RESUMO
Nemaline rod myopathy is an extremely rare muscle disease responsible for hypotonia and poor muscle strength in infants. The disease has variable phenotypic presentations across different ages, ranging from neonatal to the adult onset and from severe to asymptomatic varieties. Clinical features, muscle biopsy and genetic testing help in diagnosis. The histopathological examination shows the presence of rod-like structures or nemaline bodies in muscles. Management remains mainly supportive, and currently, there is no available curative treatment. This case report describes an infant presenting with gross hypotonia, poor handling of secretions and multiple extubation failures who was diagnosed by clinical exome sequencing. The patient harboured compound heterozygous variants in the NEB gene suggestive of nemaline rod myopathy. The newborn showed significant improvement in muscle strength after he was started on dietary L-tyrosine supplementation. This case highlights the emerging role of L-tyrosine in the supportive care of infants with nemaline rod myopathy.
Assuntos
Miopatias da Nemalina , Tirosina , Humanos , Miopatias da Nemalina/genética , Miopatias da Nemalina/tratamento farmacológico , Masculino , Tirosina/uso terapêutico , Recém-Nascido , Lactente , Hipotonia Muscular/tratamento farmacológico , Proteínas Musculares/genética , Músculo Esquelético/patologia , Resultado do TratamentoRESUMO
PET using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) has been shown to be of value for treatment monitoring in patients with brain metastases after multimodal therapy, especially in clinical situations with equivocal MRI findings. As medical procedures must be justified socioeconomically, we determined the effectiveness and cost-effectiveness of 18F-FET PET for treatment monitoring of multimodal therapy, including checkpoint inhibitors, targeted therapies, radiotherapy, and combinations thereof in patients with brain metastases secondary to melanoma or non-small cell lung cancer. Methods: We analyzed already-published clinical data and calculated the associated costs from the German statutory health insurance system perspective. Two clinical scenarios were considered: decision tree model 1 determined the effectiveness of 18F-FET PET alone for identifying treatment-related changes, that is, the probability of correctly identifying patients with treatment-related changes confirmed by neuropathology or clinicoradiographically using the Response Assessment in Neuro-Oncology criteria for immunotherapy. The resulting cost-effectiveness ratio showed the cost for each correctly identified patient with treatment-related changes in whom MRI findings remained inconclusive. Decision tree model 2 calculated the effectiveness of both 18F-FET PET and MRI, that is, the probability of correctly identifying nonresponders to treatment. The incremental cost-effectiveness ratio was calculated to determine cost-effectiveness, that is, the cost for each additionally identified nonresponder by 18F-FET PET who would have remained undetected by MRI. One-way deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: 18F-FET PET identified 94% of patients with treatment-related changes, resulting in 1,664.23 (1.00 = $1.08 at time of writing) for each correctly identified patient. Nonresponders were correctly identified in 60% by MRI and in 80% by 18F-FET PET, resulting in 3,292.67 and 3,915.83 for each correctly identified nonresponder by MRI and 18F-FET PET, respectively. The cost to correctly identify 1 additional nonresponder by 18F-FET PET, who would have remained unidentified by MRI, was 5,785.30. Conclusion: Given the considerable annual cost of multimodal therapy, the integration of 18F-FET PET can potentially improve patient care while reducing costs.
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Neoplasias Encefálicas , Análise Custo-Benefício , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Tirosina , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Tomografia por Emissão de Pósitrons/economia , Imageamento por Ressonância Magnética/economia , Tirosina/análogos & derivados , Tirosina/uso terapêutico , Terapia Combinada , Imagem Multimodal/economia , Masculino , Feminino , Análise de Custo-EfetividadeRESUMO
INTRODUCTION: Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED: In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION: The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.
Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Inibidores Enzimáticos/farmacologia , Mutação , Tirosina/genética , Tirosina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
In the past decade, numerous tyrosine kinase inhibitors (TKIs) have been introduced in the treatment of chronic myeloid leukemia. Given the significant interpatient variability in TKIs pharmacokinetics, potential drug-drug interactions (DDIs) can greatly impact patient therapy. This review aims to discuss the pharmacokinetic characteristics of TKIs, specifically focusing on their absorption, distribution, metabolism, and excretion profiles. Additionally, it provides a comprehensive overview of the utilization of TKIs in special populations such as the elderly, children, and patients with liver or kidney dysfunction. We also highlight known or suspected DDIs between TKIs and other drugs, highlighting various clinically relevant interactions. Moreover, specific recommendations are provided to guide haemato-oncologists, oncologists, and clinical pharmacists in managing DDIs during TKI treatment in daily clinical practice.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Criança , Humanos , Idoso , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Interações Medicamentosas , Tirosina/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Triple-negative breast cancer (TNBC) comprises a group of aggressive and heterogeneous breast carcinoma. Chemotherapy is the mainstay for the treatment of triple-negative tumors. Nevertheless, the success of chemotherapeutic treatments is limited by their toxicity and development of acquired resistance leading to therapeutic failure and tumor relapse. Hence, there is an urgent need to explore novel targeted therapies for TNBC. Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that are key regulators of intracellular signaling pathways controlling cell proliferation, differentiation, survival, and motility. Aberrant activity and/or expression of several types of RTKs have been strongly connected to tumorigenesis. RTKs are frequently overexpressed and/or deregulated in triple-negative breast tumors and are further associated with tumor progression and reduced survival in patients. Therefore, targeting RTKs could be an appealing therapeutic strategy for the treatment of TNBC. This review summarizes the current evidence regarding the antitumor activity of RTK inhibitors in preclinical models of TNBC. The review also provides insights into the clinical trials evaluating the use of RTK inhibitors for the treatment of patients with TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Recidiva Local de Neoplasia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/uso terapêutico , Transdução de Sinais , Proliferação de Células , Tirosina/uso terapêutico , Linhagem Celular TumoralRESUMO
Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Trastuzumab/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Fosforilação , Fator de Transcrição AP-2/metabolismo , Receptor ErbB-2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Quinases da Família src/metabolismo , Quinases da Família src/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tirosina/metabolismo , Tirosina/uso terapêuticoRESUMO
BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.
Assuntos
Linfoma de Células T Periférico , Adulto , Humanos , Masculino , Feminino , Adolescente , Pessoa de Meia-Idade , Linfoma de Células T Periférico/tratamento farmacológico , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Progressão da Doença , Janus Quinase 1/genética , Tirosina/uso terapêuticoRESUMO
OBJECTIVES: Psoriasis of the scalp is challenging to manage. The only approved oral tyrosine kinase 2 and phosphodiesterase 4 inhibitors for psoriasis are deucravacitinib and apremilast. The aim of this study was to explore their efficacy for scalp psoriasis utilizing data from randomized controlled trials. METHODS: We searched Medline, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov up to August 4, 2023. To determine risk of bias, the revised Risk of Bias assessment tool 2.0 was used. Inverse variance random effects meta-analyses were executed. Heterogeneity was assessed utilizing Q and I2 statistics. Pre-determined outcomes included the proportion of participants with cleared scalp skin (Scalp Physician's Global Assessment [ScPGA] of 0/1), mean change in Psoriasis Scalp Severity Index (PSSI), and mean improvement in Dermatology Life Quality Index (DLQI). RESULTS: Ten RCTs fulfilled inclusion criteria. Both apremilast (RR = 2.41, 95% CI = 2.08-2.79, Tau2 = 0, I2 = 0) and deucravacitinib (RR = 3.86, 95% CI = 3.02-4.94, Tau2 = 0, I2 = 0) were more effective in inducing ScPGA of 0/1 at 16 weeks compared to placebo. Furthermore, deucravacitinib was more effective than apremilast (RR = 1.70, 95% CI = 1.44-2.00, Tau2 = 0, I2 = 0). An analysis could not be executed for the rest of the outcomes. CONCLUSIONS: Apremilast and deucravacitinib are effective for scalp psoriasis. Deucravacitinib may be more efficient in clearing the scalp.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida/análogos & derivados , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/uso terapêutico , TYK2 Quinase/uso terapêutico , Couro Cabeludo , Psoríase/tratamento farmacológico , Tirosina/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. MATERIAL AND METHODS: All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. RESULTS: A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. CONCLUSION: In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria. These could help select patients that may benefit from first-line treatment with a TKI, particularly in settings with difficult access to novel therapies, such as immunotherapy-based combinations.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Tirosina/uso terapêuticoRESUMO
Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of tyramine in the body, and can cause a sudden increase in blood pressure with significant tyramine build up. This phenomenon, when it occurs, is known as tyramine pressor response. It is unknown if tyrosine administered in parenteral nutrition (PN) leads to tyramine build-up with concomitant use of MAOIs. It is also unknown if PN patients who are taking MAOI are at risk for the tyramine pressor response. This is a theoretical possibility as tyrosine endogenously undergoes decarboxylation to produce tyramine. We describe our experience with a 67-year-old woman with severe depression who was on the MAOI, transdermal selegiline. Her clinical course was complicated by an inability to take adequate per oral (PO) intake and she met criteria for unspecified severe protein-calorie-malnutrition in the context of social or environmental circumstances. Therefore, she required PN initiation. PlenamineTM (B. Braun, Bethlehem, PA, USA) was used as the amino acid source in the PN, which contains 39 mg of tyrosine per 100 ml of solution. The patient was monitored closely for any signs of hypertensive crisis while on PN and selegiline. She safely tolerated the combined therapy without any side effects. This is the first documented report of co-administration of PN containing tyrosine along with a MAOI. Our findings suggest that the dose of selegiline used in this patient can be co-administered safely in the setting of PN. However, further study is needed to verify our findings beyond this one patient. In conclusion, we recommend initiating PN and increasing it to goal in patients taking MAOIs, gradually, while monitoring for hypertensive crisis given the theoretical possibility of the tyramine pressor response.
Assuntos
Transtorno Depressivo , Inibidores da Monoaminoxidase , Feminino , Humanos , Idoso , Inibidores da Monoaminoxidase/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Selegilina/uso terapêutico , Selegilina/efeitos adversos , Tirosina/farmacologia , Tirosina/uso terapêutico , Pressão Sanguínea , Tiramina/efeitos adversosRESUMO
Renal cancer is the seventh most common cancer in men and the tenth in women. The aim of this article is to review the diagnosis, treatment, and follow-up of renal carcinoma accompanied by recommendations with new evidence and treatment algorithms. A new pathologic classification of RCC by the World Health Organization (WHO) was published in 2022 and this classification would be considered a "bridge" to a future molecular classification. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. Adjuvant treatment with pembrolizumab is an option for intermediate-or high-risk cases, as well as patients after complete resection of metastatic disease. More data are needed in the future, including positive overall survival data. Clinical prognostic classification, preferably IMDC, should be used for treatment decision making in mRCC. Cytoreductive nephrectomy should not be deemed mandatory in individuals with intermediate-poor IMDC/MSKCC risk who require systemic therapy. Metastasectomy can be contemplated in selected subjects with a limited number of metastases or long metachronous disease-free interval. For the population of patients with metastatic ccRCC as a whole, the combination of pembrolizumab-axitinib, nivolumab-cabozantinib, or pembrolizumab-lenvatinib can be considered as the first option based on the benefit obtained in OS versus sunitinib. In cases that have an intermediate IMDC and poor prognosis, the combination of ipilimumab and nivolumab has demonstrated superior OS compared to sunitinib. As for individuals with advanced RCC previously treated with one or two antiangiogenic tyrosine-kinase inhibitors, nivolumab and cabozantinib are the options of choice. When there is progression following initial immunotherapy-based treatment, we recommend treatment with an antiangiogenic tyrosine-kinase inhibitor. While no clear sequence can be advocated, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in the setting of metastatic RC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Masculino , Humanos , Feminino , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/tratamento farmacológico , Sunitinibe/efeitos adversos , Nivolumabe/uso terapêutico , Qualidade de Vida , Neoplasias Renais/terapia , Neoplasias Renais/tratamento farmacológico , Tirosina/uso terapêuticoRESUMO
