Incidenca melanoma v svetu in Sloveniji še vedno narašča, se je pa preživetje v zadnjih 20 letih izboljšalo, predvsem zaradi zgodnejšega odkrivanja melanoma in enotnih pristopov v primarnem ...zdravljenju. Posodobljena Priporočila v letu 2024 prinašajo precej novosti, predvsem v diagnostičnih postopkih odkrivanja in zamejitve zgodnjih stadijev melanoma, kot tudi natančnih priporočil sledenja po primarnem zdravljenju, na področju kirurškega zdravljenja in pa predvsem sistemskega zdravljenja, tako metastatske bolezni, predvsem pa v adjuvan- tnem sistemskem zdravljenju v visoko rizičnem stadiju II, in neo- adjuvantnem sistemskem zdravljenju operabilnega melanoma. V tokratna Priporočila smo vključili tudi poglavji prehranskega in paliativnega tima.
Melanom je zloćudni tumor kože i sluznica, izrazito sklon ranom limfogenom i hematogenom metastaziranju. Incidencija melanoma povećava se u cijelom svijetu, stoga je melanom sve značajniji ...javnozdravstveni problem. Dermatoskopija je neinvazivna dijagnostička metoda koja omogućuje vizualizaciju morfoloških struktura melanocitnih i nemelanocitnih kožnih promjena koje nisu vidljive golim okom te tako povezuje klinički pregled i patohistološku dijagnostiku. U analizi se koristi algoritam u dva koraka kojim se u prvom koraku procjenjuje je li promjena melanocitna ili nemelanocitna na temelju nazočnosti struktura kao što su pigmentna mreža, točke i globuli, homogena pigmentacija, radijalni tračci i paralelni uzorak. Ako je promjena melanocitna, u drugom koraku određujemo radi li se o dobroćudnoj ili zloćudnoj promjeni pomoću brojnih metoda kao što su analiza uzorka, lista sedam točaka, ABCD metoda te Menziesova metoda. Kod većine melanoma, neovisno o metodi koju koristimo, dermatoskopijom uočavamo neke od specifičnih kriterija za ovaj zloćudni tumor, a to su atipična pigmentna mreža, atipične točke i globuli, plavo-bijeli veo, nepravilni tračci, atipični vaskularni uzorak, asimetrična pigmentacija i regresijske strukture. No, pojedini klinički tipovi imaju i svoja specifična obilježja. Stoga, u ovom radu prikazujemo dermatoskopska obilježja vezana uz određeni tip melanoma, što dodatno omogućuje predviđanje patohistološke dijagnoze, prognoze i ishoda bolesti. Razvojem dermatoskopije došlo je do velikog napretka u ranoj dijagnostici melanoma, koja je preduvjet uspješnog liječenja.
Melanoma is a malignant tumor of the skin and mucous membranes, highly prone to early lymphatic or hematogenous metastasis. The incidence of melanoma is increasing significantly worldwide, making melanoma a major public health problem. Dermoscopy is a non-invasive diagnostic method which enables visualization of melanocytic and non-melanocytic structures that are not visible to the naked eye, thus linking clinical examination and pathohistological diagnostics. In the analysis of pigmented skin lesions, a two-step algorithm is used to first assess whether the lesion is melanocytic or non-melanocytic, based on the presence of typical structures such as pigment network, dots and globules, homogeneous pigmentation, radial streaks, and a parallel pattern. If the lesion is melanocytic, the second step is to determine whether it is a benign or malignant lesion using a number of methods such as pattern analysis, 7-point checklist, ABCD method and the Menzies method. In most melanomas, regardless of the method we use, dermoscopy reveals some of the specific criteria for this malignant tumor, such as atypical pigment network, atypical dots and globules, blue-white veil, irregular streaks, atypical vascular pattern, asymmetric pigmentation and regression structures. However, some clinical types have their own specific characteristics. Therefore, in this paper, we present the dermatoscopic features associated with a specific type of melanoma, which further enables the prediction of pathohistological diagnosis, prognosis, and outcome of the disease. With the development of dermoscopy, great progress has been made in the early diagnosis of melanoma, which is necessary for a successful treatment.
