RESUMO
BACKGROUND: Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown. METHODS: In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death. RESULTS: The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group. CONCLUSIONS: Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).
Assuntos
Angioplastia , Implante de Prótese Vascular , Isquemia Crônica Crítica de Membro , Stents Farmacológicos , Doença Arterial Periférica , Artéria Poplítea , Humanos , Implantes Absorvíveis , Angioplastia/efeitos adversos , Angioplastia/métodos , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/métodos , Implante de Prótese Vascular/métodos , Doença Crônica , Isquemia Crônica Crítica de Membro/etiologia , Isquemia Crônica Crítica de Membro/cirurgia , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Isquemia/tratamento farmacológico , Isquemia/etiologia , Isquemia/cirurgia , Doença Arterial Periférica/complicações , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/cirurgia , Artéria Poplítea/cirurgia , Alicerces Teciduais , Resultado do TratamentoRESUMO
INTRODUCTION: Purportedly, the progression of multiple sclerosis (MS) occurs when neurodegenerative processes due to derangement of axonal bioenergetics take over the autoimmune response. However, a clear picture of the causative interrelationship between autoimmunity and axonal mitochondrial dysfunction in progressive MS (PMS) pathogenesis waits to be provided. METHODS: In the present study, by adopting the NOD mouse model of PMS, we compared the pharmacological effects of the immunosuppressants dexamethasone and fingolimod with those of mTOR inhibitors rapamycin and everolimus that, in addition to immunosuppression, also regulate mitochondrial functioning. Female Non-Obese Diabetic (NOD) mice were immunized with MOG35-55 and treated with drugs to evaluate functional, immune and mitochondrial parameters during disease evolution. RESULTS: We found that dexamethasone and fingolimod did not affect the pattern of progression as well as survival. Conversely, mTOR inhibitors rapamycin and everolimus delayed disease progression and robustly extended survival of immunized mice. The same effects were obtained when treatment was delayed by 30 days after immunization. Remarkably, dexamethasone and fingolimod prompted the same degree of immunosuppression of rapamycin within both spleen and spinal cord of mice. However, only rapamycin prompted mitochondriogenesis by increasing mitochondrial content, and expression of several mitochondrial respiratory complex subunits, thereby preventing mtDNA reduction in the spinal cords of immunized mice. These pharmacodynamic effects were not reproduced in healthy NOD mice, suggesting a disease context-dependent pharmacodynamic effect. DISCUSSION: Data corroborate the key role of mitochondriogenesis to treatment of MS progression, and for the first time disclose the translational potential of mTOR inhibitors in PMS therapy.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Feminino , Animais , Camundongos , Esclerose Múltipla/patologia , Inibidores de MTOR , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Neuroproteção , Everolimo/farmacologia , Everolimo/uso terapêutico , Camundongos Endogâmicos NOD , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Dexametasona/farmacologia , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Biodegradable polymer sirolimus-eluting stents improve early stent-related clinical outcomes compared to durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. The long-term advantages of biodegradable polymer sirolimus-eluting stents after complete degradation of its polymer coating in patients with STEMI remains however uncertain. METHODS: BIOSTEMI Extended Survival (BIOSTEMI ES) was an investigator-initiated, follow-up extension study of the BIOSTEMI prospective, multicentre, single-blind, randomised superiority trial that compared biodegradable polymer sirolimus-eluting stents with durable polymer everolimus-eluting stents in patients with STEMI undergoing primary percutaneous coronary intervention at ten hospitals in Switzerland. All individuals who had provided written informed consent for participation in the BIOSTEMI trial were eligible for this follow-up study. The primary endpoint was target lesion failure, defined as a composite of cardiac death, target vessel myocardial re-infarction, or clinically indicated target lesion revascularisation, at 5 years. Superiority of biodegradable polymer sirolimus-eluting stents over durable polymer everolimus-eluting stents was declared if the Bayesian posterior probability for a rate ratio (RR) of less than 1 was greater than 0·975. Analyses were performed according to the intention-to-treat principle. The study was registered with ClinicalTrials.gov, NCT05484310. FINDINGS: Between April 26, 2016, and March 9, 2018, 1300 patients with STEMI (1622 lesions) were randomly allocated in a 1:1 ratio to treatment with biodegradable polymer sirolimus-eluting stents (649 patients, 816 lesions) or durable polymer everolimus-eluting stents (651 patients, 806 lesions). At 5 years, the primary composite endpoint of target lesion failure occurred in 50 (8%) patients treated with biodegradable polymer sirolimus-eluting stents and in 72 (11%) patients treated with durable polymer everolimus-eluting stents (difference of -3%; RR 0·70, 95% Bayesian credible interval 0·51-0·95; Bayesian posterior probability for superiority 0·988). INTERPRETATION: In patients undergoing primary percutaneous coronary intervention for STEMI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 5 years of follow-up. The difference was driven by a numerically lower risk for ischaemia-driven target lesion revascularisation. FUNDING: Biotronik.