BACKGROUND: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. METHODS: We examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who were on tyrosine-kinase inhibitor therapy for at least 90 days. t tests were used to compare mean differences in UACR, while regression analysis was used to assess the effects of drug parameters on proteinuria development while on dasatinib. We assayed plasma dasatinib pharmacokinetics using tandem mass spectroscopy and further described a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. RESULTS: Participants treated with dasatinib ( n =32) had significantly higher UACR levels (median 28.0 mg/g; interquartile range, 11.5-119.5) than participants treated with other tyrosine-kinase inhibitors ( n =50; median 15.0 mg/g; interquartile range, 8.0-35.0; P < 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR >300 mg/g) versus zero in other tyrosine-kinase inhibitors. Average steady-state concentrations of dasatinib were positively correlated with UACR ( ρ =0.54, P = 0.03) and duration of treatment ( P = 0.003). There were no associations with elevated BP or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered on termination of dasatinib treatment. CONCLUSIONS: Exposure to dasatinib was associated with a significant chance of developing proteinuria compared with other similar tyrosine-kinase inhibitors. Dasatinib plasma concentration significantly correlated with higher risk of developing proteinuria while receiving dasatinib. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000219.mp3.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Dasatinibe/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Proteinúria/tratamento farmacológico , Albuminúria/tratamento farmacológico , Tirosina/uso terapêuticoRESUMO
BACKGROUND: The presence of angiographic thrombus is associated with poor outcomes in contemporary cardiology practice. Percutaneous coronary intervention (PCI) in such lesions is associated with slow flow and no-reflow phenomenon which translate into poor clinical outcomes. METHODS: This was a single-centre, prospective, open-label, randomized controlled study with 50 patients each in intervention group and control group. Patients with angiographically proven large thrombus burden were recruited. In the intervention group, patients were given loading dose of intracoronary tirofiban (25 mcg/kg infused over 5 minutes) followed by prolonged infusion of tirofiban (0.15 mcg/kg/min for 12-18 hours) followed by PCI after 48-72 hours interval. In control group patients were taken up directly for PCI during the index procedure. Outcomes were assessed angiographically and in terms of clinical endpoints. RESULTS: The primary composite-endpoint of recurrent angina, myocardial infarction, cardiovascular death, target lesion revascularization and unscheduled CABG was significantly lower in the intervention arm compared to control arm (4% vs 16%, p = 0.04). Amongst the secondary endpoints, a statistically significant 30-day increase in ejection fraction from baseline was observed in the intervention group compared to the control group (1.6 ± 1.3 vs 0.2 ± 0.4, p = 0.0001). Overall mortality was similar in the two groups (4% vs 8%, p = 0.39). The primary safety endpoint of major bleeding was also similar in the 2 groups (2% vs 0%, p = 0.31). CONCLUSIONS: Tirofiban use prior to PCI in high thrombus burden was associated with improved clinical and angiographic endpoints with similar adverse events compared to controls.
Assuntos
Angioplastia Coronária com Balão , Trombose Coronária , Intervenção Coronária Percutânea , Humanos , Tirofibana , Estudos Prospectivos , Tirosina/uso terapêutico , Tirosina/efeitos adversos , Angioplastia Coronária com Balão/efeitos adversos , Resultado do Tratamento , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Stents , Perfusão , Angiografia , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de PlaquetasRESUMO
BACKGROUND: In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). FINDINGS: Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. INTERPRETATION: This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. FUNDING: National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Cisplatino , Pemetrexede , China , Progressão da Doença , Receptores ErbB/genética , Tirosina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-CegoRESUMO
BACKGROUND: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy. METHODS: This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing. FINDINGS: Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure). INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor. FUNDING: Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute.
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Carcinoma de Células Renais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Renais/secundário , Anticorpos Monoclonais Humanizados/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Imunoterapia , Tirosina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.
