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Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/ß-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/ß-catenin pathway without evidence of matrical differentiation, as well as four combined tumors in which a similar Wnt/ß-catenin activated carcinoma component was associated with Merkel cell carcinoma or pilomatrical carcinoma. Among the pure tumor cases, 6/16 patients were female with a median age of 80 years (range: 58-98). Tumors were located on the head and neck (n=7, 44%), upper limb (n=4, 25%), trunk (n=3, 18%), and leg (n=2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in one patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%) and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but one case. Nuclear ß-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%) and RB1 (n=47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogenous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, Merkel cell carcinoma and squamous cell carcinoma) while the 3 other cases lacking such morphologic features did not. In addition, we identified four combined neoplasms in which there was a component showing a similar poorly differentiated rosette forming carcinoma demonstrating Rb loss and beta-catenin activation associated with either Merkel cell carcinoma (n=3) or pilomatrical carcinoma (n=1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/ß-catenin activated rosette-forming carcinoma", morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes.
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Introduction: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a poor prognosis, which only improved with the introduction of immunotherapies. An MCC prediction model with high diagnostic accuracy is lacking. The aim was to develop an MCC prognostic score (MCC-PS) based on combinations of previously proposed risk factors. Methods: A multicentric, retrospective study was conducted to develop MCC-PS, which included age, neuron-specific enolase (NSE), C-reactive protein (CRP), creatinine, bilirubin, and international normalized ratio (INR). Creatinine, bilirubin, and INR were used to calculate the model of end-stage liver disease (MELD) score. A total of 98 patients were included in the study, including 36.7% with stage I according to American Joint Committee on Cancer 2018 (n = 36), 30.6% with stage II (n = 30), 25.5% with stage III (n = 25), and 7.1% with stage IV (n = 7). Survival data of MCC patients were correlated with selected laboratory parameters and risk factors. Primary endpoint was MCC-specific survival (MSS) and the secondary endpoint was progression-free survival. Several statistical methods were used to develop the prognostic score, including correlation analysis, Kaplan-Meier curves, Cox regression, and time-dependent receiver operating characteristic analysis. Results: The MCC-PS is based on the sum of the following baseline variables: elevated CRP (≥5.5 mg/l), elevated NSE (≥22.8 µg/l), MELD score ≥ 11, and age ≥ 75 years. An MELD score ≥ 11 was scored as 4 points, elevated NSE level as 3 points, elevated CRP level as 2 points, and age ≥ 75 years as 1 point. A high-risk group according to the MCC-PS was characterized by a score of 4 or more points. The high-risk group was associated with a worse prognosis than the low-risk group (1-year MSS 62%, 2-year 43.1%, 5-year 17.6% as compared to 1-year MSS 79.5%, 3-year 75%, 5-year 72%). Notably, the developed MCC-PS predicts MCC outcome measures with high accuracy (3-year MSS: area under the curve (AUC) 0.934, sensitivity 87.5% and specificity 82.2%; 5-year MSS: AUC 0.93, sensitivity 89% and specificity 82%). Conclusion: MCC-PS is the first prognostic score predicting MCC outcome with a high accuracy based on five easily available laboratory parameters and patient's age. An MCC-PS of 4 or more indicates a high-risk patient associated with a poor prognosis.
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Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation, such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and the results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed additive effects of the dual inhibition of the two pathways, in accordance with the inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies.
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Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with integration of Merkel cell polyomavirus (MCPyV). MCPyV-encoded T-antigens (TAs) are pivotal for sustaining MCC's oncogenic phenotype, i.e., repression of TAs results in reactivation of the RB pathway and subsequent cell cycle arrest. However, the MCC cell line LoKe, characterized by a homozygous loss of the RB1 gene, exhibits uninterrupted cell cycle progression after shRNA-mediated TA repression. This unique feature allows an in-depth analysis of the effects of TAs beyond inhibition of the RB pathway, revealing the decrease in expression of stem cell-related genes upon panTA-knockdown. Analysis of gene regulatory networks identified members of the E2F family (E2F1, E2F8, TFDP1) as key transcriptional regulators that maintain stem cell properties in TA-expressing MCC cells. Furthermore, minichromosome maintenance (MCM) genes, which encodes DNA-binding licensing proteins essential for stem cell maintenance, were suppressed upon panTA-knockdown. The decline in stemness occurred simultaneously with neural differentiation, marked by the increased expression of neurogenesis-related genes such as neurexins, BTG2, and MYT1L. This upregulation can be attributed to heightened activity of PBX1 and BPTF, crucial regulators of neurogenesis pathways. The observations in LoKe were confirmed in an additional MCPyV-positive MCC cell line in which RB1 was silenced before panTA-knockdown. Moreover, spatially resolved transcriptomics demonstrated reduced TA expression in situ in a part of a MCC tumor characterized by neural differentiation. In summary, TAs are critical for maintaining stemness of MCC cells and suppressing neural differentiation, irrespective of their impact on the RB-signaling pathway.
