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BACKGROUND: Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). METHODS: In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). FINDINGS: Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. FUNDING: Bristol Myers Squibb.
Assuntos
Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Masculino , Idoso , Feminino , Nivolumabe , Intervalo Livre de Doença , Ipilimumab , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia , Adjuvantes Imunológicos/uso terapêutico , Imunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Recently, molecular tumour boards (MTBs) have been integrated into the clinical routine. Since their benefit remains debated, we assessed MTB outcomes in the Comprehensive Cancer Center Ostbayern (CCCO) from 2019 to 2021. METHODS AND RESULTS: In total, 251 patients were included. Targeted sequencing was performed with PCR MSI-evaluation and immunohistochemistry for PD-L1, Her2, and mismatch repair enzymes. 125 treatment recommendations were given (49.8%). High-recommendation rates were achieved for intrahepatic cholangiocarcinoma (20/30, 66.7%) and gastric adenocarcinoma (10/16, 62.5%) as opposed to colorectal cancer (9/36, 25.0%) and pancreatic cancer (3/18, 16.7%). MTB therapies were administered in 47 (18.7%) patients, while 53 (21.1%) received alternative treatment regimens. Thus 37.6% of recommended MTB therapies were implemented (47/125 recommendations). The clinical benefit rate (complete + partial + mixed response + stable disease) was 50.0% for MTB and 63.8% for alternative treatments. PFS2/1 ratios were 34.6% and 16.1%, respectively. Significantly improved PFS could be achieved for m1A-tier-evidence-based MTB therapies (median 6.30 months) compared to alternative treatments (median 2.83 months; P = 0.0278). CONCLUSION: The CCCO MTB yielded a considerable recommendation rate, particularly in cholangiocarcinoma patients. The discrepancy between the low-recommendation rates in colorectal and pancreatic cancer suggests the necessity of a weighted prioritisation of entities. High-tier recommendations should be implemented predominantly.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Pancreáticas , Humanos , Ductos Biliares Intra-Hepáticos , Neoplasias PancreáticasRESUMO
The molecular pathomechanisms of major depressive disorder (MDD) are still not completely understood. Here, we follow the hypothesis, that mitochondria dysfunction which is inevitably associated with bioenergetic disbalance is a risk factor that contributes to the susceptibility of an individual to develop MDD. Thus, we investigated molecular mechanisms related to mitochondrial function in induced neuronal progenitor cells (NPCs) which were reprogrammed from fibroblasts of eight MDD patients and eight non-depressed controls. We found significantly lower maximal respiration rates, altered cytosolic basal calcium levels, and smaller soma size in NPCs derived from MDD patients. These findings are partially consistent with our earlier observations in MDD patient-derived fibroblasts. Furthermore, we differentiated MDD and control NPCs into iPS-neurons and analyzed their passive biophysical and active electrophysiological properties to investigate whether neuronal function can be related to altered mitochondrial activity and bioenergetics. Interestingly, MDD patient-derived iPS-neurons showed significantly lower membrane capacitance, a less hyperpolarized membrane potential, increased Na+ current density and increased spontaneous electrical activity. Our findings indicate that functional differences evident in fibroblasts derived from MDD patients are partially present after reprogramming to induced-NPCs, could relate to altered function of iPS-neurons and thus might be associated with the aetiology of major depressive disorder.