Assuntos
Stents Farmacológicos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Sirolimo/uso terapêutico , Everolimo/uso terapêutico , Seguimentos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Polímeros , Teorema de Bayes , Método Simples-Cego , Estudos Prospectivos , Resultado do Tratamento , Implantes Absorvíveis , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/métodosRESUMO
BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Estados Unidos , Adulto , Humanos , Everolimo/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Sirolimo/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgiaRESUMO
INTRODUCTION: Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral TSC organoids. However, investigation of clinical patient-derived data is lacking. AIMS: Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients. METHODS: Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell-based assay using primary patient-derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed. RESULTS: EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells. CONCLUSION: Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR-associated malformations of cortical development, including FCD2B.
Assuntos
Astrocitoma , Esclerose Tuberosa , Humanos , Everolimo/farmacologia , Everolimo/uso terapêutico , Esclerose Tuberosa/metabolismo , Afatinib/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Receptores ErbB/uso terapêuticoRESUMO
Tuberous sclerosis complex is associated with the occurrence of cardiac rhabdomyomas that may result in life-threatening arrhythmia unresponsive to standard antiarrhythmic therapy. We report the case of an infant with multiple cardiac rhabdomyomas who developed severe refractory supraventricular tachycardia (SVT) that was successfully treated with everolimus. Pharmacological mTOR inhibition rapidly improved arrhythmia within few weeks after treatment initiation and correlated with a reduction in tumor size. Intermediate attempts to discontinue everolimus resulted in rhabdomyoma size rebound and recurrence of arrhythmic episodes, which resolved on resumption of therapy. While everolimus treatment led to successful control of arrhythmia in the first years of life, episodes of SVT reoccurred at the age of 6 years. Electrophysiologic testing confirmed an accessory pathway that was successfully ablated, resulting in freedom of arrhythmic events. In summary we present an in-depth evaluation of the long-term use of everolimus in a child with TSC-associated SVT, including the correlation between drug use and arrhythmia outcome. This case report provides important information on the safety and efficacy of an mTOR inhibitor for the treatment of a potentially life-threatening cardiac disease manifestation in TSC for which the optimal treatment strategy is still not well established.