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Antígenos Transformadores de Poliomavirus , Antígenos Virales de Tumores , Poliomavirus de Células de Merkel , Células Madre Neoplásicas , Proteínas de Unión a Retinoblastoma , Humanos , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismo , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/genética , Diferenciación Celular , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes , Poliomavirus de Células de Merkel/genética , Células Madre Neoplásicas/virología , Células Madre Neoplásicas/metabolismo , Neuronas/virología , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Antígenos Transformadores de Poliomavirus/genética , Antígenos Transformadores de Poliomavirus/metabolismoRESUMEN
Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Antígenos Virales de Tumores , Carcinoma de Células de Merkel , Transdiferenciación Celular , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/patología , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/metabolismo , Masculino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/metabolismo , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismo , Poliomavirus de Células de Merkel/genética , Puntos de Control del Ciclo Celular/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Anciano , Neoplasias Complejas y Mixtas/patología , Neoplasias Complejas y Mixtas/genética , Neoplasias Complejas y Mixtas/metabolismo , Neuroblastoma/patología , Neuroblastoma/genética , Neuroblastoma/metabolismoRESUMEN
BACKGROUND: To date, only a few population-representative studies have been carried out on the rare Merkel cell carcinoma (MCC). We provide incidence and survival estimates of MCC, including the conditional relative survival. METHODS: We analyzed data from the cancer registry of North Rhine-Westphalia, Germany, 2008-2021, covering a population of 18 million. We included all newly diagnosed MCCs and calculated age-standardized (old European Standard population) incidence rates and unconditional and conditional relative survival. RESULTS: Our analysis included 2164 MCC patients. The age-standardized incidence of MCC was 5.2 (men) and 3.8 (women) per million person-years. The 5-year relative survival was 58.8% (men) and 70.7% (women). Survival was lower among men than women in all age-sex groups and was highest for MCC of the upper extremity in both men (68.2%) and women (79.3%). The sex difference in survival is particularly due to the better survival of women with MCC of the head and neck. In terms of survival, the first two years are particularly critical. CONCLUSIONS: Our data validate the worse survival among men and highlights a more favorable prognosis for MCCs located on the limbs. The first two years after diagnosis of MCC are the years with the highest excess mortality.
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In patients with COVID-19, broad panels of immune checkpoint molecules (ICPMs) and the purinergic signaling have not been studied in parallel. We aimed to perform in-depth immunophenotyping of major cell subsets present in human peripheral blood of COVID-19 patients and controls using PD1, TIM3, LAG3, TIGIT, and CD200R, as well as CD39, as markers for the purinergic signaling pathway. We studied 76 COVID-19 patients and 12 healthy controls using peripheral blood mononuclear cells on flow cytometry. Univariable and multivariable statistics were performed. All ICPMs studied were significantly overexpressed on different cell subsets of COVID-19 patients when compared with healthy controls. Elevated lactate dehydrogenase; C-reactive protein; age; and high expression of CD45+, CD39+CD45+, TIM3+CD39+CD4+CD45+, and TIM3+CD39+CD8+CD3+CD4+ cells were significantly associated with severe COVID-19. On multivariable analysis, however, only high expression of CD39+CD45+ (OR 51.4, 95% CI 1.5 to 1763) and TIM3+CD39+CD4+CD3+CD45+ (OR 22.6, 95% CI 1.8 to 277) cells was an independent predictor for severe COVID-19. In conclusion, numerous ICPMs are overexpressed in COVID-19 patients when compared with healthy controls, suggesting a pathophysiological role of these molecules in SARS-CoV-2 infection. However, only TIM3 in co-expression with CD39 remained as a significant independent prognostic ICPM on multivariable analysis. The flow cytometric evaluation of TIM3+CD39+CD4+CD3+CD45+, as well as CD39+CD45+, is a powerful tool for the prognostication of COVID-19 patients on hospital admission.