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Purpose: To analyze whether activation of endogenous wingless (Wnt)/ß-catenin signaling in Müller cells is involved in protection of retinal ganglion cells (RGCs) following excitotoxic damage. Methods: Transgenic mice with a tamoxifen-dependent ß-catenin deficiency in Müller cells were injected with N-methyl-D-aspartate (NMDA) into the vitreous cavity of one eye to induce excitotoxic damage of the RGCs, while the contralateral eye received PBS only. Retinal damage was quantified by counting the total number of RGC axons in cross sections of optic nerves and measuring the thickness of the retinal layers on meridional sections. Then, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was performed to identify apoptotic cells in retinas of both genotypes. Western blot analyses to assess the level of retinal ß-catenin and real-time RT-PCR to quantify the retinal expression of neuroprotective factors were performed. Results: Following NMDA injection of wild-type mice, a statistically significant increase in retinal ß-catenin protein levels was observed compared to PBS-injected controls, an effect that was blocked in mice with a Müller cell-specific ß-catenin deficiency. Furthermore, in mice with a ß-catenin deficiency in Müller cells, NMDA injection led to a statistically significant decrease in RGC axons as well as a substantial increase in TUNEL-positive cells in the RGC layer compared to the NMDA-treated controls. Moreover, in the retinas of the control mice a NMDA-mediated statistically significant induction of leukemia inhibitory factor (Lif) mRNA was detected, an effect that was substantially reduced in mice with a ß-catenin deficiency in Müller cells. Conclusions: Endogenous Wnt/ß-catenin signaling in Müller cells protects RGCs against excitotoxic damage, an effect that is most likely mediated via the induction of neuroprotective factors, such as Lif.
Assuntos
Células Ependimogliais/metabolismo , Nervo Óptico/metabolismo , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Tamoxifeno/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Axônios/efeitos dos fármacos , Axônios/metabolismo , Células Ependimogliais/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Fator Inibidor de Leucemia/metabolismo , Camundongos , Camundongos Transgênicos , N-Metilaspartato/toxicidade , Nervo Óptico/efeitos dos fármacos , Retina/efeitos dos fármacos , Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Via de Sinalização Wnt/genética , beta Catenina/deficiênciaAssuntos
Inteligência Artificial , Dermatologistas , Preferência do Paciente , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/diagnóstico , Estudos Prospectivos , Dermatologistas/estatística & dados numéricos , Dermatologistas/psicologia , Feminino , Masculino , Preferência do Paciente/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto , Idoso , Inquéritos e Questionários/estatística & dados numéricos , Dermatologia/métodosAssuntos
Antifúngicos , Toxidermias , Itraconazol , Humanos , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Antifúngicos/efeitos adversos , Toxidermias/etiologia , Toxidermias/patologia , Toxidermias/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Exantema/induzido quimicamenteAssuntos
Antifúngicos , Toxidermias , Itraconazol , Humanos , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Antifúngicos/efeitos adversos , Toxidermias/etiologia , Toxidermias/patologia , Toxidermias/diagnóstico , Exantema/induzido quimicamente , Exantema/patologia , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
Ultraviolet (UV) radiation has a plethora of effects on human tissues. In the UV spectrum, wavelengths above 320 nm fall into the UVA range, and for these, it has been shown that they induce reactive oxygen species (ROS), DNA mutations and are capable to induce melanoma in mice. In addition to this, it was recently shown that UVA irradiation and UVA-induced ROS also increase glucose metabolism of melanoma cells. UVA irradiation causes a persistent increase in glucose consumption, accompanied by increased glycolysis, increased lactic acid production and activation of the pentose phosphate pathway. Furthermore, it was shown that the enhanced secretion of lactic acid is important for invasion of melanoma in vitro. The current knowledge of this link between UVA, metabolism and melanoma, possible mechanisms of UVA-induced glucose metabolism and their starting points are discussed in this review with focus on ROS- and UVA-induced cellular stress signalling, DNA damage signalling and DNA repair systems. When looking at the benefits of UVA-induced glucose metabolism, it becomes apparent that there are more advantages of these metabolic changes than one would expect. Besides the role of lactic acid as initiator of protease expression and invasion, its role for immune escape of melanoma cells and the pentose phosphate pathway-derived nicotinamide adenine dinucleotide phosphate (NADPH) as part of a ROS detoxification strategy are discussed.