Assuntos
Neoplasias Cardíacas , Rabdomioma , Esclerose Tuberosa , Lactente , Criança , Humanos , Everolimo/uso terapêutico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Rabdomioma/complicações , Rabdomioma/tratamento farmacológico , Rabdomioma/patologia , Arritmias Cardíacas/complicações , Arritmias Cardíacas/tratamento farmacológico , Serina-Treonina Quinases TOR , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/tratamento farmacológico , Neoplasias Cardíacas/patologiaRESUMO
BACKGROUND: The response to everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML) varies among individuals. This study aims to identify potential factors associated with the response to everolimus. METHOD: We retrospectively examined data encompassing age, gender, tumor size, computed tomography attenuation value (CT value), CT enhancement, and tumor reduction rate in patients with TSC-RAML undergoing everolimus in two previously registered clinical trials. RESULT: A total of 33 participants (29.33 ± 6.63 years old, 20 females) were included. The correlation analysis conducted separately for tumors located in the left and right kidneys revealed significant negative correlations (P < 0.05) between tumor reduction rate and age, as well as tumor size. While significant positive correlations (P < 0.05) were observed between tumor reduction rate and unenhanced CT value as well as CT enhancement. Nonetheless, based on multiple linear regression analysis, unenhanced CT value emerged as the sole-independent predictor of tumor reduction rate among age, gender, tumor size, unenhanced CT value and CT enhancement for both left (coefficient = 0.00319, P < 0.0001) and right kidneys (coefficient = 0.00315, P = 0.0104). Notable reductions were observed in unenhanced CT value (- 3.81 vs - 24.70HU, P < 0.0001) and CT enhancement (48.16 vs 33.56HU, P < 0.0001) following a 3-month administration of everolimus. The decline in both unenhanced CT value and tumor size predominantly occurred within the initial 3 months, subsequently maintaining a relatively stable level throughout the treatment. CONCLUSION: The unenhanced CT value of TSC-RAML showed an independent correlation with the response to everolimus, suggesting its potential as a predictor of everolimus efficacy in patients with TSC-RAML.
Assuntos
Angiomiolipoma , Neoplasias Renais , Esclerose Tuberosa , Feminino , Humanos , Adulto Jovem , Adulto , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/tratamento farmacológico , Angiomiolipoma/complicações , Angiomiolipoma/diagnóstico por imagem , Angiomiolipoma/tratamento farmacológico , Everolimo/uso terapêutico , Estudos Retrospectivos , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. METHODS: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. RESULTS: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. CONCLUSIONS: Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.
Assuntos
Ciclofosfamida , Everolimo , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Condicionamento Pré-Transplante , Humanos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Feminino , Pessoa de Meia-Idade , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Masculino , Adulto , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Idoso , Condicionamento Pré-Transplante/métodos , Recidiva , Linfoma/terapia , Linfoma/mortalidade , Linfoma/diagnóstico , Resultado do Tratamento , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Transplante HomólogoRESUMO
Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.
Assuntos
Inibidores de MTOR , Mastocitose Sistêmica , Sirolimo , Humanos , Mastocitose Sistêmica/tratamento farmacológico , Projetos Piloto , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , França , Idoso , Sirolimo/uso terapêutico , Sirolimo/efeitos adversos , Inibidores de MTOR/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Everolimo/uso terapêutico , Everolimo/efeitos adversos , Resultado do Tratamento , Serina-Treonina Quinases TOR/antagonistas & inibidores , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS: This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS: From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.
Assuntos
Everolimo , Rejeição de Enxerto , Sobrevivência de Enxerto , Imunossupressores , Transplante de Fígado , Doadores Vivos , Humanos , Feminino , Masculino , Everolimo/uso terapêutico , Everolimo/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , Rejeição de Enxerto/etiologia , Imunossupressores/uso terapêutico , Seguimentos , Prognóstico , Fatores de Risco , Complicações Pós-Operatórias , Adulto , Taxa de Filtração Glomerular , Taxa de Sobrevida , Testes de Função Renal , Inibidores de Calcineurina/uso terapêuticoRESUMO
The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9 years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.