BRCA1-associated protein 1 (BAP1) is a potent tumor suppressor gene that modulates environmental carcinogenesis
1
-
3
. All carriers of inherited heterozygous germline
BAP1
inactivating mutations (
...BAP1
+/-
)
developed one and often several
BAP1
-/-
malignancies in their lifetime
4
, mostly malignant mesothelioma (MM), uveal melanoma (UVM)
2
,
5
, etc
6
-
10
. Moreover,
BAP1
acquired biallelic mutations are frequent in human cancers
8
,
11
-
14
. BAP1 tumor suppressor activity has been attributed to its nuclear localization where BAP1 helps maintaining genome integrity
15
-
17
. The possible activity of BAP1 in the cytoplasm was unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination
18
, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. We discovered that BAP1 localizes at the endoplasmic reticulum (ER). Here BAP1 binds, deubiquitylates and stabilizes type-3 inositol-1,4,5-trisphosphate-receptor (IP3R3), modulating calcium (Ca
2+
) release from the ER into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in
BAP1
+/-
carriers caused reduction of both IP3R3 levels and Ca
2+
flux, preventing
BAP1
+/-
cells that had accumulated DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survived genotoxic stress resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in
BAP1
+/-
carriers results from the combined reduced nuclear and cytoplasmic BAP1 activities. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction.
The analysis of cell-free nucleic acids (cfNAs), which are present at significant levels in the blood of cancer patients, can reveal the mutational spectrum of a tumour without the need for invasive ...sampling of the tissue. However, this requires differentiation between the nucleic acids that originate from healthy cells and the mutated sequences shed by tumour cells. Here we report an electrochemical clamp assay that directly detects mutated sequences in patient serum. This is the first successful detection of cfNAs without the need for enzymatic amplification, a step that normally requires extensive sample processing and is prone to interference. The new chip-based assay reads out the presence of mutations within 15 minutes using a collection of oligonucleotides that sequester closely related sequences in solution, and thus allow only the mutated sequence to bind to a chip-based sensor. We demonstrate excellent levels of sensitivity and specificity and show that the clamp assay accurately detects mutated sequences in a collection of samples taken from lung cancer and melanoma patients.
T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome ...vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
Systematic characterization of the cancer microbiome provides the opportunity to develop techniques that exploit non-human, microorganism-derived molecules in the diagnosis of a major human disease. ...Following recent demonstrations that some types of cancer show substantial microbial contributions
, we re-examined whole-genome and whole-transcriptome sequencing studies in The Cancer Genome Atlas
(TCGA) of 33 types of cancer from treatment-naive patients (a total of 18,116 samples) for microbial reads, and found unique microbial signatures in tissue and blood within and between most major types of cancer. These TCGA blood signatures remained predictive when applied to patients with stage Ia-IIc cancer and cancers lacking any genomic alterations currently measured on two commercial-grade cell-free tumour DNA platforms, despite the use of very stringent decontamination analyses that discarded up to 92.3% of total sequence data. In addition, we could discriminate among samples from healthy, cancer-free individuals (n = 69) and those from patients with multiple types of cancer (prostate, lung, and melanoma; 100 samples in total) solely using plasma-derived, cell-free microbial nucleic acids. This potential microbiome-based oncology diagnostic tool warrants further exploration.
