RESUMO
INTRODUCTION: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. METHODS: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. RESULTS: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki-67% was 4 (range: 0-20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1-32.0) for octreotide versus 30.1 months (95% CI: 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71-1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. CONCLUSION: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Sistema de Registros , Somatostatina/análogos & derivados , Somatostatina/análise , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Octreotida/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Prognóstico , Reprodutibilidade dos Testes , Somatostatina/administração & dosagem , Somatostatina/farmacologia , EspanhaRESUMO
BACKGROUND/OBJECTIVE: Ingenol mebutate gel is approved for actinic keratosis field therapy, but little has been published as a treatment of basal cell carcinoma (BCC). Our objective is to characterise the histopathological changes and the infiltrating cell populations to better understand its mechanism of action. METHODS: Sixteen patients with various BCC subtypes were prospectively evaluated and treated once daily for two consecutive days with ingenol mebutate gel 0.05% under occlusion. Patients were randomised to two arms: the first arm was biopsied between the third and the tenth day after treatment initiation ('early immune response'), and the second arm was biopsied at day 30 after treatment initiation ('late immune response'). The immunopathology was evaluated by immunohistochemistry: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD56, anti-CD68, anti-Bcl-2, anti-CASP3, anti-FoxP3, anti-GrzB and anti-TIA-1. RESULTS: Ten BCCs were in complete remission after 2 years of follow-up. The early immune response was characterised by a quick recruitment of T lymphocytes, macrophages and natural killer cells. At later time-points, T-regulatory cells and some pro-apoptotic markers were detected. Treatment-related adverse events were described. CONCLUSION: Ingenol mebutate gel produces a transient immuno-inflammatory response and an important necrosis reaction in BCCs. Larger studies will be required to determine the maximum effective tolerated dose of ingenol mebutate gel for BCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Diterpenos/uso terapêutico , Inflamação/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Idoso , Carcinoma Basocelular/complicações , Feminino , Humanos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/complicações , Resultado do TratamentoRESUMO
Since its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45-expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies.
Assuntos
Antígenos Comuns de Leucócito/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Animais , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Deleção de Genes , Células-Tronco Hematopoéticas/citologia , Integrases/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos KnockoutRESUMO
Basal cell carcinoma (BCC) seems to originate from ultraviolet light-induced mutations involving the bulge or the outer sheath of the hair follicle cells. However, the etiopathogenic mechanisms involved in the development of these tumors in nonphotoexposed and in hairless areas remain unclear. The cytokeratin (CK) profile (including CK5/6, CK7, CK14, CK15, CK17, and CK19) from a series of different BCC subtypes developing in sun-exposed and non-sun-exposed areas, including hairless regions, was evaluated. The authors have observed that CK7 expression in BCC is associated with the anatomical localization of the tumor and its sun-exposition, but not with other factors such as histological subtype. The expression of this CK is higher in BCCs located in non-sun-exposed and nonhairy areas, such as the vulvar semimucosa and the nipple. Because CK7 is a marker of simple glandular epithelia, the authors suggest a glandular origin for BCCs located in hairless and nonphotoexposed areas.
Assuntos
Carcinoma Basocelular/patologia , Queratinas/biossíntese , Neoplasias Cutâneas/patologia , Adulto , Carcinoma Basocelular/etiologia , Feminino , Folículo Piloso/patologia , Humanos , Masculino , Neoplasias de Anexos e de Apêndices Cutâneos/etiologia , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Neoplasias Cutâneas/etiologia , Luz Solar/efeitos adversosRESUMO
Basal cell carcinomas (BCC) are the most frequent tumours in humans and normally appear in photoexposed areas of the skin. It is widely accepted that BCCs originate at follicular stem cells and consequently are very rare in nonhairy areas. Here, we report 4 cases of vulvar BCC, 3 of which were located in a vulvar semimucous area, a nonphotoexposed area, and a nonhairy area. We have determined the CK7 and CK19 profile of all cases; both are markers of simple epithelium with glandular differentiation. Interestingly, all cases were positively stained for CK7 and CK19. Considering that the vulvar region is rich in sebaceous and apocrine units, we hypothesise a glandular origin of BCCs situated in the vulvar region.
