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.
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.
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.
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.
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.
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They ...are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4
and CD8
T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers
and strategies to augment clinical response have largely focused on the T cell ...compartment. However, other immune subsets may also contribute to anti-tumour immunity
, although these have been less well-studied in ICB treatment
. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling
that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter
) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
PDF
