RESUMEN
Everolimus is an orally administered mechanistic target of rapamycin inhibitor in solid-organ transplant patients. In addition to the common adverse side effects of this treatment, such as hyperlipidemia, rash, stomatitis, anorexia, diarrhea, anemia, thrombocytopenia, and leukopenia, pulmonary toxicity is also an important adverse side effect. Although pulmonary toxicity due to everolimus has been reported mostly as pneumonitis, cases of pleural effusion due to everolimus have also been reported rarely. Chylothorax is defined as the accumulation of lymphatic fluid in the pleural space. It may develop secondary to trauma or malignancy. In this case report, we present a patient with chylothorax after everolimus treatment.
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Quilotórax , Everolimus , Inmunosupresores , Humanos , Quilotórax/inducido químicamente , Quilotórax/tratamiento farmacológico , Everolimus/efectos adversos , Everolimus/administración & dosificación , Inmunosupresores/efectos adversos , Resultado del Tratamiento , Masculino , Inhibidores mTOR/efectos adversos , Trasplante de Riñón , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: There was no study evaluating the effects of an aspirin-free strategy in patients undergoing complex percutaneous coronary intervention (PCI). OBJECTIVES: The authors aimed to evaluate the efficacy and safety of an aspirin-free strategy in patients undergoing complex PCI. METHODS: We conducted the prespecified subgroup analysis based on complex PCI in the STOPDAPT-3 (ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3), which randomly compared low-dose prasugrel (3.75 mg/d) monotherapy to dual antiplatelet therapy (DAPT) with low-dose prasugrel and aspirin in patients with acute coronary syndrome or high bleeding risk. Complex PCI was defined as any of the following 6 criteria: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or a target of chronic total occlusion. The coprimary endpoints were major bleeding events (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) at 1 month. RESULTS: Of the 5,966 study patients, there were 1,230 patients (20.6%) with complex PCI. Regardless of complex PCI, the effects of no aspirin relative to DAPT were not significant for the coprimary bleeding (complex PCI: 5.30% vs 3.70%; HR: 1.44; 95% CI: 0.84-2.47; P = 0.18 and noncomplex PCI: 4.26% vs 4.97%; HR: 0.85; 95% CI: 0.65-1.11; P = 0.24; P for interaction = 0.08) and cardiovascular (complex PCI: 5.78% vs 5.93%; HR: 0.98; 95% CI: 0.62-1.55; P = 0.92 and noncomplex PCI: 3.70% vs 3.10%; HR: 1.20; 95% CI: 0.88-1.63; P = 0.25; P for interaction = 0.48) endpoints without significant interactions. CONCLUSIONS: The effects of the aspirin-free strategy relative to standard DAPT for the cardiovascular and major bleeding events were not different regardless of complex PCI. (ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111).
Asunto(s)
Aspirina , Enfermedad de la Arteria Coronaria , Esquema de Medicación , Stents Liberadores de Fármacos , Terapia Antiplaquetaria Doble , Everolimus , Hemorragia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Clorhidrato de Prasugrel , Diseño de Prótesis , Humanos , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/mortalidad , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Masculino , Factores de Tiempo , Femenino , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/uso terapéutico , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Factores de Riesgo , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/efectos adversos , Clorhidrato de Prasugrel/uso terapéutico , Everolimus/administración & dosificación , Everolimus/efectos adversos , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/mortalidad , Trombosis Coronaria/etiología , Trombosis Coronaria/prevención & control , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/diagnóstico por imagen , Aleaciones de Cromo , Medición de Riesgo , Quimioterapia CombinadaRESUMEN
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.
Asunto(s)
Inhibidores mTOR , Mastocitosis Sistémica , Sirolimus , Humanos , Mastocitosis Sistémica/tratamiento farmacológico , Proyectos Piloto , Femenino , Masculino , Persona de Mediana Edad , Adulto , Francia , Anciano , Sirolimus/uso terapéutico , Sirolimus/efectos adversos , Inhibidores mTOR/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Everolimus/uso terapéutico , Everolimus/efectos adversos , Resultado del Tratamiento , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Anciano de 80 o más AñosRESUMEN
BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.
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Androstadienos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Everolimus , Calidad de Vida , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Everolimus/administración & dosificación , Everolimus/efectos adversos , Receptor ErbB-2/metabolismo , Anciano , Persona de Mediana Edad , Androstadienos/administración & dosificación , Androstadienos/uso terapéutico , Androstadienos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores de Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Anciano de 80 o más Años , Adulto , Posmenopausia , Supervivencia sin ProgresiónRESUMEN
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.