Assuntos
Corticosteroides , Everolimo , Rejeição de Enxerto , Transplante de Coração , Imunossupressores , Sistema de Registros , Humanos , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Pessoa de Meia-Idade , Masculino , Feminino , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , República da Coreia/epidemiologia , Rejeição de Enxerto/prevenção & controle , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Resultado do Tratamento , Sobrevivência de Enxerto , Estudos RetrospectivosRESUMO
Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset and difficult-to-treat seizures. Several cellular, molecular and pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction and abnormal connectivity, may play a role in this epileptogenic process and may also contribute to the associated developmental encephalopathy. Disease-specific antiseizure medications or drugs targeting the mTOR pathway have proved to be effective in TSC-associated epilepsy. Pre-symptomatic administration of vigabatrin, a GABAergic drug, delays seizure onset and reduces the risk of a subsequent epileptic encephalopathy, such as infantile spasms syndrome or Lennox-Gastaut syndrome. Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizure frequency, especially in younger patients. This evidence suggests that everolimus should be considered early in the course of epilepsy. Future trials are needed to optimize the use of everolimus and determine whether earlier correction of mTOR dysregulation can prevent progression to developmental and epileptic encephalopathies or mitigate their severity in infants with TSC. Clinical trials of several other potential antiseizure drugs (cannabidiol and ganaxolone) that target contributing mechanisms are also underway. This review provides an overview of the different biological mechanisms occurring in parallel and interacting throughout the life course, even beyond the epileptogenic process, in individuals with TSC. These complexities highlight the challenges faced in preventing and treating TSC-related developmental and epileptic encephalopathy.
Assuntos
Epilepsia , Esclerose Tuberosa , Lactente , Humanos , Everolimo/uso terapêutico , Esclerose Tuberosa/complicações , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Epilepsia/metabolismo , Convulsões/tratamento farmacológico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Anticonvulsivantes/uso terapêuticoRESUMO
OBJECTIVE: This study aimed to evaluate the efficacy and safety of six new antiseizure medications (ASMs) for adjunctive treatment in adult patients with focal epilepsy and adolescents with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), or tuberous sclerosis complex (TSC). METHODS: A comprehensive literature search was performed using PubMed, Medline, Embase, and Cochrane library databases from inception to October 13, 2023. We included published studies for a systematic review and a network meta-analysis (NMA). The efficacy and safety were reported in terms of a 50% response rate and dropout rate along with serious adverse events (SAEs). The outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). RESULTS: Twenty eligible trials with 5516 patients and 21 interventions, including placebo, contributed to the analysis. Included ASMs were brivaracetam (BRV), cenobamate (CBM), cannabidiol (CBD), fenfluramine (FFM), everolimus (ELM), and soticlestat (SLT). The six new ASMs were compared in four different epilepsy subtypes. In focal epilepsy treatment, BRV seemed to be safe [vs placebo, risk ratio (RR) = 0.69, 95 % confidence interval (CI): 0.25-1.91] and effective (vs placebo, RR = 2.18, 95 % CI: 1.25-3.81). In treating focal epilepsy, CBM 300 mg was more effective at a 50 % response rate (SUCRA 91.8 %) compared with BRV and CBD. However, with the increase in dosage, more SAEs (SUCRA 85.6 %) appeared compared with other ASMs. CBD had good efficacy on LGS (SUCRA 88.4) and DS (SUCRA 66.2), but the effect on adult focal epilepsy was not better than that of placebo [vs placebo, RR = 0.83 (0.36-1.93)]. The NMA indicated that the likelihood of the most appropriate intervention (SUCRA 91.2 %) with minimum side effectsï¼SUCRA 12.5 %ï¼for the DS was FFM. Compared with CBD, high exposure to ELM demonstrated a more effective treatment of TSC (SUCRA 89.7 %). More high-quality SLT studies are needed to further evaluate the efficacy and safety. The comparison-adjusted funnel plots of annualized relapse rate and side effects in the included studies revealed no significant funnel plot asymmetry. CONCLUSIONS: This NMA indicated that the most effective treatment strategy for focal epilepsy, DS, Lennox-Gastaut syndrome, and TSC, respectively, included CBM 300 mg, FFM, CBD, and ELM. However, the aforementioned findings need further confirmation.