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Apirasa , COVID-19 , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos CD/sangre , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/mortalidad , Citometría de Flujo , Proteínas de Punto de Control Inmunitario/genética , Proteínas de Punto de Control Inmunitario/metabolismo , Inmunofenotipificación , Leucocitos Mononucleares/inmunología , Pronóstico , Estudios Prospectivos , SARS-CoV-2/inmunología , Índice de Severidad de la EnfermedadRESUMEN
Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition in MCC, the importance of immunotherapy and vaccines in MCC has increased in recent years. In this article, we aim to present the current progress and perspectives in the development of vaccines for this disease. Here, we summarize and discuss the current literature and ongoing clinical trials investigating vaccines against MCC. We identified 10 articles through a PubMed search investigating a vaccine against MCC. From the international clinical trial database Clinical.Trials.gov, we identified nine studies on vaccines for the management of MCC, of which seven are actively recruiting. Most of the identified studies investigating a vaccine against MCC are preclinical or phase 1/2 trials. The vaccine principles mainly included DNA- and (synthetic) peptide-based vaccines, but RNA-based vaccines, oncolytic viruses, and the combination of vaccines and immunotherapy are also under investigation for the treatment of MCC. Although the management of MCC is changing, when compared to times before the approval of immune checkpoint inhibitors, it will still take some time before the first MCC vaccine is ready for approval.
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AIMS: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. METHODS AND RESULTS: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. CONCLUSION: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.
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5-Metilcitosina , Recurrencia Local de Neoplasia , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Recurrencia Local de Neoplasia/prevención & control , Femenino , Masculino , Anciano , Persona de Mediana Edad , Histiocitoma Fibroso Benigno/patología , Histiocitoma Fibroso Benigno/diagnóstico , Anciano de 80 o más Años , Sarcoma/patologíaRESUMEN
Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.
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Carcinoma de Células de Merkel , Inhibidores de Puntos de Control Inmunológico , Neoplasias Cutáneas , Carcinoma de Células de Merkel/terapia , Carcinoma de Células de Merkel/epidemiología , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/diagnóstico , Humanos , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Poliomavirus de Células de Merkel/inmunologíaRESUMEN
OBJECTIVES: Bitewing radiography is considered to be of high diagnostic value in caries detection, but owing to projections, lesions may remain undetected. The novel bitewing plus (BW +) technology enables scrolling through radiographs in different directions and angles. The present study aimed at comparing BW + with other 2D and 3D imaging methods in terms of sensitivity, specificity, and user reliability. MATERIALS AND METHODS: Five human cadavers were used in this study. In three cadavers, natural teeth were transplanted post-mortem. BW + , two-dimensional (digital sensors, imaging plates, 2D and 3D bitewing radiographs) and 3D methods (high and low dose CBCT) were taken. Carious lesions were evaluated on 96 teeth at three positions (mesial, distal, and occlusal) and scored according to their level of demineralization by ten observers, resulting in 35,799 possible lesions across all observers and settings. For reference, µCT scans of all teeth were performed. RESULTS: Overall, radiographic evaluations showed a high rate of false-negative diagnoses, with around 70% of lesions remaining undetected, especially enamel lesions. BW + showed the highest sensitivity for dentinal caries and had comparatively high specificity overall. CONCLUSIONS: Within the limits of the study, BW + showed great potential for added diagnostic value, especially for dentinal caries. However, the tradeoff of diagnostic benefit and radiation exposure must be considered according to each patient's age and risk.