Asunto(s)
Everolimus , Hipoglucemia , Insulinoma , Neoplasias Pancreáticas , Humanos , Femenino , Everolimus/uso terapéutico , Everolimus/efectos adversos , Insulinoma/secundario , Insulinoma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Resultado Fatal , Diazóxido/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: Everolimus in combination with exemestane was shown to offer benefit versus exemestane monotherapy in hormone receptor (HR)-positive, HER2-negative advanced breast cancer patients who progressed after aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: The medical records of metastatic breast cancer patients, treated with everolimus, were retrospectively reviewed to generate real life safety and efficacy data. RESULTS: Sixty-eight percent of the patients had received chemotherapy (for early or metastatic disease) and 26% had received chemotherapy for metastatic disease. Among the 25 included patients, the most common adverse events were fatigue, neutropenia, epistaxis, stomatitis, and pneumonitis. Toxicity led to treatment discontinuation in 3 patients (12%). The median progression-free survival (PFS) was 7 months (95%CI=3.5-10.5). With a median follow-up of 73.3 months, the median overall survival was not reached. Twenty-five percent of the patients had received prior therapy with CDK4/6 inhibitors. Median PFS was significantly shorter in this subgroup (p=0.025). There was also a trend towards a longer PFS in patients with grade 3 breast cancer (p=0.085) and in patients receiving everolimus as first-line treatment (p=0.081). Some long responses were noted, with four patients exhibiting a PFS >5 years. CONCLUSION: These real-life data show that everolimus in combination with AI in patients with HER2-negative, HR-positive advanced breast cancer is an effective treatment with an acceptable toxicity profile.
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Neoplasias de la Mama , Everolimus , Humanos , Femenino , Everolimus/efectos adversos , Neoplasias de la Mama/patología , Receptor ErbB-2 , Inhibidores de la Aromatasa/efectos adversos , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Androstadienos/efectos adversosRESUMEN
BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.
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Everolimus , Enfermedades Pulmonares Intersticiales , Tomografía Computarizada por Rayos X , Humanos , Everolimus/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/patología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Biomarcadores , Antineoplásicos/efectos adversos , Índice de Severidad de la Enfermedad , Proteína C-Reactiva/análisis , L-Lactato Deshidrogenasa , Pulmón/patología , Pulmón/diagnóstico por imagen , Pulmón/efectos de los fármacos , Adulto , Anciano de 80 o más Años , Mucina-1Asunto(s)
Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Humanos , Everolimus/efectos adversos , Sirolimus , Inmunosupresores/farmacología , Resultado del Tratamiento , Intervención Coronaria Percutánea/efectos adversos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Diseño de PrótesisRESUMEN
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.).
Asunto(s)
Angioplastia , Implantación de Prótesis Vascular , Isquemia Crónica que Amenaza las Extremidades , Stents Liberadores de Fármacos , Enfermedad Arterial Periférica , Arteria Poplítea , Humanos , Implantes Absorbibles , Angioplastia/efectos adversos , Angioplastia/métodos , Angioplastia de Balón/efectos adversos , Angioplastia de Balón/métodos , Implantación de Prótesis Vascular/métodos , Enfermedad Crónica , Isquemia Crónica que Amenaza las Extremidades/etiología , Isquemia Crónica que Amenaza las Extremidades/cirugía , Everolimus/administración & dosificación , Everolimus/efectos adversos , Everolimus/uso terapéutico , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Isquemia/tratamiento farmacológico , Isquemia/etiología , Isquemia/cirugía , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Arteria Poplítea/cirugía , Andamios del Tejido , Resultado del TratamientoRESUMEN
BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Humanos , Everolimus/efectos adversos , Tacrolimus/efectos adversos , Sirolimus/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Estudios Prospectivos , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Receptores de TrasplantesRESUMEN
PURPOSE: The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS: Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION: Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.