Assuntos
Carcinoma Basocelular/metabolismo , Queratina-19/metabolismo , Queratina-7/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Vulvares/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Neoplasias Vulvares/patologiaRESUMO
Introduction: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods: This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results: Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion: These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.
Assuntos
Espessura Intima-Media Carotídea , Hepatopatia Gordurosa não Alcoólica , Índice de Gravidade de Doença , Vasa Vasorum , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Masculino , Feminino , Vasa Vasorum/patologia , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Túnica Adventícia/patologia , Aterosclerose/patologia , Obesidade/patologia , Obesidade/complicaçõesRESUMO
INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is an escalating health concern linked to obesity and type 2 diabetes. Despite liver biopsy being the gold standard, its invasiveness underscores the need for noninvasive diagnostic methods. METHODS: A cross-sectional study was performed to assess MASLD using the noninvasive OWLiver® serum lipidomics test in a cohort of 117 patients with severe obesity undergoing bariatric surgery, comparing outcomes with liver biopsy. Exclusions (n = 24) included insufficient data, liver disease etiology other than MASLD, corticosteroid treatment, excessive alcohol consumption, low glomerular filtration rate, and declination to participate. Comprehensive laboratory tests, demographic assessments, and liver biopsies were performed. Serum metabolites were analyzed using OWLiver®, a serum lipidomic test that discriminates between healthy liver, steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and MASH with fibrosis ≥2 by means of three algorithms run sequentially. RESULTS: Liver biopsy revealed a MASLD prevalence of 95.7%, with MASH present in 28.2% of cases. OWLiver® demonstrated a tendency to diagnose more severe cases. Body mass index (BMI), rather than the presence of type 2 diabetes, emerged as the sole independent factor linked to the probability of concordance. Therefore, the all-population concordance of 63.2% between OWLiver® and liver biopsy notably raised to 77.1% in patients with a BMI <40 kg/m2. These findings suggest a potential correlation between lower BMI and enhanced concordance between OWLiver® and biopsy. CONCLUSION: This study yields valuable insights into the concordance between liver biopsy and the noninvasive serum lipidomic test, OWLiver®, in severe obesity. OWLiver® demonstrated a tendency to amplify MASLD severity, with BMI values influencing concordance. Patients with BMI <40 kg/m2 may derive optimal benefits from this noninvasive diagnostic approach.
RESUMO
OBJECTIVE: To assess the intraoperative positive sentinel lymph node (SLN) total tumor load (TTL, defined as the amount of CK19 mRNA copies [copies/µL] in all positive SLNs) obtained by one-step nucleic acid amplification (OSNA) and to determine whether it is predictive of non-SLNs involvement. SUMMARY/BACKGROUND/DATA: The OSNA assay (Sysmex Corporation, Kobe, Japan) is a new diagnostic technique that uses molecular biological techniques to analyze SLN that has been validated as an accurate method for detection of positive SLN. Although the American College of Surgeons Oncology Group Z0011 trial has defined a select cohort of patients in whom a completion axillary lymph node dissection (cALND) may be safely omitted, there are a still a number of patients where prediction of non-SLN metastasis may be helpful for cALND decision making. Multiple studies suggest that specific pathologic characteristics of the primary tumor and the SLN metastases are associated with an increased likelihood of additional positive non-SLN. METHODS: This is a retrospective multicentric cohort study of 697 patients with cT1-3N0 breast cancer, who had had intraoperative SLN evaluation by OSNA assay with a cALND. TTL is defined as the amount of CK19 mRNA copies number in all positives SLN (copies/µL). RESULTS: Univariate logistic regression showed that, in addition to TTL (p < 0.001), the number of affected SLNs (p < 0.001), tumor size (p < 0.001), HER2 status (p = 0.007), and lymphovascular invasion (LVI, p < 0.001) were predictive of ALND status. The multivariate logistic regression analysis showed that TTL is an independent predictor of metastatic non-SLNs, after adjusting for the tumor size, HER2 status, LVI and, in particular, the number of affected SLNs. CONCLUSIONS: TTL by OSNA is a newly standardized and automated tool that predicts axillary node status better and independently of the number of affected SLNs and the type of surgery. This value can then help clinicians to personalize surgical treatment. Prospective studies will be carried out to determine the clinical impact of this variable in the management of patients.