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Cadáver , Caries Dental , Radiografía de Mordida Lateral , Sensibilidad y Especificidad , Humanos , Caries Dental/diagnóstico por imagen , Imagenología Tridimensional , Reproducibilidad de los Resultados , Tomografía Computarizada de Haz CónicoRESUMEN
Sebaceous gland carcinomas are rare malignant cutaneous adnexal tumors with sebocytic differentiation. The typical predilection area is the head and neck region, where sebaceous gland carcinomas are the most common malignant adnexal tumors of the skin. According to their localization a distinction is made between periocular and extraocular sebaceous gland carcinomas. Muir-Torre syndrome (MTS) should always be ruled out if it is suspected. In terms of prognosis, sebaceous gland carcinomas are potentially aggressive tumors with a clear tendency to recur and metastasize. Only small extraocular sebaceous gland carcinomas that have been completely resected have a very good prognosis. Sebaceous gland carcinomas most frequently metastasize lymphogenously to regional or distant lymph nodes; organ metastasis occurs less frequently. Periocular sebaceous gland carcinomas have a higher metastasis rate (up to 15%) than extraocular sebaceous gland carcinomas (up to 2%). Complete micrographically controlled surgery (MCS) of the primary tumor is the therapy of first choice, regardless of periocular or extraocular localization. Adjuvant or therapeutic radiotherapy may be considered. There is currently no established standard therapy for advanced, inoperable, or metastatic sebaceous gland carcinomas. Local procedures and systemic therapies such as chemotherapy or immunotherapy can be considered. The procedure should be determined individually by an interdisciplinary tumor board. Close follow-up care is recommended for these potentially aggressive carcinomas.
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Neoplasias de las Glándulas Sebáceas , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias de las Glándulas Sebáceas/terapia , Neoplasias de las Glándulas Sebáceas/diagnóstico , Humanos , Síndrome de Muir-Torre/patología , Síndrome de Muir-Torre/diagnóstico , Síndrome de Muir-Torre/terapia , Pronóstico , Adenocarcinoma Sebáceo/patología , Adenocarcinoma Sebáceo/terapia , Adenocarcinoma Sebáceo/diagnóstico , Dermatología/normas , Alemania , Cirugía de Mohs , Guías de Práctica Clínica como AsuntoRESUMEN
Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.
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Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Antígenos Virales de Tumores , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/genética , Receptor de Muerte Celular Programada 1/genética , Linfocitos T CD8-positivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genéticaRESUMEN
BACKGROUND: Recent evidence suggests additional immunomodulatory properties of RANKL inhibition possibly boosting the clinical efficacy of immune checkpoint inhibitors (ICI). METHODS: We conducted a prospective, multicentre clinical trial in unresectable stage IV melanoma patients with bone metastases who received denosumab in parallel with dual ICI (BONEMET) and performed comprehensive immune monitoring at baseline and 4, 12, and 24 weeks after initiation of therapy. Secondary endpoints included tolerability and efficacy. For comparison, biospecimens from melanoma patients treated with dual ICI without denosumab were analyzed accordingly and served as retrospective reference cohort. RESULTS: In both the BONEMET (n = 16) and the reference cohort (n = 18) serum levels of 17 cytokines, including IFNγ were significantly increased after 4 weeks of treatment. Patients who received ICI and denosumab showed a significantly higher increase in serum CXCL-13 and a significant decrease in VEGFc compared with the reference cohort. While no changes in T cell composition were observed at 4 weeks, patients in the BONEMET cohort showed a significant decrease in the peripheral naïve T-cell population and an increase in CD8+ effector cells after 12 weeks. Treatment-related adverse events occurred with comparable frequency (93.8% in the BONEMET cohort versus 83.3% in the reference cohort). 7/16 patients in the BONEMET cohort and 8/18 patients in the reference cohort achieved disease control. CONCLUSION: Denosumab in combination with dual ICI modulates cytokine expression and T-cell composition in peripheral blood. The upregulation of CXCL-13, a key factor for initiating tertiary lymphoid structures, strengthens the hypothesis that denosumab indeed boost immunological effects.