ZusammenfassungHintergrund und ZieleDie steigende Hautkrebshäufigkeit in Deutschland hat den Bedarf an sekundärpräventiven Maßnahmen erhöht. Hierfür wurde zum 01.07.2008 ein gesetzliches ...Hautkrebsscreening für Versicherte ab 35 Jahren eingeführt. Ziel dieses Arbeitspakets im Innovationsfonds‐Projekt „Perspektiven einer multimodalen Evaluation der Hautkrebsfrüherkennung“ (Pertimo) war die Erprobung einer Evaluation des Hautkrebsscreenings anhand von Sekundärdaten.Patienten und MethodikDatengrundlage waren gesetzlich Versicherte der DAK‐Gesundheit ab 35 Jahren, die zum 31.12.2010 versichert waren und bis Ende 2015 nachbeobachtet wurden. Die Raten der Teilnahme sowie der im Hautkrebsscreening entdeckten Hauttumoren (Tumordetektionen) und der Intervalltumoren, welche innerhalb von zwei Jahren nach einem befundfreien Hautkrebsscreening auftraten, wurden berechnet.ErgebnisseDie zweijährliche Hautkrebsscreening‐Inanspruchnahmerate in 2014 und 2015 lag bei Frauen bei 33,6% und bei Männern bei 32,6%. Von den Gescreenten hatten 4,2% im Zuge des Hautkrebsscreenings einen Hautkrebsbefund (Tumordetektion). Von allen inzidenten Hautkrebsdiagnosen (2012–2015) wurden 50,1% im Hautkrebsscreening entdeckt. Bei 1,5% der Versicherten mit Hautkrebsscreening ohne Befund wurde in den folgenden zwei Jahren ein inzidenter Hauttumor diagnostiziert (Intervalltumor).SchlussfolgerungenDie Daten der gesetzlichen Krankenversicherung bildeten das Hautkrebsscreening‐Geschehen in Deutschland ab und verdeutlichten die Wichtigkeit von Dermatologen im Screeningprozess. Die Analyse lieferte wichtige neue Erkenntnisse.
Zusammenfassung
Hintergrund und Ziele
Die steigende Hautkrebshäufigkeit in Deutschland hat den Bedarf an sekundärpräventiven Maßnahmen erhöht. Hierfür wurde zum 01.07.2008 ein gesetzliches ...Hautkrebsscreening für Versicherte ab 35 Jahren eingeführt. Ziel dieses Arbeitspakets im Innovationsfonds‐Projekt „Perspektiven einer multimodalen Evaluation der Hautkrebsfrüherkennung“ (Pertimo) war die Erprobung einer Evaluation des Hautkrebsscreenings anhand von Sekundärdaten.
Patienten und Methodik
Datengrundlage waren gesetzlich Versicherte der DAK‐Gesundheit ab 35 Jahren, die zum 31.12.2010 versichert waren und bis Ende 2015 nachbeobachtet wurden. Die Raten der Teilnahme sowie der im Hautkrebsscreening entdeckten Hauttumoren (Tumordetektionen) und der Intervalltumoren, welche innerhalb von zwei Jahren nach einem befundfreien Hautkrebsscreening auftraten, wurden berechnet.
Ergebnisse
Die zweijährliche Hautkrebsscreening‐Inanspruchnahmerate in 2014 und 2015 lag bei Frauen bei 33,6% und bei Männern bei 32,6%. Von den Gescreenten hatten 4,2% im Zuge des Hautkrebsscreenings einen Hautkrebsbefund (Tumordetektion). Von allen inzidenten Hautkrebsdiagnosen (2012–2015) wurden 50,1% im Hautkrebsscreening entdeckt. Bei 1,5% der Versicherten mit Hautkrebsscreening ohne Befund wurde in den folgenden zwei Jahren ein inzidenter Hauttumor diagnostiziert (Intervalltumor).
Schlussfolgerungen
Die Daten der gesetzlichen Krankenversicherung bildeten das Hautkrebsscreening‐Geschehen in Deutschland ab und verdeutlichten die Wichtigkeit von Dermatologen im Screeningprozess. Die Analyse lieferte wichtige neue Erkenntnisse.
Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with ...treatment-refractory tumours
. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4
and CD8
T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
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