Melanoma-bearing Libechov minipig (MeLiM) represents a large animal model for melanoma research. This model shows a high incidence of complete spontaneous regression of melanoma - a phenomenon uncommon in humans. Here, we present the first metabolomic characterisation of the MeLiM model comparing animals with progressing and spontaneously regressing melanomas. Plasma samples of 19 minipigs with progression and 27 minipigs with evidence of regression were analysed by a targeted metabolomic assay based on mass spectrometry detection. Differences in plasma metabolomics patterns were investigated by univariate and multivariate statistical analyses. Overall, 185 metabolites were quantified in each plasma sample. Significantly altered metabolomic profile was found, and 42 features were differentially regulated in plasma. Besides, the machine learning approach was used to create a predictive model utilising Arg/Orn and Arg/ADMA ratios to discriminate minipigs with progressive disease development from minipigs with regression evidence. Our results suggest that progression of melanoma in the MeLiM model is associated with alteration of arginine, glycerophospholipid and acylcarnitines metabolism. Moreover, this study provides targeted metabolomics characterisation of an animal model of melanoma with progression and spontaneous regression of tumours.
- MeSH
- metabolomika metody MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- prasata MeSH
- progrese nemoci MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.
- MeSH
- compassionate use trials MeSH
- dospělí MeSH
- imidazoly aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom farmakoterapie genetika MeSH
- nádory kůže farmakoterapie genetika MeSH
- oximy aplikace a dávkování MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- pyridony aplikace a dávkování MeSH
- pyrimidinony aplikace a dávkování MeSH
- retrospektivní studie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In several solid tumors, an increased stathmin expression is associated with both poor prognosis and resistance to certain chemotherapy types. However, the data regarding melanocytic lesions are very limited. The goals of our study are as follows: the assessment of stathmin expression in benign and malignant melanocytic lesions, and the significance of its expression for the differential diagnostics between benign and malignant lesions; the analysis of the prognostic significance of stathmin expression in melanoma; and the evaluation of stathmin expression in melanoma and melanoma metastases with respect to possible therapeutic targeting. Immunohistochemical analysis of stathmin expression was done in 323 melanocytic lesions, including 205 primary cutaneous melanomas, 60 melanoma metastases, and 58 melanocytic nevi. Stathmin expression was found in all analyzed groups of melanocytic lesions. Using the H-scoring system, the observed intensity of expression was as follows: melanocytic nevi: 146.1 (mean) and 150 (median); melanomas: 116.7 (mean) and 110 (median); and melanoma metastases: 136.8 (mean) and 140 (median). The stathmin expression was significantly lower in the cohort of primary melanomas when compared with metastases and nevi (P=0.001). The stathmin expression showed no prognostic significance. The high stathmin expression in melanoma suggests that stathmin might be a promising marker for therapeutic targeting in ongoing clinical trials. Compared with several other solid tumors, stathmin expression in melanoma showed no prognostic significance. The potential use of stathmin expression in differential diagnostics is limited by its common expression, and despite the statistically significant differences between nevi and melanoma, it may not be used in this setting.
- MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanocyty metabolismus patologie MeSH
- melanom krev patologie MeSH
- nádorové biomarkery metabolismus MeSH
- nádory kůže krev patologie MeSH
- prognóza MeSH
- stathmin metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.
- MeSH
- centra terciární péče MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom diagnóza patologie MeSH
- nádory kůže diagnóza patologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- systematický přehled MeSH
- Geografické názvy
- Švýcarsko MeSH
The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.
- MeSH
- dospělí MeSH
- kohortové studie MeSH
- lidé MeSH
- lokální recidiva nádoru patologie chirurgie MeSH
- melanom komplikace patologie chirurgie MeSH
- míra přežití MeSH
- mladý dospělý MeSH
- nádorové komplikace v těhotenství patologie chirurgie MeSH
- následné studie MeSH
- těhotenství MeSH
- výsledek těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
Microsatellite instability (MSI) and mismatch repair deficiency are an emerging issue in oncology and molecular pathology. Besides being associated with better clinical outcome in colon cancer, MSI also harbors the potential to predict response to chemotherapy and immunotherapy. MSI was also observed in other solid tumors, including endometrial cancer, ovarian cancer, and melanoma, besides colon cancer. Strong evidence shows that MSI is a frequent event in melanoma. However, the data on MSI prevalence, pathogenesis, and clinical consequences in melanoma are limited. Therefore, we summarize the current knowledge on MSI in melanoma and outline future perspectives and clinical implications, including its role as a prognostic and/or a predictive factor.
