Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of ...LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A,
n
= 78) versus those without LDT (cohort B,
n
= 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months;
P
= 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months;
P
= 0.054). The objective response rate to any ICB (16.7% vs. 3.8%,
P
= 0.0073) and combined ICB (14.1% vs. 4.5%,
P
= 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
Background/Aim: Uveal melanoma (UM) is the most common malignant tumor of the eye in adults. Metastases develop in 50% of the patients, predominantly in the liver. In UM, the cut-off concentrations ...of the blood-based tumor markers S100b and MIA are inconclusive. Patients and Methods: In this retrospective monocenter study, we statistically evaluated 1,878 S100b and 1,768 MIA measurements in 244 patients with UM from 2011-2020. Threshold optimization was performed using receiver operating characteristic (ROC) curves. Results: A total of 171 patients with non-metastatic UM (nmUM) and 73 patients with metastatic UM (mUM) showed no differences in sex, age at diagnosis or the affected eye. In mUM, 80% of the patients developed metastases to the liver at a median of 46 months after initial diagnosis. The sensitivity and specificity of S100b was 16.10% and 94.52%, and that of MIA was 31.86% and 81.42%, respectively. ROC curves revealed poor values for the area under the curve of 0.57 for S100b and 0.55 for MIA. The optimal cut-off concentration to detect metastases was 0.14 μg/l for S100b and 17.4 ng/ml for MIA. With at least one tumor marker elevated, optimized sensitivity was 20.40% and specificity 96.76%. Conclusion: Current thresholds for S100b and MIA in UM are not able to detect early metastatic disease and require additional diagnostics to clarify false positive results. Threshold optimization considering both S100b and MIA results in a better diagnostic validity with an acceptable specificity and a poor sensitivity. Highly sensitive blood-based and imaging methods to detect metastases early in UM are urgently needed.
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Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now ...present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response CR + partial response PR) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.
Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare ...immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.
This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).
In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4-49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.
Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint ...blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
Ethnic skin types are known to differ in their morphological and physiological features. Thus, treatment responses may vary among different races. We aimed to assess skin morphology of different ...ethnicities and to compare the effect of short-term moisturizer application using optical coherence tomography (OCT) and reflectance confocal microscopy (RCM).
Thirty healthy female subjects of European, Asian and Black ethnicity at 30-45 years of age were included in the study. OCT and RCM imaging was performed on the cheek to compare morphology. Following the 2-week application of a moisturizer cream (Sebamed® lotion) on one forearm, imaging was performed on both forearms to assess and compare treatment responses.
Epidermal thickness and morphology of pores varied between the three ethnic groups, with Black subjects displaying the thickest epidermis and largest skin pores. On the treated forearm, OCT measurements revealed a significantly thicker epidermis in all groups as compared to the untreated forearm. Width of skin folds on the treated forearm was measured by RCM to be significantly lower in all ethnic groups as compared to the untreated forearm.
Different ethnic skin types showed variations in skin morphology and treatment response to short-term moisturizer application. OCT and RCM were useful methods for noninvasive, real-time, repeated assessment of ethnic skin.
Videodermatoscopy (VD) is a useful device for supporting dermatologists in the distinction between benign and malignant lesions. However, only few patients have access to VD in daily practice.
To ...investigate patient attitudes towards VD.
A cross-sectional study was conducted between May and June 2018. Patients were asked to complete a self-administered questionnaire on the popularity of VD. Descriptive analysis was performed including contingency tables and χ2 tests to investigate associations between sociodemographic data and the popularity of VD.
A total of 61.2% (123/201) of the patients had not heard of VD at the time of assessment or were unsure. Of the 38.8% of patients (78/201) who already knew of VD, 64.1% (50/78) reported that they had already been investigated by VD; 57.5% (111/193) were willing to pay an extra fee for VD. A high level of education and private insurance status had a statistically significant association with the popularity of VD (p = 0.036 and p = 0.026, respectively).
There was a strong information deficit, especially in patients with lower education and statutory health insurance. Nevertheless, the willingness to pay an extra fee for a VD-assisted skin examination was high. Dermatologists should actively offer and inform their patients about VD when performing skin cancer screening.
Background: Recently, the notion of tumour-educated platelets has emerged as a novel source of tumour RNA biomarkers. We sought to confirm the suitability of the platelet blood fraction for liquid ...biopsy approaches. Since publications have claimed that tumour RNA and other tumour-derived material is transferred from tumour cells to the platelets and that tumor-derived transcripts can be detected in platelets, we chose to focus on RNA carrying a mutation as being of bona fide tumour origin. Methods: Prospective blood samples from a cohort of 10 melanoma patients with tissue-confirmed BRAF V600E mutation were collected after informed consent, according to an ethics committee-approved protocol. Each specimen was processed using three different protocols in parallel isolating exosomes and other extracellular vesicles (EVs), platelet poor plasma (PPP) and platelets, respectively. The EV fraction was prepared using a commercial protocol for spin column-based isolation of extracellular vesicles, followed by purification of the RNA, whereas platelets and PPP were processed by centrifugation protocols reported in literature, followed by a similar RNA purification. The RNA from each fraction was analysed by a highly sensitive ARMS RT-qPCR with a wild-type blocker for detection of BRAF V600E mutations. This assay enables the quantification of the mutant allele fraction (%MAF) of BRAF V600E down to 0.01% in a background of up to 100,000 wild-type copies. Results: Comparing all three fractions, only the EVs contained detectable BRAF V600E in 10 out of 10 patients and showed a substantially higher %MAF of BRAF V600E than the other two fractions. In three patients with the overall lowest mutant signal, BRAF V600E was only detectable in the EV fraction, but not in platelets or PPP. The platelet fraction from all 10 patients contained too high amounts of wild-type BRAF signal to accurately quantify any mutation signal above the elevated background noise. Summary/conclusion: Our observations suggest that if tumour RNA is indeed transferred to platelets, this phenomenon occurs below detection limit, since even a very sensitive qPCR assay did not allow for a reliable detection of BRAF V600E in the platelet fraction. In contrast, the EV fractions from the same patients allowed for detection of BRAF V600E in all 10 specimens.
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