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BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744 to 26,248 in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.
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Esquema de Medicação , Neoplasias , Nivolumabe , Humanos , Nivolumabe/administração & dosagem , Nivolumabe/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Simulação por Computador , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacocinética , Adulto , Idoso de 80 Anos ou mais , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacocinética , Modelos BiológicosRESUMO
BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.
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BACKGROUND: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported. MATERIALS AND METHODS: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. RESULTS: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations. CONCLUSIONS: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.
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BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.
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Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Célula de Merkel/patologia , Ensaios de Uso Compassivo , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
PURPOSE: BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) significantly improved metastatic melanoma prognosis. Ocular adverse effects (OAEs) represent an uncommon but disabling toxicity of these drugs. We aimed to characterize the ocular safety profile of BRAFi or MEKi and to detect possible safety signals. METHODS: We performed a retrospective, observational, pharmacovigilance study using VigiBase, the World Health Organization global safety database. Ocular adverse effects were classified according to the eye segments and the inflammatory pattern based on the Standardization of Uveitis Nomenclature. Associations among BRAFi monotherapy, MEKi monotherapy, and BRAFi+MEKi combination therapy and OAE reporting were assessed using disproportionality analysis. Results were expressed with the reporting odds ratio (ROR) and its 95% confidence interval (CI). RESULTS: From January 2010 to October 2019, 1568 OAE cases were reported with BRAFi or MEKi. Among them, 1006 cases with sufficient data were included, corresponding to 310 (30.8%), 124 (12.3%), and 572 (56.9%) cases reported with BRAFi, MEKi, or BRAFi+MEKi combination therapy, respectively. BRAF inhibitor monotherapy was significantly associated with the reporting of iris and ciliary body abnormalities (ROR, 8.7; 95% CI, 6.0-12.5), diffuse abnormalities (ROR, 7.1; 95% CI, 5.4-9.4), anterior uveitis (ROR, 8.6; 95% CI, 6.0-12.1), and panuveitis (ROR, 7.1; 95% CI, 5.4-9.4). MEK inhibitor monotherapy was associated with the reporting of retinal and choroid abnormalities (ROR, 9.5; 95% CI, 7.4-12.2), diffuse abnormalities (ROR, 2.5; 95% CI, 1.1-6.1), and panuveitis (ROR, 2.5; 95% CI, 1.1-6.1). Combinations of BRAFi and MEKi therapies were associated with OAEs from both drugs, with a possible synergistic or additive effect for diffuse abnormalities and panuveitis. CONCLUSIONS: Our study characterizes the ocular safety profile of BRAFi and MEKi. We identify possible safety signals for several OAEs not previously reported with BRAFi and MEKi. Our data provide the rationale for a personalized management of OAE in patients with BRAFi+MEKi combination therapy according to the type of ocular reaction.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Oftalmopatias/induzido quimicamente , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Farmacovigilância , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Idoso , Bases de Dados Factuais , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Oftalmopatias/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Organização Mundial da SaúdeRESUMO
BACKGROUND: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. METHODS: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. RESULTS: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2). CONCLUSIONS: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.
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Inflamação/genética , Inflamação/terapia , Neoplasias/genética , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos de Coortes , Feminino , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Transcriptoma , Pesquisa Translacional Biomédica , Resultado do TratamentoRESUMO
BACKGROUND: Programmed cell death protein-1 (PD-1) inhibitors (pembrolizumab and nivolumab) have been approved for the treatment of advanced melanoma. Over the past decades, patients older than 85 years represent an expanding group of patients in developed countries. In France, 25% of melanomas are diagnosed in patients older than 75 years. OBJECTIVE: To perform a monocentric retrospective study of patients older than 85 years and treated with pembrolizu-mab for unresectable or metastatic melanoma in order to evaluate tolerance and potential benefits of this immunotherapy. METHODS: Medical records of patients treated with the PD-1 inhibitor pembrolizumab between January 2015 and January 2018 were reviewed. RESULTS: Nine patients (6 women and 3 men) older than 85 years were included in the study. The mean age was 89.6 (85-97) years at inclusion. All patients were PS 0 or 1. The mean number of infusions was 4 (1-12). However, most patients were not able to tolerate the 4-infusion schedule. One patient refused the second infusion for personal reasons. Seven patients had grade 3 or 4 treatment-related adverse events. CONCLUSION: These results indicate that pembrolizumab treatment in patients older than 85 years may induce responses but is associated with a high risk of toxicity and impaired autonomy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Melanoma/tratamento farmacológico , Segurança do Paciente , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Tolerância a Medicamentos , Feminino , Seguimentos , Avaliação Geriátrica , Humanos , Infusões Intravenosas , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Estudos Retrospectivos , Medição de Risco , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Background The identification of the melanoma patients sensitive to anti-PD-1 inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an urgent need. We hypothesized that the natural history of the disease might partly reflect the immune state of the patients. Methods We analyzed our cohort of melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our institution. Objective response was defined as a complete or partial response according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients, the overall response rate was 43%. Median time from diagnosis to anti-PD-1 initiation was longer among responders than non-responders (64 months vs. 35 months, p = 0.02). The response rate was 10% in patients starting anti-PD-1 within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status (PS) 0 was also associated with enhanced tumor response: 70% of responders were PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type BRAF status were significant predictors of progression free survival. Conclusion A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical features might reflect a potentially intact immune system of the host.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Melanoma/patologia , Recidiva Local de Neoplasia/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m2) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m2 and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Melanoma/tratamento farmacológico , Sobrepeso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcopenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe , Sobrepeso/tratamento farmacológico , Estudos Retrospectivos , Sarcopenia/tratamento farmacológico , Adulto JovemRESUMO
The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAFV600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS.