Assuntos
Neoplasias da Mama/patologia , Queratina-19/análise , Metástase Linfática/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Carga Tumoral , Idoso , Área Sob a Curva , Neoplasias da Mama/genética , Estudos de Coortes , Feminino , Humanos , Período Intraoperatório , Queratina-19/genética , Pessoa de Meia-Idade , RNA Mensageiro/análise , Curva ROC , Estudos Retrospectivos , Biópsia de Linfonodo SentinelaAssuntos
Doenças Autoimunes/imunologia , Autoimunidade , Dermatoses Faciais/imunologia , Imunoglobulina G/imunologia , Pele/imunologia , Idoso , Doenças Autoimunes/patologia , Biomarcadores/sangue , Biópsia , Dermatoses Faciais/patologia , Glucocorticoides/administração & dosagem , Humanos , Imunoglobulina G/sangue , Imuno-Histoquímica , Masculino , Nariz , Indução de Remissão , Pele/patologia , Resultado do TratamentoRESUMO
When primary acquired melanosis (PAM) with atypia affects the tarsal conjunctiva, a radical surgery can be mutilating, requiring reconstructive surgery of the eyelid. Topical chemotherapy associated to local cryotherapy may be an alternative. A 64-year-old Caucasian female presented with diffuse PAM of the right eye involving the inferior tarsal conjunctiva, fornix, and inferotemporal bulbar conjunctiva. Histological study showed a PAM with atypia (C-MIN 5). Given the extent of the lesion and its location, a wide mutilating excision was ruled out. Topical interferon alpha 2b (IFN-α2b) treatment (1,000,000 IU/mL, 4 times a day) was administered during 10 weeks. However, the regression was very slow. Then local cryotherapy was proposed (8 s at -80°C per application) to the entire pigmented lesion. This afforded progressive depigmentation, which was completed 2 months later. No recurrence of the lesion has been noted during 3 years of follow-up. The combination of the two procedures reduces IFN-α2b eyedrop administration time, enhancing patient compliance. The combination may eradicate the tumor without compromising ocular cosmesis.
RESUMO
Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK-Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA-ROCK-Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73-ROCK-Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.
Assuntos
Adenocarcinoma , Amoeba , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Adenocarcinoma/patologia , Amoeba/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proteínas do Citoesqueleto , Terapia de Imunossupressão , Miosina Tipo II/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente TumoralRESUMO
Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/beta-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, beta-catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma-carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also overexpressed, with significant intra-case heterogeneity. Increased cytoplasmic and/or nuclear beta-catenin staining was seen in 94% and 80% of the adenomas. beta-Catenin nuclear staining was strongly associated with MYC levels (p value 0.03) but not with KRAS mutations. Copy number aberrations were rare. However, the recurrent chromosome changes observed more frequently contained Wnt pathway genes (p value 0.012). Based on beta-catenin staining and Wnt pathway target genes alterations the Wnt pathway appears to be constitutively activated in all APC-FAP tumours, with alterations occurring both upstream and downstream of APC. Wnt aberrations are present at both the DNA and the RNA level. Somatic profiling of APC-FAP tumours provides new insights into the role of APC in tumourigenesis.