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Glucose/metabolismo , Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Glicólise/efeitos da radiação , Humanos , Ácido Láctico/metabolismo , Melanoma/imunologia , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADP/metabolismo , Invasividade Neoplásica , Via de Pentose Fosfato , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Pirúvico/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Evasão TumoralAssuntos
Pestanas , Melanoma , Pestanas/patologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologiaAssuntos
Antineoplásicos Imunológicos/administração & dosagem , Produtos Biológicos/administração & dosagem , Imunoterapia/métodos , Neoplasias do Seio Maxilar/tratamento farmacológico , Melanoma/tratamento farmacológico , Terapia Combinada , Feminino , Herpesvirus Humano 1 , Humanos , Injeções Intralesionais , Pessoa de Meia-Idade , Mucosa NasalRESUMO
(1) Background: Rare skin cancers include epithelial, neuroendocrine, and hematopoietic neoplasias as well as cutaneous sarcomas. Ultraviolet (UV) radiation and sunburns are important drivers for the incidence of certain cutaneous sarcomas; however, the pathogenetic role of UV light is less clear in rare skin cancers compared to keratinocyte cancer and melanoma. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure among selected rare skin cancers (atypical fibroxanthoma [AFX], pleomorphic dermal sarcoma [PDS], dermatofibrosarcoma protuberans [DFSP], Kaposi sarcoma [KS], Merkel cell carcinoma [MCC], and leiomyosarcoma [LMS]) while taking into account relevant clinical variables (age, sex, and body site). (2) Methods: We newly established a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 210 rare skin cancers from 210 patients with their clinical variables. (3) Results: TEG values were correlated with age and whether tumors arose on UV-exposed body sites. TEG values were significantly higher in AFX and PDS cases compared to all other analyzed rare skin cancer types. As expected, TEG values were low in DFSP and KS, while MCC cases exhibited intermediate TEG values. (4) Conclusions: High cumulative UV exposure is more strongly associated with AFX/PDS and MCC than with other rare skin cancers. These important results expand the available data associated with rare skin cancers while also offering insight into the value of differentiating among these tumor types based on their relationship with sun exposure, potentially informing preventative, diagnostic and/or therapeutic approaches.
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BACKGROUND: In melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients' survival. METHODS: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004-2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. RESULTS: We identified 1143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n = 71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p = 0.915 and HR=1.295, p = 0.479, respectively), RFS (HR=1.050, p = 0.849 and HR=1.220, p = 0.544, respectively), and cumulative recurrence rate (HR=1.234, p = 0.441 and HR=1.220, p = 0.544), respectively). CONCLUSION: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.
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Excisão de Linfonodo , Melanoma , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Melanoma/cirurgia , Melanoma/patologia , Melanoma/mortalidade , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Feminino , Masculino , Estudos Retrospectivos , Excisão de Linfonodo/métodos , Pessoa de Meia-Idade , Idoso , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Melanoma Maligno Cutâneo , Adulto , Recidiva Local de Neoplasia/patologia , Metástase LinfáticaRESUMO
We have recently shown that cancer cells of various origins take up extracellular citrate through the plasma membrane citrate carrier (pmCiC), a specific plasma membrane citrate transporter. Extracellular citrate is required to support cancer cell metabolism, in particular fatty acid synthesis, mitochondrial activity, protein synthesis and histone acetylation. In addition, cancer cells tend to acquire a metastatic phenotype in the presence of extracellular citrate. Our recent study also showed that cancer-associated stromal cells synthesise and release citrate and that this process is controlled by cancer cells. In the present study, we evaluated the expression of pmCiC, fibroblast activation protein-α (FAP) and the angiogenesis marker cluster of differentiation 31 (CD31) in human cancer tissues of different origins. In the cohort studied, we found no correlation between disease stage and the expression of FAP or CD31. However, we have identified a clear correlation between pmCiC expression in cancer cells and cancer-associated stroma with tumour stage. It can be concluded that pmCiC is increased in cancer cells and in cancer-supporting cells in the tumour microenvironment at the later stages of cancer development, particularly at the metastatic sites. Therefore, pmCiC expression has the potential to serve as a prognostic marker, although further studies are needed.