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Nature-based Solutions (NbS) are actions that harness nature to help address major societal challenges. The assessment frameworks for NbS proposed in the literature differ in scope and intended use. In 2020, the International Union for Conservation of Nature (IUCN) introduced their Global Standard for NbS as a framework that can be used by anyone working on different types of NbS. Since research on the applicability of the IUCN Standard remains limited, the aim of this paper is to analyse whether the IUCN Standard may be used as an overarching assessment framework for NbS in river flood management applications and to identify the main differences in content with other NbS-frameworks. This was achieved through a comparison with 29 assessment frameworks for NbS, that are applicable to physical interventions for riverine flood risk reduction. The comparisons showed that the IUCN Standard has the largest breadth in scope of application and may therefore be used as an overarching framework. In addition, we identified a distinction between frameworks for the assessment of project processes (process-oriented) and project results (results-oriented), where the IUCN Standard can be characterized as process-oriented. This implies that the IUCN Standard may be used to assess the processes (e.g. stakeholder engagement and adaptive management) of planned, ongoing or completed NbS projects for a wide variety of environmental contexts and societal challenges. This will help persuade policy makers to consider NbS as one of the solutions in flood management issues, next to or in combination with e.g. engineering solutions or changing land use. We also identified that, while the IUCN Standard is straightforward to use and incorporates stakeholder input, the environmental context specificity as well as guidance depth on resources for assessment can be improved.
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AIM: Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice. METHODS: This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months. RESULTS: Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9-21.3) in the overall population, 15.9 months (95 % CI, 8.6-28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7-19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %-60.8 %) and 40.5 % (95 % CI, 33.2 %-47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7-7.5) and the objective response rate was 55.3 % (95 % CI, 45.3-65.4), including complete response in 31.9 %. CONCLUSIONS: Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células de Merkel , Bases de Datos Factuales , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Anciano , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/patología , Francia , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Anciano de 80 o más Años , Persona de Mediana Edad , Antineoplásicos Inmunológicos/uso terapéutico , Resultado del Tratamiento , AdultoRESUMEN
AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Poroma , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Carcinoma de Células de Merkel/metabolismo , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/complicaciones , Neoplasias Cutáneas/patología , GenómicaAsunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/cirugía , Carcinoma de Células de Merkel/patología , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Antineoplásicos Inmunológicos/uso terapéutico , Adyuvantes Inmunológicos/uso terapéuticoRESUMEN
Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/patología , Histonas/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Neoplasias Cutáneas/patología , Poliomavirus de Células de Merkel/genética , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismoRESUMEN
To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan−Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1−2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1−38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4−26.6] and 37.0 months [24.6−NA], respectively, in radiated patients, and 2.2 [1.5−2.6] and 4.3 months [2.6−7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6−25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.
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Antineoplásicos Inmunológicos , Carcinoma de Células de Merkel , Ipilimumab , Neoplasias Renales , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.
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Carcinoma de Células de Merkel , Infecciones por VIH , Neoplasias Cutáneas , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/patología , Carcinoma de Células de Merkel/terapia , Consenso , Infecciones por VIH/complicaciones , Humanos , Masculino , Estadificación de Neoplasias , Biopsia del Ganglio Linfático Centinela/efectos adversos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/terapiaRESUMEN
MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR + = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/patología , Humanos , Poliomavirus de Células de Merkel/metabolismo , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/metabolismo , Proteínas de Unión a Retinoblastoma , Factores de Transcripción SOXB1/metabolismo , Neoplasias Cutáneas/patología , Infecciones Tumorales por Virus/complicaciones , Ubiquitina-Proteína LigasasRESUMEN
Although virus-negative Merkel cell carcinoma (MCC) is characterized by a high frequency of UV-induced mutations, the expression of two viral oncoproteins is regarded as a key mechanism driving Merkel cell polyomavirusâpositive MCC. The cells in which these molecular events initiate MCC oncogenesis have yet not been identified for both MCC subsets. A considerable proportion of virus-negative MCC is found in association with squamous cell carcinoma (SCC), suggesting (i) coincidental collision, (ii) one providing a niche for the other, or (iii) one evolving from the other. Whole-exome sequencing of four combined tumors consisting of SCC in situ and Merkel cell polyomavirusânegative MCC showed many mutations shared between SCC and MCC in all cases, indicating a common ancestry and thereby a keratinocytic origin of these MCCs. Moreover, analyses of the combined cases as well as of pure SCC and MCC suggest that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.