Assuntos
Canabidiol , Carbamatos , Clorofenóis , Epilepsias Mioclônicas , Epilepsias Parciais , Epilepsia , Síndrome de Lennox-Gastaut , Tetrazóis , Adulto , Adolescente , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Metanálise em Rede , Canabidiol/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/induzido quimicamente , Everolimo/uso terapêutico , Anticonvulsivantes/efeitos adversosRESUMO
BACKGROUND: Immunosuppression after heart transplantation (HTX) with mammalian target of rapamycin (mTOR) inhibitors serves as a prophylaxis against rejection and to treat coronary vascular injury. However, there is little data on the early, preventive use of everolimus after pediatric HTX. METHODS: Retrospective study of 61 pediatric HTX patients (48 cardiomyopathy and 13 congenital heart disease), 28 females, median age 10.1 (range 0.1-17.9) years transplanted between 2008 and 2020. We analyzed survival, rejection, renal function, occurrence of lymphoproliferative disorder, and allograft vasculopathy together with adverse effects of early everolimus therapy combined with low-dose calcineurin inhibitors. RESULTS: Everolimus therapy was started at a median 3.9 (1-14) days after HTX. Median follow-up was 4.3 (range 0.5-11.8) years, cumulative 184 patient years. The estimated 1- and 5-year survival probability was 89% (CI 82%:98%) and 87% (CI 78%:97%). Four patients developed rejection (6.6%) (maximum 2R ISHLT criteria). No patient suffered from chronic renal failure. Three patients (4.9%) developed post-transplant lymphoproliferative disorder. Five patients suffered relevant wound-healing disorders after transplantation, four of them carrying relevant risk factors before HTX (mechanical circulatory support (n = 3), delayed chest closure after HTX (n = 3)). No recipient developed cardiac allograft vasculopathy. CONCLUSION: Initiating everolimus within the first 14 days after HTX seems to be well tolerated, enabling a low incidence of rejection, post-transplant lymphoproliferative disorders, renal failure, and reveals no evidence of cardiac allograft vasculopathy as well as good overall survival in pediatric heart transplant recipients.
Assuntos
Traumatismos Cardíacos , Transplante de Coração , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Aloenxertos , Everolimo/uso terapêutico , Coração , Estudos Retrospectivos , MasculinoRESUMO
Breast cancer (BC) is the most commonly diagnosed cancer among women. Prognosis has improved over the years, to a large extent, owing to personalized therapy informed by molecular profiling of hormone receptors. However, there is a need for new therapeutic approaches for a subgroup of BCs lacking molecular markers, the Triple Negative Breast Cancer (TNBC) subgroup. TNBC is the most aggressive type of BC, lacks an effective standard of care, shows high levels of resistance and relapse is often inevitable. High resistance to therapy has been hypothesized to be associated with high intratumoral phenotypic heterogeneity. To characterize and treat this phenotypic heterogeneity, we optimized a whole-mount staining and image analysis protocol for three-dimensions (3D) spheroids. Applying this protocol to TNBC spheroids located in the outer region of the spheroid the cells with selected phenotypes: dividing, migrating, and high mitochondrial mass phenotypes. To evaluate the relevance of phenotype-based targeting these cell populations were targeted with Paclitaxel, Trametinib, and Everolimus, respectively, in a dose-dependent manner. Single agents cannot specifically target all phenotypes at the same time. Therefore, we combined drugs that should target independent phenotype. With this rationale we observed that combining Trametinib and Everolimus achieves the highest cytotoxicity at lower doses from all the tested combinations. These findings suggest a rational approach to design treatments can be evaluated in spheroids prior to pre-clinical models and potentially reduce adverse effects.
Assuntos
Everolimo , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Everolimo/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Microscopia , Linhagem Celular Tumoral , Recidiva Local de Neoplasia , FenótipoRESUMO
INTRODUCTION: Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression. CASE PRESENTATION: We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression. CONCLUSION: Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.