Assuntos
Polipose Adenomatosa do Colo/genética , Genes APC , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Wnt/fisiologia , Proteínas ras/fisiologia , Polipose Adenomatosa do Colo/metabolismo , Proteína da Polipose Adenomatosa do Colo/biossíntese , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Núcleo Celular/metabolismo , Hibridização Genômica Comparativa , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais/fisiologia , Adulto Jovem , beta Catenina/metabolismo , Proteínas ras/genéticaRESUMO
BACKGROUND: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. METHODS: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. RESULTS: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. CONCLUSIONS: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.
RESUMO
PURPOSE: The role of E-cadherin in carcinogenesis is of great interest, but few studies have examined its relevance to pancreatic carcinoma. EXPERIMENTAL DESIGN: We evaluated E-cadherin protein expression by immunohistochemistry in pancreatobiliary cancers having a noncohesive histologic phenotype (21 undifferentiated adenocarcinomas and 7 signet ring carcinomas), comparing the results with pancreatic cancers having a cohesive phenotype (25 moderately differentiated and 14 poorly differentiated adenocarcinomas). RESULTS: Twenty of 21 undifferentiated cancers had complete absence of E-cadherin expression, as did two signet ring carcinomas. In contrast, cohesive cancers (n = 39) had E-cadherin labeling at the plasma membrane (P < 0.001). Subsets of cancers were also evaluated for beta-catenin expression. All of the cohesive lesions (n = 28) showed a membranous beta-catenin expression pattern, whereas noncohesive foci (n = 7) were characterized by either cytoplasmic labeling or complete absence of beta-catenin protein expression, suggestive of a deficient zonula adherens in noncohesive cancers. E-cadherin promoter hypermethylation was observed in an undifferentiated pancreatic cancer cell line, MiaPaCa-2, whereas two pancreatic cancer cell lines derived from differentiated lesions lacked any evidence of E-cadherin promoter methylation. No pattern of E-cadherin promoter methylation could be determined in three primary cancers having mixed histologic patterns (contained both cohesive and noncohesive foci). No somatic mutations in E-cadherin were identified in noncohesive pancreatic cancers having inactivated E-cadherin. CONCLUSIONS: Noncohesive pancreatic cancers were characterized by the loss of E-cadherin protein expression. Promoter hypermethylation is a possible mechanism of E-cadherin gene silencing in a subset of these cancers.
Assuntos
Caderinas/metabolismo , Carcinoma de Células em Anel de Sinete/metabolismo , Neoplasias Pancreáticas/metabolismo , beta Catenina/metabolismo , Caderinas/genética , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Regiões Promotoras GenéticasRESUMO
PURPOSE: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS: We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS: We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION: The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.
Assuntos
Hormônios/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Feminino , Hormônios/farmacologia , Humanos , Masculino , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Somatostatina/farmacologia , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Prenatal gene transfer may enable early causal intervention for the treatment or prevention of many devastating diseases. Nevertheless, permanent correction of most inherited disorders requires a sustained level of expression from the therapeutic transgene, which could theoretically be achieved with integrating vectors. METHODS: Rabbit fetuses received 8.5 x 10(6) HIV-based recombinant lentivirus particles containing the enhanced green fluorescent protein (EGFP) transgene by intrahepatic, intra-amniotic or intraperitoneal injection at 22 days of gestation. Provirus presence and transgene expression in rabbit tissues were evaluated at both 1.5 and 16 weeks post-in utero intervention by polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively. Moreover, we assessed persistence of EGFP by immunohistochemistry. Enzyme-linked immunosorbent assays confirmed the development of antibodies specific against both the viral vector and the reporter protein. RESULTS: Regardless of the route of administration employed, lentiviral vector-based in utero gene transfer was safe and reached 85% of the intervened fetuses at birth. However, the integrated provirus frequency was significantly reduced to 50% of that in young rabbits at 16 weeks post-treatment. In these animals, EGFP expression was evident in many tissues, including cytokeratin 5-rich basal cells from stratified and pseudostratified epithelia, suggesting that the lentiviral vector might have reached progenitor cells. Conversely, we identified the presence of immune-inflammatory infiltrates in several EGFP-expressing tissues. Moreover, almost 70% of the lentiviral vector-treated rabbits elicited a humoral immune response against the viral envelope and/or the EGFP. CONCLUSIONS: At two-thirds gestational age, the adaptive immune system of the rabbit appears a relevant factor limiting transgene persistence and expression following lentiviral vector-mediated in utero gene transfer.
