Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG

BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

Treatment options for condylomata acuminata and anal dysplasia

Human papillomavirus (HPV) infections belong to the most common sexually transmitted infections but most infections are asymptomatic. Approximately 40 of the so far more than 200 completely classified HPV types belong to the genus Alpha and predominantly lead to infections of the anogenital region. Condylomata acuminata are caused by low-risk HPV types and belong to the most common sexually transmitted diseases. High-grade anal dysplasia is a potential precursor lesion of invasive anal carcinoma and is induced by high-risk HPV types. As condylomata acuminata and anal dysplasia are both intraepithelial lesions, treatment which is gentle on the tissue and superficial should always be performed. Treatment options for anogenital warts and anal dysplasia do not substantially differ and can be divided into ablative and topical procedures. Condylomata acuminata and a large proportion of anal dysplasias are preventable by prophylactic HPV vaccination. In the case of an already present HPV infection or HPV-induced lesions, prophylactic HPV vaccination cannot be recommended

Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients

Background: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. Methods: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. Results: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. Conclusions: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional

TRP2 and p53 expression in melanoma tissue.

<p>(A) Representative immunohistochemical staining for TRP2 and p53 in consecutive sections of a primary melanoma; scale bars: upper panel 1 mm, lower panel 100 µm. (B) Linear regression analysis of p53 and TRP2 histology scores derived from the analysis of 172 melanomas (139 primary and 33 metastatic melanoma) evaluated by a histopathologist. Staining intensity was scored between 0 and 3 and the extent of positivity between 0 and 4. By multiplying both values a minimum score of 0 and a maximum of 12 was derived; linear regression analysis comparing p53 and TRP2 histology scores revealed borderline-significant (p = 0,352) positive correlation and a coefficient of determination (R²) of 0,0258. (C) Since the number of individual dots in B cannot be visualized the distribution of individual p53 and TRP2 histology scores are displayed in the table.</p

Ectopic re-expression of TRP2 does not rescue the p53 activation induced by TRP2-shRNA_#2.

<p>Indicated melanoma cell lines were stably transduced with a lentiviral p53 reporter construct and a modified TRP2 expression construct coding for TRP2 mRNAs in which the shRNA-binding site is modified by six silent mutations (TRP2in). On day 4 following infection total cell lysates were analyzed for TRP2 and p53 expression by immunoblotting (lower part) with tubulin used as a loading control. In the upper part the corresponding mean GFP fluorescence intensity is depicted, normalized to the relative reporter vector load of the cell lines determined by real time PCR.</p

Knockdown of TRP2 by shRNA does not affect p53 expression level.

<p>(A) TRP2 and p53 expression in indicated melanoma cell lines was determined by western blot. Tubulin was used as a loading control. (B) The indicated melanoma cell lines were transduced with three different lentiviral TRP2 shRNAs (TRP2_#1, #2, #3) and on day four after shRNA infection the efficiency of the knockdown and p53 expression were analyzed by immunoblotting; a scrambled (scr) shRNA was used as a control.</p

Effects of TRP2 inhibition by shRNA on transcriptional activity of p53.

<p>Indicated melanoma cell lines were stably transduced with a lentiviral pGreenFire reporter construct encoding for green fluorescence protein (GFP) under the control of a p53 responsive element (4× CGACATGCCCGGGCATGT). The cells were then infected with the different lentiviral supernatants carrying the shRNA expression construct KH1 containing either a scrambled or a sequence targeting TRP2. Mean GFP activity four days post infection is depicted, normalized to the relative vector load of the cell lines determined by Real time PCR.</p