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Everolimus , Glioma , Humanos , Niño , Femenino , Preescolar , Adolescente , Adulto Joven , Adulto , Masculino , Everolimus/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt , Fosfatidilinositol 3-Quinasas , Glioma/tratamiento farmacológico , Glioma/genética , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/uso terapéutico , BiomarcadoresRESUMEN
OBJECTIVE: Sirolimus (SRL) and everolimus (EVL) are increasingly included in immunosuppressive protocols after heart transplantation. They present some side effects, including the appearance of painful lesions in the oral cavity. Therefore, this systematic review aimed to verify the global prevalence and clinical characteristics of oral lesions induced by SRL and EVL in heart transplant patients. STUDY DESIGN: A systematic review was performed using 5 main electronic databases (Medline/PubMed, SCOPUS, EMBASE, Web of Science, and LILACS), in addition to the gray literature. Studies were independently assessed by 2 reviewers based on established eligibility criteria. The risk of bias was assessed using the Joanna Briggs Institute appraisal tools, and the certainty of evidence was evaluated through GRADE assessment. RESULTS: Seventeen studies (860 patients) were included in the qualitative analysis. Of these, 11 studies were pooled in a meta-analysis of prevalence. The worldwide prevalence of oral lesions induced by SRL and EVL in heart transplant patients was 10.0%, and most lesions were described as ulcers >1.0 cm, related to significant pain. CONCLUSIONS: Oral lesions induced by SRL and/or EVL, although not very prevalent, have a relevant impact on patient's lives and the continuity of treatment.
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Everolimus , Trasplante de Corazón , Humanos , Everolimus/efectos adversos , Sirolimus/efectos adversos , Prevalencia , Inmunosupresores/efectos adversos , Trasplante de Corazón/efectos adversosRESUMEN
BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.
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Angiomiolipoma , Antineoplásicos , Astrocitoma , Epilepsia , Neoplasias Renales , Esclerosis Tuberosa , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Adulto Joven , Angiomiolipoma/tratamiento farmacológico , Antineoplásicos/efectos adversos , Astrocitoma/inducido químicamente , Astrocitoma/complicaciones , Astrocitoma/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Everolimus/efectos adversos , Neoplasias Renales/complicaciones , Convulsiones/tratamiento farmacológico , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/complicacionesRESUMEN
BACKGROUND/AIM: Everolimus (EVE)-based treatment is an option for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but a predictive marker has not yet been established. The recommended dose of EVE in combination with endocrine therapy is 10 mg/day, but due to adverse effects, patients are frequently forced to reduce the dose. However, the correct maintenance dose to achieve a therapeutic effect is still under debate. Employing real-world data, we examined clinicopathological factors to predict the efficacy of EVE-based treatment, particularly focusing on daily dose intensity (DDI). PATIENTS AND METHODS: Ninety-five patients with MBC who received EVE-based treatment in combination with exemestane during the period from 2014 to 2022 were retrospectively investigated. Doses of EVE were reduced as needed and DDI was calculated with total doses of EVE and the duration of the treatment. RESULTS: Mean time-to-treatment-termination (TTT) was 25.4 weeks. Patients with tumors with a high Ki67 labeling index, low absolute lymphocyte count, and small DDI of EVE had significantly shorter TTT (p=0.006, 0.043, and 0.030, respectively). When patients were categorized based on DDI of EVE, patients with DDI ≤5 mg/day had significantly shorter TTT (p=0.002). There were no correlations between RDI and factors such as age, body weight, and numbers of previous treatments for MBC. CONCLUSION: Maintaining a DDI of at least 5 mg/day seems crucial to achieving a therapeutic effect. Our data might be useful for determining the dosage of EVE in clinical practice.
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Neoplasias de la Mama , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Peso Corporal , Neoplasias de la Mama/tratamiento farmacológico , Everolimus/efectos adversos , Everolimus/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: The Synergy MegatronTM is an everolimus-drug eluting stent that may offer advantages in the treatment of aorto-ostial disease and large proximal vessels. AIMS: To report the short- to medium-term clinical outcomes from the European Synergy MegatronTM Implanters' Registry. METHODS: This registry was an investigator-initiated study conducted at 14 European centers. The primary outcome was target lesion failure (TLF), defined as the composite of cardiovascular death, target vessel myocardial infarction (MI), and target lesion revascularisation. RESULTS: Five hundred seventy-five patients underwent PCI with MegatronTM between 2019 and 2021. Patients were 69 ± 12 years old, 26% had diabetes mellitus, 24% had moderate-severe left ventricular impairment and 59% presented with an acute coronary syndrome. 15% were deemed prohibitively high risk for surgical revascularisation. The target vessel involved the left main stem in 55%, the ostium of the RCA in 13% and was a true bifurcation (Medina 1,1,1) in 50%. At 1 year, TLF was observed in 40 patients, with 26 (65%) occurring within the first 30 days. The cumulative incidence of TLF was 4.5% at 30 days and 8.6% (95% CI 6.3-11.7) at 1 year. The incidence of stent thrombosis was 0.5% with no late stent thromboses. By multivariate analysis, the strongest independent predictors of TLF were severe left ventricular impairment (HR 3.43, 95% CI: 1.67-6.76, p < 0.001) and a target vessel involving the left main (HR 4.00 95% CI 1.81-10.15 p = 0.001). CONCLUSIONS: Use of the Synergy MegatronTM everolimus eluting stent in a 'real-world' setting shows favorable outcomes at 30 days and 1 year.