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Fator de Crescimento de Hepatócito/sangue , Indóis/sangue , Indóis/uso terapêutico , Linfócitos/patologia , Melanoma/sangue , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/sangue , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Indóis/farmacocinética , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/farmacocinética , VemurafenibRESUMO
BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial disorder due to FH mutation. Despite a considerable increase in information about the genetic background, inter- and intrafamilial phenotypic variability/penetrance are not well documented. OBJECTIVE: To describe a large French HLRCC family and provide new data on penetrance and intrafamilial variability. MATERIALS AND METHODS: The whole family was contacted for clinical examination, skin biopsy, uterine and kidney imagery and molecular analysis. RESULTS: The family included 22 members in 3 generations. The second generation consisted of 13 members who were older than the expected age of onset of disease manifestations. Of the 12 available members of this second generation, 6 (1 man and 5 women, aged 44-57 years) had a novel FH mutation. All had the same mild phenotype with cutaneous asymptomatic leiomyomas, uterine fibroids (if women) and no kidney tumor. The other 6 members not bearing the familial mutation had normal clinical and radiological findings. In this second generation, the penetrance was therefore complete, and there was no intrafamilial variability in the clinical expression of the mutation. CONCLUSION: This study provides additional data on genotype/phenotype correlation, intrafamilial variability and penetrance that should help to improve prognosis and genetic counseling.
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Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Predisposição Genética para Doença , Neoplasias Renais/genética , Leiomiomatose/genética , Mutação , Penetrância , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/diagnóstico , Criança , DNA/genética , Análise Mutacional de DNA , Família , Feminino , Fumarato Hidratase/metabolismo , Genótipo , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Leiomiomatose/complicações , Leiomiomatose/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Pele/patologia , Adulto JovemRESUMO
BACKGROUND: Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. OBJECTIVES: We describe 5 cases of sarcoidosis in patients treated with vemurafenib. METHODS: Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. RESULTS: Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. CONCLUSION: BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.
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Antineoplásicos/efeitos adversos , Autoimunidade/efeitos dos fármacos , Indóis/efeitos adversos , Melanoma/tratamento farmacológico , Sarcoidose/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Uveíte/induzido quimicamente , Corticosteroides/uso terapêutico , Adulto , Antineoplásicos/imunologia , Toxidermias/tratamento farmacológico , Toxidermias/etiologia , Toxidermias/patologia , Feminino , Humanos , Indóis/imunologia , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Peptidil Dipeptidase A/sangue , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia , Neoplasias Cutâneas/patologia , Sulfonamidas/imunologia , VemurafenibAssuntos
Produtos Biológicos/uso terapêutico , Interleucina-1/antagonistas & inibidores , Urticária/tratamento farmacológico , Vasculite/tratamento farmacológico , Adulto , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Receptor de Morte Celular Programada 1/imunologia , Indução de Remissão , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Sarcoidosis is a systemic disease that affects the skin in about 25% of patients. The treatment of cutaneous sarcoidosis is guided by the extent of lesions, associated symptoms and organ involvement. To evaluate rates of response to various potential first-line treatments for cutaneous sarcoidosis during the year following treatment initiation. This retrospective multicentre study included 120 patients with cutaneous sarcoidosis. Treatment response was assessed retrospectively from the patients' medical records. Univariate logistic regression analysis, with an estimation of unadjusted odds ratios (OR) and their 95% CI ,was performed to identify factors associated with complete cutaneous remission (CR), followed by multivariate logistic regression analysis. At one year, 43 of the 120 (36%) included patients had CR. The best response rates were obtained with oral corticosteroids (12/21, 57%), followed by a combination of hydroxychloroquine and topical steroids (6/13, 46%). In multivariate analysis, lupus pernio was the only predictor of a poor cutaneous response. We suggest the use of a combination of hydroxychloroquine and topical steroids as an optimal first-line treatment for cutaneous sarcoidosis, given the known adverse effects of systemic corticosteroids.
Assuntos
Sarcoidose , Dermatopatias , Humanos , Estudos Retrospectivos , Hidroxicloroquina/uso terapêutico , Dermatopatias/patologia , Sarcoidose/patologia , Corticosteroides/uso terapêutico , EsteroidesRESUMO
While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.
RESUMO
Primary cutaneous mucinous carcinoma (PCMC) is a rare malignant skin adnexal tumor. Recurrences are most often localized, and long-term follow-up after complete surgery consists essentially of self-examination of skin. We report one case of metastatic PCMC with elevated levels of serum CEA and CA15.3. Because of the difficulty to differentiate PCMC and metastasis of mucinous breast cancer, the hypothesis of a metastasized breast cancer was ruled out. These tumor markers contributed to the monitoring of the metastatic disease. Since metastatic disease was diagnosed after several years of seeming complete remission, CEA and CA15.3 would likely have allowed the clinicians to detect the relapse earlier. Although the use of tumor biomarkers in PCMC is not rooted in clinical practice and not mentioned in guidelines, we suggest that CEA and CA15.3 could be of particular interest to monitor and detect early metastatic PCMC.