RESUMO
Rosai-Dorfman disease (RDD) is a rare myeloproliferative disorder involving histiocytes, with an incidence of 1:200 000 and approximately 100 new cases diagnosed annually in the USA. The condition presents a diverse range of clinical manifestations, and early recognition and treatment generally result in a favourable prognosis. However, diagnosing RDD poses challenges due to its rarity. The clinical management of RDD lacks a consensus, further complicating its diagnostic and therapeutic approach. We present a case of a man in his late 50s with RDD who experienced worsening cytopenias, including severe neutropenia and respiratory distress, despite an initial positive response to steroids, rituximab and lenalidomide. Genetic testing revealed mutations in POLE, KRAS (G13C), NDE1 and EZH2, suggesting potential new therapeutic targets. Sirolimus was initiated and led to complete radiological remission of the disease. This case adds strength to the growing evidence supporting the efficacy of sirolimus in refractory RDD cases.
Assuntos
Histiocitose Sinusal , Sirolimo , Humanos , Histiocitose Sinusal/tratamento farmacológico , Histiocitose Sinusal/diagnóstico , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Imunossupressores/uso terapêuticoAssuntos
Angiofibroma , Relação Dose-Resposta a Droga , Neoplasias Nasofaríngeas , Sirolimo , Humanos , Angiofibroma/tratamento farmacológico , Angiofibroma/diagnóstico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/diagnóstico , Sirolimo/uso terapêutico , Sirolimo/administração & dosagem , Masculino , Antibióticos Antineoplásicos/uso terapêutico , Antibióticos Antineoplásicos/administração & dosagem , AdolescenteRESUMO
BACKGROUND: The long-term impact of drug-coated balloon (DCB) angioplasty for the treatment of patients with de novo coronary artery lesions remains uncertain. We aimed to assess the non-inferiority of DCB angioplasty with rescue stenting to intended drug-eluting stent (DES) deployment for patients with de novo, non-complex coronary artery lesions. METHODS: REC-CAGEFREE I was an open-label, randomised, non-inferiority trial conducted at 43 sites in China. After successful lesion pre-dilatation, patients aged 18 years or older with de novo, non-complex coronary artery disease (irrespective of target vessel diameter) and an indication for percutaneous coronary intervention were randomly assigned (1:1), via a web-based centralised system with block randomisation (block size of two, four, or six) and stratified by site, to paclitaxel-coated balloon angioplasty with the option of rescue stenting due to an unsatisfactory result (DCB group) or intended deployment of second-generation thin-strut sirolimus-eluting stents (DES group). The primary outcome was the device-oriented composite endpoint (DoCE; including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation) assessed at 24 months in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Non-inferiority was established if the upper limit of the one-sided 95% CI for the absolute risk difference was smaller than 2·68%. Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT04561739. It is closed to accrual and extended follow-up is ongoing. FINDINGS: Between Feb 5, 2021, and May 1, 2022, 2272 patients were randomly assigned to the DCB group (1133 [50%]) or the DES group (1139 [50%]). Median age at the time of randomisation was 62 years (IQR 54-69), 1574 (69·3%) of 2272 were male, 698 (30·7%) were female, and all patients were of Chinese ethnicity. 106 (9·4%) of 1133 patients in the DCB group received rescue DES after unsatisfactory DCB angioplasty. As of data cutoff (May 1, 2024), median follow-up was 734 days (IQR 731-739). At 24 months, the DoCE occurred in 72 (6·4%) of 1133 patients in the DCB group and 38 (3·4%) of 1139 in the DES group, with a risk difference of 3·04% in the cumulative event rate (upper boundary of the one-sided 95% CI 4·52; pnon-inferiority=0·65; two-sided 95% CI 1·27-4·81; p=0·0008); the criterion for non-inferiority was not met. During intervention, no acute vessel closures occurred in the DCB group and one (0·1%) of 1139 patients in the DES group had acute vessel closure. Periprocedural myocardial infarction occurred in ten (0·9%) of 1133 patients in the DCB group and nine (0·8%) in the DES group. INTERPRETATION: In patients with de novo, non-complex coronary artery disease, irrespective of vessel diameter, a strategy of DCB angioplasty with rescue stenting did not achieve non-inferiority compared with the intended DES implantation in terms of the DoCE at 2 years, which indicates that DES should remain the preferred treatment for this patient population. FUNDING: Xijing Hospital and Shenqi Medical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Assuntos
Angioplastia Coronária com Balão , Doença da Artéria Coronariana , Stents Farmacológicos , Paclitaxel , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Angioplastia Coronária com Balão/métodos , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Doença da Artéria Coronariana/terapia , Idoso , Sirolimo/uso terapêutico , Sirolimo/administração & dosagem , Resultado do Tratamento , Materiais Revestidos Biocompatíveis , China/epidemiologia , Intervenção Coronária Percutânea/métodosRESUMO
Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.