Dermatoscopy is used to aid in the differential diagnosis of pigmented skin lesions. The aim of this study was to identify dermatoscopic differences between atypical melanocytic naevi and thin malignant melanomas. A set of 180 difficult cases (60 thin melanomas, 120 clinically atypical benign melanocytic naevi) was analysed. Differences in structure, distribution of pigmentation, presence or absence of important structures, total number of colours and asymmetry of the lesions were identified. The three-structure type, multifocal distribution of pigmentation, eccentric peripheral hyperpigmentation, multiple colours (three or more) and asymmetry of structures/colours in the dermatoscopic image were considerably more frequent in melanomas than in benign lesions (P<0.001, chi-squared test). No single dermatoscopic criterion exists to discriminate between all melanocytic lesions with sufficient confidence. Some criteria are helpful in the differential diagnosis and management of difficult cases.
- MeSH
- dermatoskopie metody MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- financování organizované MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom diagnóza MeSH
- mladiství MeSH
- nádory kůže diagnóza MeSH
- pigmentace kůže MeSH
- pigmentový névus diagnóza MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
Sentinel lymph node biopsy in patients with head and neck mucosal melanomas has not been performed so far. Therefore, this method as a staging tool was tested in a pilot study. In two consecutive patients, a lymphoscintigraphy, elective neck dissection with radio-guided sentinel lymph node identification, and resection of the primary were performed. The histopathological status of the sentinel lymph node was compared with the lymphadenectomy specimen and with the clinical course. Patient no. 1, in whom both the sentinel lymph node and the lymphadenectomy specimen were found to be free of tumour, is well and with no evidence of disease, the follow-up interval being 19 months. Patient no. 2, with the sentinel lymph node and remaining lymphatic basin being positive and negative, respectively, developed hematogenous dissemination 3 months after the primary treatment, and he was started on palliative chemotherapy. In mucosal melanoma, the prognostic significance of clinical nodal status is controversial, resulting in the lack of an official, applicable TNM classification and also of therapeutic guidelines. The presence of microscopic metastatic focus in the sentinel lymph node was associated with an early hematogenous dissemination. Therefore, sentinel lymph node biopsy, which represents a potentially efficient staging tool, warrants further investigation.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- biopsie sentinelové lymfatické uzliny metody MeSH
- dospělí MeSH
- fluorodeoxyglukosa F18 diagnostické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- melanom diagnóza MeSH
- nádory hlavy a krku diagnóza MeSH
- pozitronová emisní tomografie metody MeSH
- prognóza MeSH
- radioisotopová scintigrafie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
The signal transducers and transcription activators (STATs) and their endogenous inhibitors of the suppressors of cytokine signalling (SOCS) family are major proteins harmonizing the transmission of external signals from the surface membrane to target genes in the nucleus. To correlate the induction of SOCS 3 by interferons (IFNs) on messenger RNA and protein levels with STAT 1 phosphorylation in human malignant melanoma cell lines, we used a unique collection of 18 established malignant melanoma cell lines and six human non-malignant normal cells (two melanocytes, two skin keratinocytes and two fibroblasts). IFN-gamma induced SOCS 3 in 83% of melanoma cell lines, whereas IFN-alpha stimulated SOCS 3 expression in only 11% of cases. Similarly, melanocytes showed strong induction of SOCS 3 by IFN-gamma and, to a lesser extent, by IFN-alpha. In most cases, SOCS 3 expression was paralleled by STAT 1 phosphorylation at tyrosine residues (Y701). In several lines, however, SOCS 3 was not induced despite STAT 1 phosphorylation and, in a few lines, SOCS 3 induction occurred without detectable STAT 1 phosphorylation, indicating that STAT 1 might not be an exclusive inducer of SOCS 3. Similarly, non-malignant cells displayed STAT 1 activation and high levels of SOCS 3 expression after IFN-gamma (but not IFN-alpha) treatment. In conclusion, in contrast to IFN-alpha, IFN-gamma appeared to induce SOCS 3 apparently at the transcription level and exhibited higher cytotoxic effects regardless of the cell origin.
- MeSH
- buňky - růstové procesy účinky léků MeSH
- fosforylace MeSH
- interferon gama * farmakologie MeSH
- interferon typ I * farmakologie MeSH
- lidé MeSH
- melanom farmakoterapie genetika metabolismus MeSH
- messenger RNA biosyntéza genetika MeSH
- nádorové buněčné linie MeSH
- northern blotting MeSH
- proteiny SOCS * biosyntéza genetika MeSH
- rekombinantní proteiny MeSH
- signální transdukce MeSH
- transkripční faktor STAT1 * metabolismus MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