Assuntos
Everolimo , Hipoglicemia , Insulinoma , Neoplasias Pancreáticas , Humanos , Feminino , Everolimo/uso terapêutico , Everolimo/efeitos adversos , Insulinoma/secundário , Insulinoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Evolução Fatal , Diazóxido/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. Due to the implication of mTOR pathway dysregulation in the disease pathology, increasing evidence supports the use of mTOR inhibitors for treating multiple manifestations of TSC. METHODS: In this study, we conducted a retrospective analysis of clinical findings and treatment data from 38 patients diagnosed with tuberous sclerosis who were followed up in the Pediatric Oncology Clinic between 2010 and 2020. We collected information on patients' ages, genders, affected sites, familial history, imaging findings, presence of tumors, and treatments. RESULTS: Among the patients, nine individuals with TSC manifestations were treated with mTOR inhibitors. Specifically, everolimus was successfully administered to five patients with inborn cardiac rhabdomyoma causing hemodynamic impairment. In addition, two patients with refractory seizures received everolimus in combination with anti-epileptic drugs. A patient with renal angiomyolipomas larger than 3 cm was treated with everolimus, while a patient with extensive facial angiofibroma received topical sirolimus. All patients tolerated the mTOR inhibitors well, and the side effects were deemed acceptable. CONCLUSION: The utilization of mTOR inhibition in TSC is expected to become more prevalent in clinical practice, as current research is anticipated to provide a better understanding of the therapeutic roles of these treatments in TSC.
Assuntos
Everolimo , Esclerose Tuberosa , Criança , Humanos , Feminino , Masculino , Everolimo/uso terapêutico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/genética , Inibidores de MTOR , Estudos Retrospectivos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/uso terapêutico , Sirolimo/uso terapêuticoRESUMO
The prognosis after heart transplantation continues to improve. Therefore, the prevention of chronic post-transplant sequelae, such as chronic kidney disease, allograft vasculopathy, and malignancies is becoming increasingly important. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is increasingly used for immunosuppression after heart transplantation. However, everolimus may cause a characteristic complex of adverse effects, including dyslipidemia. Currently there are no guidelines for the long-term screening and treatment of dyslipidemia in heart transplant recipients treated with everolimus. This article presents a clinical case of hypercholesterolemia that developed after the start of the everolimus treatment in a heart recipient. The patient was a 39-year-old man who underwent orthotopic heart transplantation for ischemic cardiomyopathy in 2012 (at the age of 27). In 2019, the patient's immunosuppressive therapy was converted from mycophenolate mofetil to everolimus due to the development of cardiac allograft vasculopathy. The change in the immunosuppressive therapy was associated with increases in total cholesterol and low-density lipoprotein cholesterol, which were not reversed with a combined lipid-lowering therapy (maximum doses of rosuvastatin, ezetimibe, fenofibrate). A decrease in lipid levels was achieved with a blocker of hepatic proprotein convertase subtilisin/kexin type 9 synthesis at the level of microribonucleic acid (inclisiran). This case demonstrates the difficulties in correcting dyslipidemia in patients with cardiac allograft, since the treatment with the immunosuppressant everolimus worsens existing dyslipidemia. However, the combination lipid-lowering therapy, that affects various elements of the pathogenesis (specifically, the combined inhibition of hydroxymethylglutaryl-CoA reductase with a statin, cholesterol absorption from the small intestine with ezetimibe, and PCSK9 messenger RNA with inclisiran), provides an effective control of blood lipids and minimizing the adverse effects of immunosuppressive therapy, such as cardiac allograft vasculopathy.
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Everolimo , Transplante de Coração , Humanos , Masculino , Adulto , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Inibidores de PCSK9 , Complicações Pós-Operatórias/tratamento farmacológico , Resultado do Tratamento , RNA Interferente PequenoRESUMO
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified. DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models. RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death. CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.
Assuntos
Carcinoma Ductal Pancreático , Everolimo , Lipídeos , Lisossomos , Inibidores de MTOR , Neoplasias Pancreáticas , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Glutamina/metabolismo , Lipídeos/biossíntese , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Nutrientes , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Everolimo/uso terapêutico , Inibidores de MTOR/uso terapêutico , Glutaminase , Neoplasias PancreáticasRESUMO
In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8+ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.