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Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Trombosis , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Everolimus/efectos adversos , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/cirugía , Intervención Coronaria Percutánea/efectos adversos , Resultado del Tratamiento , Factores de Riesgo , Sistema de RegistrosRESUMEN
Background: Although regarded as a potentially efficient approach to address tuberous sclerosis complex (TSC)-associated complications, the adverse event profile of everolimus has not yet been fully elucidated. The present study aimed to clarify the adverse event spectrum in patients with TSC who are using everolimus for common indications, in comparison to those who do not use everolimus. Materials and Methods: We recruited patients with TSC who were followed up annually at TSC integrated clinics or referred for medical assistance. Medical reviews and laboratory investigations were performed at baseline and annually by clinical physicians. The adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Common adverse events in everolimus users included hypercholesterolemia (55%), gingivostomatitis (50%), proteinuria (50%), and hyperglycemia (40%). Compared with everolimus nonusers, the occurrence of gingivostomatitis and proteinuria was significantly higher in everolimus users (gingivostomatitis, p=0.02; proteinuria, p=0.02). Among the everolimus users, 12 patients had level I CTCAE, and five had level II CTCAE. None of the everolimus users presented with CTCAE level III or higher. Conclusion: Patients with TSC who are everolimus users had a higher tendency to develop gingivostomatitis and proteinuria compared to nonusers. However, no differences were observed in the occurrence of other adverse events between everolimus users and nonusers.
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Angiomiolipoma , Antineoplásicos , Astrocitoma , Neoplasias Renales , Esclerosis Tuberosa , Humanos , Everolimus/efectos adversos , Angiomiolipoma/tratamiento farmacológico , Angiomiolipoma/complicaciones , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/epidemiología , Neoplasias Renales/tratamiento farmacológico , Astrocitoma/tratamiento farmacológico , Astrocitoma/complicaciones , Proteinuria/inducido químicamente , Antineoplásicos/efectos adversosRESUMEN
BACKGROUND: Diabetic patients are at higher risk of recurrent adverse events following percutaneous coronary intervention (PCI) than the nondiabetics. Despite the introduction of new generation drug-eluting stents, their efficacy in the diabetics is still limited. AIMS: To evaluate the efficacy of the Abluminus DES+ biodegradable polymer sirolimus-eluting stent in reducing neointimal hyperplasia in diabetic patients, compared to a durable polymer everolimus-eluting stent (DP-EES). METHODS: A total of 131 patients with diabetes and coronary artery disease were enrolled in six Italian centers and randomized in a 2:1 fashion to PCI with Abluminus DES+ or DP-EES: 85 were assigned to Abluminus DES+ and 46 to DP-EES. The primary endpoint was optimal coherence tomography (OCT)-derived neointimal volume at 9-12 months. Secondary endpoints included OCT-derived neointimal area, neointimal volume obstruction and adverse clinical events. RESULTS: The primary endpoint, neointimal volume, did not differ between Abluminus DES+ and DP-EES (29.11 ± 18.90 mm3 vs. 25.48 ± 17.04 mm3 , p = 0.40) at 9-12-month follow-up. This finding remained consistent after weighing for the sum of stents lengths (1.14 ± 0.68 mm3 vs. 0.99 ± 0.74 mm3 for Abluminus DES+ and DP-EES, respectively, p = 0.38). Similarly, other OCT-derived and clinical secondary endpoints did not significantly differ between the two groups. Rate of target lesion failure was high in both groups (21.2% for Abluminus DES+ and 19.6% for DP-EES). CONCLUSIONS: This preliminary study failed to demonstrate the superiority of the Abluminus DES+ over the DP-EES in diabetic patients in terms of neointimal proliferation.
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Diabetes Mellitus , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Humanos , Implantes Absorbibles , Everolimus/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Polímeros , Sirolimus/efectos adversos , Tomografía de Coherencia Óptica , Resultado del TratamientoRESUMEN
BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Everolimus/efectos adversos , Temozolomida , Calidad de Vida , Estudios Prospectivos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patologíaRESUMEN
BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.