Assuntos
Adenoviridae , Neoplasias Pulmonares , Terapia Viral Oncolítica , Vírus Oncolíticos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met , Sirolimo , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas/genética , Adenoviridae/genética , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Squamous Cell Carcinoma (SCC) is a subtype of Non-Melanoma Skin Cancer, the most common group of malignancies worldwide. Photodynamic therapy (PDT) is a non-invasive treatment approved for specific subtypes of SCC. Some malignancies resist PDT, forming more aggressive tumors and multiple relapses. Thus, new approaches aimed at optimizing the response to PDT are needed. The mTORC1 inhibitor rapamycin, also known as Sirolimus (SRL), interferes with protein synthesis and cell metabolism. The use of SRL as an immunosuppressant is associated to lower rates of SCC in kidney-transplanted patients, which are frequently affected by this pathology. We have evaluated SRL pre-treatment efficacy to enhance the damage induced by PDT with Methyl 5-aminolevulinate in two different cutaneous SCC established cell lines (SCC13 and A431) in vitro and therapy sensitization in PDT-resistant cell lines. We tested for the first time the SRL + PDT combination in a SKH-1 mouse model of photocarcinogenesis, diminishing the frequency of lesions and restraining tumor growth. Molecular studies revealed that protoporphyrin IX and reactive oxygen species production induced by PDT were promoted by SRL pre-treatment. Lastly, SRL modifies the expression and intracellular location of NRF2, interfering with the downstream antioxidant response modulated by NQO1 and HO-1. In conclusion, we propose SRL as a potential adjuvant to enhance PDT efficacy for SCC treatment.
Assuntos
Carcinoma de Células Escamosas , Fator 2 Relacionado a NF-E2 , Fotoquimioterapia , Transdução de Sinais , Sirolimo , Neoplasias Cutâneas , Fator 2 Relacionado a NF-E2/metabolismo , Fotoquimioterapia/métodos , Animais , Camundongos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ácido Aminolevulínico/uso terapêutico , Ácido Aminolevulínico/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , FemininoRESUMO
OBJECTIVES: To evaluate long-term renal graft prognosis and the role of rapamycin from a single-center in China over a 30-year follow-up. METHODS: This study enrolled a total of 654 patients who underwent kidney transplantation between 1989 and 2020. The basic characteristics of the included patients were collected. Graft survival was described and compared using Kaplan-Meier curves (K-M curves). Both continuous and categorical variables were included in a multivariate Cox proportional-hazards model. Patients were divided into rapamycin-based quadruple immunosuppression regimen group (rapa group, n = 41) and conventional tacrolimus-based triple immunosuppression regimen group (control group, n = 218). The indication biopsy results of the two groups were further reviewed to compare the incidence of rejection, acute rejection, and banff score. RESULTS: The overall 5, 10, 15, 20-year graft survival rate of our center is 87.5%, 62.4%, 46.4% and 20.9%, respectively. The median survival time after surgery is 14 years. Multiple Cox regression analysis identified BMI (p = 0.035), dialysis type (p < 0.001), immunosuppressants (p < 0.01), urine albumen (p < 0.001), globulin (p = 0.041), and blood glucose (p = 0.002) as risk factors. The 20-year, 10-year and 5-year AUC is 0.78, 0.75 and 0.75. The combination of FK506 and rapamycin was further suggested by the model to effectively improve the graft prognosis (p < 0.01, HR = 0.763). The K-M curve showed that the long-term survival rate of renal grafts in the rapa group was significantly better than that in the conventional group (p < 0.001). In addition, indication biopsy records revealed a lower possibility of immune rejection in the rapa group than that in the conventional group (p < 0.001). Banff score indicated that rapa group had less vascular inflammation in the transplanted kidney. CONCLUSIONS: In this study, a 30-year follow-up was performed in a single center, and a total graft 20-year survival rate of 20.9% was reported. The prognostic model and subgroup analysis suggested that FK506 combined with rapamycin could effectively improve the prognosis of renal transplantation, which could be explained by reduced acute rejection and less vascular inflammation.