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Neoplasias Óseas , Melanoma , Humanos , Denosumab/efectos adversos , Melanoma/tratamiento farmacológico , Estudios Retrospectivos , Estudios Prospectivos , Neoplasias Óseas/secundarioRESUMEN
Intratumoural as well as systemic inflammation in melanoma has thoroughly been studied in the context of patients treated with immune checkpoint inhibitors but not with BRAF/MEK inhibitors (BRAFi/MEKi). We aimed to study whether parameters of intratumoral and systemic inflammation correlate with clinical outcome in patients with BRAF-mutant metastatic melanoma treated with BRAFi/MEKi. We studied 51 CM patients with unresectable stage III or IV who had the indication for BRAFi/MEKi treatment based on confirmed BRAF mutation. Baseline systemic immune-inflammation markers such as the systemic immune-inflammation index (SII) and the expression of intratumoral inflammation markers such as COX-2 protein expression were correlated with clinical outcome measures. On multivariable analyses, lower intratumoral COX-2 expression (OR 33.9, 95% CI 3.2-356.8) and lower SII (OR 6.3, 95% CI 1.1-34.8) proved to be significant independent predictors for objective response to targeted therapy. Elevated S100B (HR 1.2, 95% CI 1.03-1.3) was a significant predictor for progressive disease. Moreover, elevated S100B (HR 1.37, 95% CI 1.14-1.65) and LDH (HR 1.002, 95% CI 1.0001-1.003) were significant independent predictors for melanoma-specific death. In conclusion, the present study indicates that low SII values and low intratumoral COX-2 protein expression are significant independent predictors for treatment response to BRAFi/MEKi.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ciclooxigenasa 2 , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamenteAsunto(s)
Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Nivolumab/uso terapéutico , Ipilimumab/efectos adversos , Receptor de Muerte Celular Programada 1 , Carcinoma de Células de Merkel/tratamiento farmacológico , Antígeno B7-H1 , Neoplasias Cutáneas/tratamiento farmacológico , Inmunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE/OBJECTIVES: Due to the coronavirus disease 2019 (COVID-19) pandemic, undergraduate education shifted towards online-only formats from April 2020 until July 2021. Previous research indicated a negative effect on students' competence development, and it remains unclear whether blended learning concepts could provide compensation. Therefore, the present study aimed to compare pre- to post-pandemic students' performance in standardized baseline (BL) and final exams (FE), as well as the associated knowledge gain (KG) in three consecutive undergraduate blended learning-based oral radiology courses (C1-3). METHODS: Ninety-four students participated during two pre-pandemic semesters (October 17-July 18), and ninety-eight students during two post-pandemic semesters (October 21-July 22). Before the pandemic, conventional face-to-face lectures were combined with an oral radiology platform. Two years into the COVID-19 pandemic, additional video-based e-learning modules were adopted from the pandemic online-only curriculum. In each semester, skills and KG were assessed by conducting standardized BL and FE. Students' performance in BL, FE, and the associated KG during pre-pandemic semesters was compared to post-pandemic semesters. RESULTS: In post-pandemic courses, students showed significantly lower BL scores, whereas KG was significantly higher in post- compared to pre-pandemic semesters (27.42% vs. 10.64%, p < 0.001, respectively). FE scores in C1 significantly improved from pre- to post-pandemic semesters. CONCLUSIONS: Within the limitations of our study, the lower BL scores confirmed the negative effect of the pandemic on competence development. Blended learning concepts seem to compensate for this effect and enable students to return to pre-pandemic levels. Future studies are needed to assess the additional impact of video-based e-learning modules.
Asunto(s)
COVID-19 , Radiología , Humanos , COVID-19/epidemiología , Curriculum , Aprendizaje , Pandemias , Radiología/educaciónRESUMEN
INTRODUCTION: Blended learning seems to be an effective teaching concept in oral radiology. During the COVID-19 pandemic, blended learning shifted towards online-only learning. The aim of the present study was to compare the effectiveness of pandemic online-only and pre-pandemic blended learning in three consecutive oral radiology courses (C1, C2 and C3) and to examine whether additional video-based e-learning modules (VBLMs) had a positive impact on undergraduate students' performance during pandemic semesters. MATERIALS AND METHODS: Data from 205 undergraduate dental students participating either in a blended learning or an online-only learning concept were analysed. Pre-pandemic blended learning comprised face-to-face seminars and access to an oral radiology platform (ORP). Pandemic online-only learning comprised online seminars, access to the ORP and additional VBLMs (two VBLMs for C1, four VBLMs for C2 and six VBLMs for C3). Through standardised e-exams at the beginning and end of each semester, performance in final exams and knowledge gain were compared between the two groups. RESULTS: No significant differences in scores in final exams (p = .11) and knowledge gain (p = .18) were found when comparing the pre-pandemic and pandemic groups. On course level, however, students receiving a lower number of VBLMs performed significantly worse in final exams (C1: p < .01, C2: p = .02) and showed inferior knowledge gain (C2: p < .01) during the pandemic. CONCLUSIONS: Within the limitations of the study, the present investigation confirmed that pandemic online-only learning involving VBLMs might be as effective as pre-pandemic blended learning.