk melanoma (pT1a) completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS), and the EQ-5D questionnaire, as well as self-constructed questions on the socio-demographic background. Results: MeanFoP-Q-SF sum score was 30.1 points (± 8.4 points SD) and the median 29 points. Two thirds of patients deviated not more than 1 SD from the mean. Risk factors for elevated FoP were female gender (p < 0.01), young age (p = 0.04) and working (p = 0.02) patients and patients with severe comorbidities (p = 0.03). Cancer in closely related persons predicted higher FoP (p < 0.01). HADS anxiety scale (r = 0.49, p < 0.01) and depression scale (r = 0.26, p < 0.01) correlated with FoP. A negative correlation with the EQ-5D index was found (r = -0.34, p < 0.01). Conclusions: As in many other malignancies,FoP is prevalent in low-risk melanoma patients and is associated with reduced QoL. Severe comorbidities, cancer in related persons, gender and income could be identified as predictors of FoP. Considerable high levels of FoP even in patients with low-risk malignancies underline the need of psychosocial support and intervention for special subgroups of melanoma patients to enable the patient to manage FoP more successfully.

TPS9113^ Background: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), a metaanalysis could only show ...

Introduction Non-invasive, nanosecond, stepwise two-photon laser excitation of skin tissue was shown to induce melanin fluorescence spectra that allow for the differentiation of melanocytic nevi from cutaneous melanoma. Methods and analysis This prospective, non-controlled, multicentre clinical study is performed to evaluate the diagnostic performance of the stepwise two-photon excited melanin fluorescence in the detection of cutaneous melanoma. The comparator will be the histopathological diagnosis. A total of 620 pigmented skin lesions suspicious for melanoma and intended for excision will be enrolled. Ethics and dissemination Ethics approval was provided by the local ethics committees of the medical faculties of the University of Tuebingen, Heidelberg and Berlin. Study registration The FLIMMA study NCT02425475.