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Alcaptonúria , Ocronose , Tirosinemias , Humanos , Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Ocronose/tratamento farmacológico , Tirosina/uso terapêutico , Ácido Homogentísico/metabolismoRESUMO
BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fosfoproteínas/genética , Fatores de Transcrição/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Sinalização YAP , Colangiocarcinoma/genética , Ductos Biliares Intra-Hepáticos/patologia , Tirosina/genética , Tirosina/metabolismo , Tirosina/uso terapêutico , Linhagem Celular TumoralRESUMO
PURPOSE: Cancer cell-derived exosomes are the mediator of the tumor microenvironment and the molecular content of exosomes presents a promising prognostic or predictive marker in tumor progression and the treatment response of cancer patients. The aim of this study was to identify the expression levels of receptor tyrosine kinases (RTKs) and AKT1 and mTOR before and after neoadjuvant chemotherapy (NACT) in the exosomes of BC patients compared with healthy females. METHODS: After isolating exosomes in the serum of 25 BC patients and characterization by flow cytometry, the mRNA levels of FGFR2, FGFR3, PDGFRB, AKT1 and mTOR in the exosomes were analyzed by RT-PCR. RESULTS: Our preliminary findings showed that FGFR2, PDGFRB, AKT1 and mTOR levels were significantly upregulated in BC patients before NACT compared with the healthy group (p < 0.05). Furthermore, the mRNA levels PDGFRB and AKT1 were significantly down-regulated after NACT compared with control. PDGFRB expression level could predict pathological non-response and significantly correlated with tumor size after NACT. CONCLUSION: Therefore, especially FGFR2, PDGFRB and AKT1 could be a therapeutic target as a prognostic marker, whereas PDGFRB may be a promising predictive indicator of therapy response in BC patients. However, the prognostic or predictive role of RTKs and PI3K/AKT/mTOR signaling in the exosomes should be further investigated in a large patient population.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Terapia Neoadjuvante , Receptor beta de Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Receptores Proteína Tirosina Quinases , RNA Mensageiro , Tirosina/uso terapêutico , Microambiente TumoralRESUMO
It was demonstrated that effervescent glutamine supplementation in HIV+ individuals treated with antiretroviral therapy (ART) increased CD4+ T lymphocytes, decreased inflammation biomarkers, and brought health benefits. This pilot study aimed to explore serum metabolite variations in the HIV+ group under ART after 30 days of supplementation with glutamine, and in comparison to the matched HIV- group. The group of HIV+ showed lower levels of choline, creatine, pyruvate, glutamate, lysine, and tyrosine when compared to the HIV- group. Glucose, lipids, lactate, glutamine, phenylalanine, threonine, and phenylalanine/tyrosine were higher in HIV+ patients under long ART. Serum metabolome variations were shown to be consistent with the health improvements observed in the HIV+ group after effervescent glutamine supplementation, which might aid in ART in HIV+ individuals.
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Glutamina , Infecções por HIV , Humanos , Glutamina/uso terapêutico , Projetos Piloto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Tirosina/uso terapêutico , Fenilalanina/uso terapêutico , Administração OralRESUMO
Vemurafenib-induced drug resistance in melanoma has been linked to receptor tyrosine kinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators of melanocyte and melanoma development. Here, we aimed to explore the complex mechanisms behind the MITF/SOX10-controlled RTK-induced drug resistance in melanoma. To achieve this, we used a number of molecular techniques, including melanoma patient data from TCGA, vemurafenib-resistant melanoma cell lines, and knock-down studies. The melanoma cell lines were classified as proliferative or invasive based upon their MITF/AXL expression activity. We measured the change of expression activity for MITF/SOX10 and their receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved in RTK-induced drug resistance after vemurafenib treatment. We find that melanoma cell lines characterized as proliferative (high MITF low AXL), transform into an invasive (low MITF, high AXL) cell state after vemurafenib resistance, indicating novel feedback loops and advanced compensatory regulation mechanisms between the master regulators, receptors, and ligands involved in vemurafenib-induced resistance. Together, our data disclose fine-tuned mechanisms involved in RTK-facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma.