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1.
Cancers (Basel) ; 13(23)2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34885091

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

2.
Clin Exp Med ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591219

RESUMO

The aim of our study was to describe the epidemiology, diagnosis, and treatment of the most complex pheochromocytoma and paraganglioma (PGL) cases, including pheochromocytoma/PGL during pregnancy, in cyanotic congenital heart diseases (CCHDs), and metastatic pheochromocytoma. The English and Spanish literature was thoroughly evaluated searching for articles reporting clinical studies, case reports, or reviews of pheochromocytoma/PGL in pregnancy and in CCHD and metastatic pheochromocytoma/PGL. Particular settings in the diagnosis and management of pheochromocytoma and PGLs remain challenging. Those special situations include the diagnosis during pregnancy or in the context of CCHD since the typical clinical features of pheochromocytoma may be confounded with preeclampsia during pregnancy and with the complications commonly observed in CCHD. In addition, although some clinical and genetic features have been associated with higher risk of metastatic pheochromocytoma, the detection and prediction of the development of metastatic disease involve another complex situation that may require special hormonal determinations as plasmatic 3-methoxytyramine and nuclear medicine studies including 18FDG PET-CT or 18F-FDOPA PET-CT, among others. Furthermore, the selection of the most appropriate treatment in these situations, as well as the moment to carry it out, requires special care as limited evidence is available. This article reviews the epidemiology, diagnosis, and treatment of the pheochromocytoma/PGL during pregnancy, metastatic pheochromocytoma/PGL, and pheochromocytoma/PGL in CCHD. The diagnosis, and especially the treatment, of metastatic pheochromocytomas and pheochromocytoma/PGL during pregnancy and in CCHD is challenging. Thus, these cases should be management in reference centres by multidisciplinary teams specialized in the pheochromocytoma/PGL treatment.

3.
Ther Adv Urol ; 13: 17562872211043341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552666

RESUMO

Introduction: Androgenic deprivation therapies have been linked to the development of metabolic syndrome (MS) and cardiovascular diseases, which may lead to a poorer survival in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC). We aimed to analyze whether some cardiovascular or neurological disorders, together with other medical and urological complications, may have an effect on survival outcomes, at baseline and during treatment from patients treated with androgen pathway inhibitors (API). Material and Methods: A retrospective study of a consecutive series of patients diagnosed with mCRPC between 2010 and 2018 treated with API in the first line setting in a single center. Results: Seventy-three patients met the inclusion criteria. Baseline prognostic factors associated with worse survival were diabetes mellitus (DM) with insulin needs compared to patients without DM [hazard ratio (HR) = 0.19, p = 0.025], hypertension (HTN) (HR = 0.46, p = 0.035), and a history of stroke (HR = 0.16, p < 0.001). However, previous history of hypercholesterolemia, arrythmias, and cognitive disorders did not result in a significant worsening on survival. During treatment, patients who developed de novo HTN had the best progression free survival (PFS) (HR = 0.38, p = 0.048) and overall survival (OS) (HR 0.08, p = 0.012) compared with patients with previous HTN. Other factors related to worse outcomes included the presence of heart failure (HR = 0.31, p = 0.001), the requirement for major opioids for pain relief (HR = 0.33, p = 0.023), and the presence of bilateral ureterohydronephrosis (HR = 0.12, p = 0.008). Conclusions: Some comorbidities may be strongly involved in patient outcomes when receiving API for mCRPC. In this sense, collaborative networking between specialists and caregivers treating prostate cancer (PC) patients should be recommended, focusing on MS features, cardiovascular and neurological disorders in order to anticipate medical and surgical complications.

4.
Target Oncol ; 16(5): 625-632, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34338966

RESUMO

BACKGROUND: Renal cell carcinoma with sarcomatoid differentiation is a highly aggressive form of kidney cancer. OBJECTIVE: We aimed to analyze the outcomes of patients treated with cabozantinib for metastatic renal cell carcinoma with sarcomatoid features. METHODS: We retrospectively collected data from 16 worldwide centers. Overall survival and progression-free survival were analyzed using Kaplan-Meier curves. Cox proportional models were used for univariate and multivariate analyses. RESULTS: We collected data from 66 patients with metastatic sarcomatoid renal cell carcinoma receiving cabozantinib as second-line (51%) or third-line (49%) therapy. The median progression-free survival from the start of cabozantinib was 7.59 months (95% confidence interval [CI] 5.75-17.49) and was longer in male patients (8.81 vs 5.95 months, p = 0.042) and in patients without bone metastases (7.59 vs 5.11 months, p = 0.010); the median overall survival was 9.11 months (95% CI 7.13-23.80). At the multivariate analysis, female sex (hazard ratio = 1.81; 95% CI 1.02-3.37, p = 0.046), bone metastases (hazard ratio = 2.62; 95% CI 1.34-5.10, p = 0.005), and International Metastatic Renal Cell Carcinoma Database Consortium criteria (hazard ratio = 3.04; 95% CI 1.54-5.99, p = 0.001) were significant predictors of worse overall survival. CONCLUSIONS: Our data show that cabozantinib is active in pretreated patients with sarcomatoid renal cell carcinoma. Biomarkers are needed in this field to select patients for multi-kinase inhibitors or other options.

5.
Oncologist ; 26(11): 941-949, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34190375

RESUMO

BACKGROUND: Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs). METHODS: Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1. RESULTS: From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6-18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations. CONCLUSION: SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062) IMPLICATIONS FOR PRACTICE: Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.

6.
Biomedicines ; 9(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809752

RESUMO

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

7.
Target Oncol ; 16(3): 283-294, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33710533

RESUMO

Following platinum-based regimens becoming the reference standard of care, it has taken almost four decades to find a systemic treatment that improved overall survival in metastatic urothelial tumors. Single-agent immune checkpoint inhibitors have not only improved overall survival but also the quality of life of patients with metastatic urothelial tumors after failure of platinum-based regimens and as a maintenance therapy after four to six cycles of standard first-line chemotherapy. In addition, very promising data are emerging when single-agent immunotherapy is offered as adjuvant or neoadjuvant treatment for patients with muscle-invasive disease and also in the non-muscle-invasive setting. There is an extensive debate about the role of PD-L1 expression as a reliable biomarker to predict the activity of immune-based regimens. Furthermore, the lack of consensus concerning its utility means that there is a need for more and better tools to identify patients who are likely to benefit from these novel approaches. The field of urothelial tumors now additionally exploits novel antibody-drug conjugates and fibroblast growth factor-receptor inhibitors that are being tested in combination with immunotherapy. This added complexity contributes to an enormous increase in the challenges that will be faced shortly.


Assuntos
Imunoterapia/métodos , Neoplasias Urológicas/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino
8.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451055

RESUMO

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.


Assuntos
Biomarcadores Tumorais , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/etiologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Ensaios Clínicos como Assunto , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/etiologia , Neoplasias Urológicas/diagnóstico
9.
Healthcare (Basel) ; 9(1)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467441

RESUMO

COVID-19 is affecting many countries all around the world. Unfortunately, no treatment has already been approved for the management of patients infected by SARS-CoV-2. It seems that SARS-CoV-2 can induce the activation of an exaggerated immune response against itself according to different mechanisms that are not really well known. Inflammatory interleukins, such as IL-6 among others, play a central role in this uncontrolled immune response. There is a strong rational under ibrutinib use in in the treatment of immune-based diseases, such a as GVHD or RA. Ibrutinib achieves a reduction in the production of TNFα, IL1, IL-6 and Monocyte chemo-attractant protein-1 (MCP-1) by neutrophils and macrophages, that are key players in keeping the inflammatory process. We present our clinical experience about ibrutinib use in ARDS secondary to SARS-CoV-2 in a patient with chronic lymphocytic leukemia (CLL).

10.
Int J Mol Sci ; 21(22)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198314

RESUMO

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.


Assuntos
Neoplasias/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico/metabolismo , Carcinogênese , Receptores ErbB/metabolismo , Humanos , Imunoterapia , Ligantes , Neovascularização Patológica , Fosforilação , Medicina de Precisão , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor ErbB-2/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor trkA/metabolismo , Transdução de Sinais
11.
Int J Mol Sci ; 21(14)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668761

RESUMO

Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Neoplasias da Glândula Tireoide/terapia , Adenocarcinoma Folicular/enzimologia , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/terapia , Adenoma Oxífilo/enzimologia , Adenoma Oxífilo/genética , Adenoma Oxífilo/terapia , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Medular/enzimologia , Carcinoma Medular/genética , Carcinoma Medular/terapia , Carcinoma Papilar/enzimologia , Carcinoma Papilar/genética , Carcinoma Papilar/terapia , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Previsões , Genes Neoplásicos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoconjugados/uso terapêutico , Imunoterapia , Radioisótopos do Iodo/uso terapêutico , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/genética , Microambiente Tumoral/imunologia
12.
Arch Esp Urol ; 73(5): 360-366, 2020 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32538805

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 virus has caused an important health impact that has affected renal cell carcinoma management, among other urology areas. The high cancellation rate of surgeries, including those related to renal cancer, will cause an inevitable healthcare overload and probably a potential negative impact on its oncological outcomes, especially in locally advanced and metastatic renal cancer. Kidney cancer scenarios are quite different depending on their stage, distinguishing mainly between low priority of localized disease or high priority of locally advanced and metastatic under active treatment. The unknown pandemic duration and possibly fluctuating prevalence of the virus are likely to force an adaptation in the management of renal cell carcinoma among urology and oncology departments, ideally individualized ona case-by-case basis within multidisciplinary units. To this end, we present algorithms and tables regarding renal cell carcinoma management adapted to the COVID-19 period and stratified according to oncological stage, which might be useful for specialists dedicated to this uro-oncology area.


Assuntos
Betacoronavirus , Carcinoma de Células Renais , Infecções por Coronavirus , Neoplasias Renais , Pandemias , Pneumonia Viral , Algoritmos , COVID-19 , Carcinoma de Células Renais/terapia , Infecções por Coronavirus/epidemiologia , Humanos , Neoplasias Renais/terapia , Pneumonia Viral/epidemiologia , SARS-CoV-2
13.
Oncotarget ; 11(22): 2137-2140, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32547710

RESUMO

Currently, more and more patients receive first-line treatment with immunotherapy combinations and not all patients respond in metastatic renal cell carcinoma. After IO-IO progression, we don't have a standard of treatment because it is not available prospective data on this setting. We present the case of a patient with metastatic renal cell carcinoma who suffered hyperprogression with IO-IO combination in first line. Second line with cabozantinib results in a deep response of the disease. We performed a Foundation One testing to the patient which showed a mutation in NOTCH. The molecular mechanism to explain patient's response, it's the probably crosstalk between MET and NOTCH pathway. Nowadays, there is not clear the subsequent treatment in those patients who progress to IO-IO first line. More efforts in biomarkers development should be made to better selection of patients treatment along the disease.

14.
Cancers (Basel) ; 12(6)2020 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-32545884

RESUMO

Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.