Assuntos
Rejeição de Enxerto , Sobrevivência de Enxerto , Imunossupressores , Transplante de Rim , Sirolimo , Tacrolimo , Humanos , Sirolimo/uso terapêutico , Masculino , Feminino , Imunossupressores/uso terapêutico , Adulto , Seguimentos , Pessoa de Meia-Idade , Rejeição de Enxerto/prevenção & controle , Tacrolimo/uso terapêutico , Estudos Retrospectivos , Fatores de Tempo , Modelos de Riscos Proporcionais , Quimioterapia CombinadaRESUMO
To investigate the clinical efficacy of sirolimus in treating children with refractory nephrotic syndrome, the clinical data for 22 children from the Children's Hospital of Hebei Province were analyzed retrospectively. There were 16 boys and six girls, and the treatment period was from September 2015 to April 2021. There were two patients with steroid-dependent nephrotic syndrome (SDNS), six patients with frequently relapsing nephrotic syndrome (FRNS), and 14 patients with steroid-resistant nephrotic syndrome (SRNS). All patients were defined as having refractory nephrotic syndrome. There were 12 patients (including nine SRNS patients and three FRNS patients) with minimal change disease (MCD), three patients (three SRNS patients) with focal segmental glomerular sclerosis (FSGS), one FRNS patient with mesangial proliferative glomerulonephritis (MsPGN), and six patients without a kidney biopsy. Compared with levels before sirolimus treatment, 24-hour urine protein (24-h UP), low-density lipoprotein cholesterol (LDL-C), urea (Ur) and serum creatinine (SCr) levels were significantly lower (all p < 0.05). Moreover, albumin (Alb) was significantly increased (p < 0.05), and there were no significant differences in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), immunoglobulin A (IgA), immunoglobulin G (IgG) or immunoglobulin M (IgM) (all p > 0.05) at the first follow-up. Sirolimus is effective as the first treatment of some children with refractory nephrotic syndrome, but its long-term efficacy and adverse reactions still require follow-up.
Assuntos
Imunossupressores , Síndrome Nefrótica , Sirolimo , Humanos , Síndrome Nefrótica/tratamento farmacológico , Masculino , Feminino , Sirolimo/uso terapêutico , Criança , Estudos Retrospectivos , Pré-Escolar , Imunossupressores/uso terapêutico , Adolescente , Resultado do Tratamento , Creatinina/sangue , Nefrose Lipoide/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , LDL-Colesterol/sangue , Lactente , Rim/patologia , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , ChinaRESUMO
BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.
Assuntos
Sirolimo , Humanos , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Criança , Feminino , Adolescente , Pré-Escolar , Adulto , Masculino , Lactente , Adulto Jovem , Pessoa de Meia-Idade , Recém-Nascido , Idoso , Esclerose Tuberosa/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Estudos ProspectivosRESUMO
Since the introduction of post-transplantation cyclophosphamide (PTCy), haploidentical hematopoietic stem cell transplantation (haploSCT) has become a real alternative for patients who lack other eligible donors. The standard graft-versus-host disease (GVHD) prophylaxis after PTCy has been a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) (up to day +35), but promising results with sirolimus (with or without MMF) and single-agent tacrolimus have been published recently. This multicenter retrospective study compared the outcomes of 372 adult haploSCT recipients who received conditioning with thiotepa, busulfan, and fludarabine (TBF), PTCy, and additional GVHD prophylaxis with 1 of 3 strategies: cohort A, single-agent tacrolimus (n = 222); cohort B, CNI + MMF (n = 49); or cohort C, sirolimus + MMF (n = 101). No differences among the 3 cohorts were found in terms of grade II-IV acute GVHD (20% in cohort A, 25% in cohort B, and 30% in cohort C) or grade III-IV acute GVHD (9%, 6%, and 15%, respectively) at 100 days; however, cohort A had the lowest incidence of overall chronic GVHD (24%, 47%, and 52%, respectively; P = .001) and moderate-severe chronic GVHD (13%, 35%, and 33%, respectively; P = .001). There were no differences in 3-year overall survival, progression-free survival, nonrelapse mortality, or relapse among the 3 cohorts. Overall, our study suggests that single-agent tacrolimus, CNI + MMF, and sirolimus + MMF GVHD prophylaxis lead to similar outcomes following haploSCT with TBF and PTCy, with a low incidence of grade III-IV acute GVHD, although possible differences in chronic GVHD require further investigation.
Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Ácido Micofenólico , Sirolimo , Tacrolimo , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Ácido Micofenólico/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Tacrolimo/uso terapêutico , Sirolimo/uso terapêutico , Masculino , Feminino , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/administração & dosagem , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Transplante Haploidêntico/efeitos adversos , Imunossupressores/uso terapêutico , Idoso , Condicionamento Pré-Transplante/métodos , Adulto Jovem , Adolescente , Linfócitos T/imunologiaRESUMO
BACKGROUND: Immune response and inflammation play important roles in the physiological and pathophysiological processes of heart failure (HF). In our previous study, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with anti-inflammatory and immunosuppressive functions, were shown to exert cardioprotective effects in HF. The pharmacological targeting of MDSCs using rapamycin may emerge as a promising strategy for the prevention and treatment of HF. However, the specific mechanisms underlying rapamycin-induced MDSC accumulation remain unclear. Our study aimed to clarify the effects of rapamycin on the recruitment and function of MDSCs in HF, exploring new therapeutic options for the prevention and treatment of HF. METHODS: We used transverse aortic constriction surgery and isoproterenol injection to establish HF models. Flow cytometry, reverse transcription polymerase chain reaction, transcriptomics and western blot were used to explore the regulation of rapamycin on recruitment and function of MDSCs in HF. Furthermore, rapamycin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined to induce exogenous MDSCs from bone marrow cells. RESULTS: Rapamycin promotes the recruitment of MDSCs by inhibiting their maturation and differentiation via suppression of the Wnt signaling in HF mice and enhanced the immunosuppressive function of MDSCs via the NF-κB signaling. Furthermore, exogenous MDSCs induced by rapamycin and GM-CSF can significantly alleviate transverse aortic constriction-induced cardiac dysfunction. CONCLUSIONS: The pharmacological targeting of MDSCs using rapamycin is a promising strategy for the prevention and treatment of HF.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Insuficiência Cardíaca , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides , Sirolimo , Animais , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Masculino , Camundongos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Modelos Animais de Doenças , NF-kappa B/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células CultivadasAssuntos
Angioplastia Coronária com Balão , Paclitaxel , Sirolimo , Animais , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Coelhos , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/métodos , Modelos Animais de Doenças , Stents Farmacológicos , Materiais Revestidos Biocompatíveis , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacosRESUMO
BACKGROUND: Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome (JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal bleeding, protein-losing enteropathy, malnutrition and immune deficiency. CASE PRESENTATION: We report a case of a girl initially presented with pallor at 7 months of age, which progressed to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both upper gastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated the presence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletion on chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reduction in the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remained necessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia. CONCLUSION: This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate the need for aggressive polypectomy.
Assuntos
Polipose Intestinal , Sirolimo , Humanos , Feminino , Sirolimo/uso terapêutico , Polipose Intestinal/congênito , Polipose Intestinal/genética , Polipose Intestinal/tratamento farmacológico , Polipose Intestinal/diagnóstico , Lactente , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Imunossupressores/uso terapêutico , PTEN Fosfo-Hidrolase/genéticaRESUMO
Topical therapy remains a critical component in the management of immunemediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroidfree therapeutic alternatives. Despite their potential for skinselective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrierbased delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential antiinflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hardtoformulate' macromolecules in the context of psoriasis and atopic dermatitis.
Assuntos
Inibidores de Calcineurina , Inibidores de MTOR , Humanos , Inibidores de Calcineurina/uso terapêutico , Animais , Inibidores de MTOR/uso terapêutico , Administração Tópica , Nanotecnologia/métodos , Dermatite Atópica/tratamento farmacológico , Nanopartículas/química , Tacrolimo/uso terapêutico , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Sirolimo/uso terapêutico , Sirolimo/farmacologia , Sistemas de Liberação de Medicamentos/métodosRESUMO
BACKGROUND: Gain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. METHODS: Twenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response. RESULTS: mTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance. CONCLUSIONS: The data illustrate the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response.
Assuntos
Ketamina , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Quinases S6 Ribossômicas 70-kDa , Humanos , Feminino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pessoa de Meia-Idade , Ketamina/farmacologia , Adulto , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fosforilação , Transtornos Mentais/metabolismo , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , Ansiedade/metabolismo , Adulto Jovem , IdosoAssuntos
Angioplastia Coronária com Balão , Doença da Artéria Coronariana , Sistema de Registros , Sirolimo , Humanos , Doença da Artéria Coronariana/terapia , Sirolimo/uso terapêutico , Sirolimo/administração & dosagem , Resultado do Tratamento , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Stents FarmacológicosRESUMO
mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.
Assuntos
Neoplasias do Colo , Imidazóis , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Metabolômica , Sirolimo , Triazinas , Humanos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Células HCT116 , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Espectrometria de Massa com Cromatografia Líquida , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Metabolômica/métodos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Espectrometria de Massas em Tandem , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Dasatinibe , Irinotecano , Recidiva Local de Neoplasia , Neuroblastoma , Sirolimo , Temozolomida , Humanos , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico , Irinotecano/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/genética , Pré-Escolar , Criança , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Dasatinibe/efeitos adversos , Adolescente , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Lactente , Adulto , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Adulto Jovem , Alemanha , Resistencia a Medicamentos Antineoplásicos , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. METHODS: ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. FINDINGS: Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. INTERPRETATION: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. FUNDING: The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).