Assuntos
Feto/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Lentivirus/genética , Transgenes , Animais , Feminino , Imunofluorescência , Engenharia Genética , Proteínas de Fluorescência Verde/análise , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , HIV-1/genética , HIV-1/metabolismo , Lentivirus/metabolismo , Modelos Animais , Gravidez , Coelhos , Células-Tronco/citologia , Células-Tronco/metabolismo , Transgenes/imunologia , Transgenes/fisiologiaRESUMO
The family of receptor tyrosine kinases EPH and their Ephrin ligands regulate cell proliferation, migration, and attachment. An important role in colorectal carcinogenesis is emerging for some of its members. In this study, we evaluate the role of EPHB4 in colorectal cancer and its value as a prognostic marker. EPHB4 levels were assessed by immunohistochemical staining of tissue microarrays of 137 colorectal tumors and aberrant hypermethylation of the EPHB4 promoter was investigated using methylation-specific PCR. We found that EPHB4 expression is frequently reduced or lost in colorectal tumors. Patients with low EPHB4 tumor levels had significantly shorter survival than patients in the high EPHB4 group (median survival, 1.8 and >9 years, respectively; P < 0.01, log-rank test), and this finding was validated using an independent set of 125 tumor samples. In addition, we show that EPHB4 promoter hypermethylation is a common mechanism of EPHB4 inactivation. Moreover, reintroduction of EPHB4 resulted in a significant reduction in the clonogenic potential of EPHB4-deficient cells, whereas abrogation of EPHB4 in cells with high levels of this receptor lead to a significant increase in clonogenicity. In summary, we identified EPHB4 as a useful prognostic marker for colorectal cancer. In addition, we provide mechanistic evidence showing that promoter methylation regulates EPHB4 transcription and functional evidence that EPHB4 can regulate the long-term clonogenic potential of colorectal tumor cells, revealing EPHB4 as a potential new tumor suppressor gene in colorectal cancer.
Assuntos
Neoplasias Colorretais/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptor EphB4/biossíntese , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA , Regulação para Baixo , Genes Supressores de Tumor , Células HT29 , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Regiões Promotoras Genéticas , Receptor EphB4/genética , Fatores de RiscoRESUMO
Fewer than 90 cases of granular cell tumour (GCT) of the biliary tract have been reported, including only five cases of multiple GCTs. We present the unusual case of a 40-year-old woman with multifocal GCTs affecting the intrahepatic biliary tree, which were initially suspected to be hepatic multiple metastases from a malignancy of unknown origin. The surgical specimen consisted of a hepatic segment in which five whitish nodular lesions were observed. On microscopic examination, nodular lesions were found in the portal tracts; these were composed of large polygonal cells with abundant highly granular cytoplasm. The nuclei were small and centrally located. The tumour cells tested diffusely positive for CD68-PGM1, S100 protein and α-inhibin, so a diagnosis of multifocal GCT of the biliary tree was made. Three years later, the patient is still alive and a MRI has shown no changes.
Assuntos
Sistema Biliar/diagnóstico por imagem , Sistema Biliar/patologia , Tumor de Células Granulares/diagnóstico por imagem , Tumor de Células Granulares/patologia , Adulto , Assistência ao Convalescente , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Sistema Biliar/ultraestrutura , Feminino , Tumor de Células Granulares/ultraestrutura , Humanos , Inibinas/metabolismo , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Proteínas S100/metabolismoAssuntos
Nevo , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Nevo/patologia , DermoscopiaRESUMO
The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results.