16.
Arch. esp. urol. (Ed. impr.) ; 73(5): 360-366, jun. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-189692

RESUMO

La pandemia COVID-19 causada por el virus SARS-CoV-2 ha provocado un importante impacto sanitario que ha afectado, entre otras áreas de la urología, al manejo del cáncer renal, tanto en su ámbito diagnóstico como de tratamiento. La elevada suspensión de intervenciones quirúrgicas, incluidas aquellas destinadas al tratamiento de esta patología, ocasionará una inevitable sobrecarga asistencial y quizá un potencial efecto deletéreo sobre sus resultados oncológicos, en especial en el cáncer renal localmente avanzado y en el metastásico. Los escenarios clínicos del carcinoma de células renales son bien distintos en función de su estadiaje, distinguiendo principalmente entre la baja prioridad de la enfermedad localizada o la alta prioridad del localmente avanzado y el metastásico en tratamiento activo. La duraciónin determinada y prevalencia posiblemente oscilante de la pandemia previsiblemente obligue a adaptar el manejo del cáncer renal en los servicios de urología y oncología, debiendo ser idealmente invidualizados según cada caso en el seno de unidades multidisciplinares. Para ello, se presentan algoritmos y tablas de manejo del cáncer renal adaptadas al periodo COVID-19 y estratificados según el estadio de la enfermedad, que puedan ser de utilidad para los especialistas dedicados a esta área de la uro-oncología


The COVID-19 pandemic caused by SARS-CoV-2 virus has caused an important health impact that has affected renal cell carcinoma management, among other urology areas. The high cancellation rate of surgeries, including those related to renal cancer, will cause an inevitable healthcare overload and probably a potential negative impact on its oncological outcomes, especially in locally advanced and metastatic renal cancer. Kidney cancer scenarios are quite different depending on their stage, distinguishing mainly between low priority of localized disease or high priority of locally advanced and metastatic under active treatment. The unknown pandemic duration and possibly fluctuating prevalence of the virus are likely to force an adaptation in the management of renal cell carcinoma among urology and oncology departments, ideally individualized on a case-by-case basis within multidisciplinary units. To this end, we present algorithms and tables regarding renal cell carcinoma management adapted to the COVID-19 period and stratified according to oncological stage, which might be useful for specialists dedicated to this uro-oncology area


Assuntos
Humanos , Neoplasias Renais/terapia , Neoplasias Renais/diagnóstico , Administração Hospitalar , Infecções por Coronavirus/prevenção & controle , Pneumonia Viral/prevenção & controle , Pandemias , Prioridades em Saúde/organização & administração , Telemedicina , Seguimentos
17.
Oncologist ; 25(8): e1259, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32436340
19.
Oncologist ; 25(9): 745-e1265, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32045050

RESUMO

LESSONS LEARNED: Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors. Predictive biomarkers that improve patient selection should be investigated in future studies of palbociclib. BACKGROUND: Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines. Here we prospectively assessed the activity and safety of palbociclib in monotherapy in metastatic refractory pNETs. METHODS: This was a nonrandomized, open-label, phase II study of patients with metastatic grade (G)1/2 pNETs recruited from 10 centers in Spain. Palbociclib 125 mg was orally administered once daily for 21 of 28 days until disease progression or unacceptable toxicity. RESULTS: Twenty-one patients were included; 52.4% were men, and median age was 57.4 years (range, 37.4-73.4). Patients had previously received a median of three prior lines of systemic therapy (range, 1-10) for advanced disease (somatostatin analogues, 71.4%; sunitinib, 81.0%; everolimus, 47.6%; chemotherapy, 47.6%). Nineteen patients were evaluated for objective response rate (ORR), with a median follow-up of 12.4 months (range, 7.53-19.33). No objective and confirmed responses were observed (0%); 11 (57.9%) patients had stable disease, and 6 of them lasted more than 6 months; 8 (42.1%) patients had disease progression as best response. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 0-14.4) and median overall survival (OS) was 18.7 months (95% CI, 7.4-29.9; Fig. 1). Most frequent toxicities of any grade were asthenia (76.2%), neutropenia (42.9%), diarrhea (33.3%), and nausea (33.3%). Five (23.8%) patients developed G3-4 neutropenia and two (9.5%) patients developed G3-4 thrombocytopenia. CONCLUSION: Lack of activity was observed with palbociclib as a single agent in molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Piperazinas/efeitos adversos , Piridinas , Espanha
20.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597249

RESUMO

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neovascularização Patológica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Biomarcadores , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Gradação de Tumores , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/etiologia , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Resultado do Tratamento
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