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Carcinoma in Situ , Carcinoma de Células de Merkel , Carcinoma de Células Escamosas , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Humanos , Poliomavirus de Células de Merkel/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Despite its low efficacy, chemotherapy with dacarbazine remains an option in metastatic melanoma patients after failure of immune checkpoint inhibitors (ICI) ± targeted therapy. Some observations suggested an increased efficacy of chemotherapy in melanoma or lung cancer patients previously treated with ICI; we aimed to evaluate the efficacy of dacarbazine in a controlled-group study of patients pre-treated or not with ICI. METHODS: We retrospectively collected data from all consecutive patients treated with dacarbazine for advanced cutaneous melanoma without brain metastasis, in our skin cancer centre between June 2006 and September 2019. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rates (ORR), overall survival (OS) and safety of dacarbazine. RESULTS: Among 72 patients, 17 (23.6%) received dacarbazine after ICI and 55 (76.3%) without prior ICI. Despite less favourable prognostic factors in patients ICI-pre-treated, median PFS was 4.27 months (range 0.89-43.69) in this group versus 2.04 months (range 1.25-39.25) P = 0.03 in non-ICI-pre-treated patients; ORR were 35.3% and 12.7%, respectively. The median OS and the occurrence of adverse events were similar in both groups. CONCLUSION: Dacarbazine seems to offer a short-lived benefit in patients with progressive advanced disease despite ICI (±targeted therapy), and could be an alternative before considering best supportive care.
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Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.
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BACKGROUND: Wide local excision constitutes the standard of care for Merkel cell carcinoma, but the optimal margin width remains controversial. OBJECTIVES: To assess whether narrow margins (0.5-1 cm) were associated with outcome. METHODS: Patients were recruited from a retrospective French multicentric cohort and included if they had had excision of primary tumor with minimum lateral margins of 0.5 cm. Factors associated with mortality and recurrence were assessed by multivariate regression. RESULTS: Among the 214 patients included, 58 (27.1%) had undergone excision with narrow margins (0.5-1 cm) versus 156 (72.9%) with wide margins (>1 cm). During a median follow-up of 50.7 months, cancer-specific survival did not differ between groups (5-year specific survival rate 76.8% [95% confidence interval 61.7%-91.9%] and 76.2% [95% confidence interval 68.8%-83.6%], respectively). Overall survival, any recurrence-free survival, and local recurrence-free survival did not significantly differ between groups. Cancer-specific mortality was associated with age, male sex, American Joint Committee on Cancer stage III, and presence of positive margins. LIMITATIONS: Retrospective design, heterogenous baseline characteristics between groups. CONCLUSION: Excision with narrow margins was not associated with outcome in this cohort, in which most patients had clear margins and postoperative radiation therapy. Residual tumor, mostly found on deep surgical margins, was independently associated with prognosis.
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Carcinoma de Células de Merkel/patología , Márgenes de Escisión , Recurrencia Local de Neoplasia/patología , Neoplasias Cutáneas/patología , Anciano , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/cirugía , Estudios de Cohortes , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Neoplasia Residual , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/radioterapia , Neoplasias Cutáneas/cirugía , Análisis de SupervivenciaRESUMEN
Importance: Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives: To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures: Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures: The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy. Results: Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance: The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.
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Neoplasias Encefálicas/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Estimación de Kaplan-Meier , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/inmunología , Recurrencia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patologíaRESUMEN
Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3-5 sessions, 20-26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.
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Quimioradioterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Estudios Prospectivos , Hipofraccionamiento de la Dosis de Radiación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patologíaRESUMEN
PURPOSE: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. PATIENTS AND METHODS: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. RESULTS: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.
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Carcinoma de Células de Merkel/tratamiento farmacológico , Electroporación/métodos , Técnicas de Transferencia de Gen , Inmunoterapia/métodos , Interleucina-12/administración & dosificación , Plásmidos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Estudios de Cohortes , Femenino , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Seguridad del Paciente , Proyectos Piloto , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (nâ¯=â¯3) and tumor antigens (nâ¯=â¯47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting.
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Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Neoplasias Cutáneas/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/inmunología , Humanos , Masculino , Proteínas de Neoplasias/inmunologíaRESUMEN
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer. Treatment options for inoperable advanced cSCC cases are limited. The efficacy of anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAb) has been reported recently in some patients with cSCC. OBJECTIVES: To evaluate the efficacy of anti-PD-1 mAb in a case series of inoperable advanced cSCC and to analyse the efficacy of concurrent radiotherapy. MATERIALS AND METHODS: We retrospectively analysed the files of all patients with advanced inoperable cSCC treated with anti-PD-1 mAb and concurrent radiotherapy outside clinical trials in our skin cancer centre before December 31, 2017. RESULTS: A total of four patients with locally or regionally advanced cSCC were identified. All patients received pembrolizumab at 2 mg/kg every three weeks and concurrent radiotherapy. Two patients who received pembrolizumab as first-line therapy with concurrent radiotherapy (one with skull and leptomeningeal invasion and one with rapidly progressing regional cSCC) had a complete response, allowing treatment discontinuation, without recurrence after a median of 11 months off treatment. All other patients experienced progressive disease. The median progression-free survival and overall survival were 14.4 and 15.6 months, respectively. No toxicity was observed. CONCLUSION: There appears to be a place for pembrolizumab as first-line treatment for unresectable or advanced cSCC. Further studies are needed to evaluate concomitant radiotherapy with anti-PD1 antibodies.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/radioterapia , Fraccionamiento de la Dosis de Radiación , Humanos , Inmunoterapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios RetrospectivosRESUMEN
PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. EXPERIMENTAL DESIGN: Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375-specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. RESULTS: miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P < 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P = 0.037) but not in tumor-free (P = 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC = 0.954 and 0.800) as well as in the prospective cohorts (AUC = 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions. CONCLUSIONS: Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.