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BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal mucinous carcinomatosis with largely unknown underlying molecular mechanisms. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the only therapeutic option; however, despite its use, recurrence with a fatal outcome is common. The lack of molecular characterisation of PMP and other mucinous tumours is mainly due to the physicochemical properties of mucin. RESULTS: This manuscript describes the first protocol capable of breaking the mucin barrier and isolating proteins from mucinous tumours. Briefly, mucinous tumour samples were homogenised and subjected to liquid chromatography using two specific columns to reduce mainly glycoproteins, albumins and immunoglobulin G. The protein fractions were then subjected to mass spectrometry analysis and the proteomic profile obtained was analysed using various bioinformatic tools. Thus, we present here the first proteome analysed in PMP and identified a distinct mucin isoform profile in soft compared to hard mucin tumour tissues as well as key biological processes/pathways altered in mucinous tumours. Importantly, this protocol also allowed us to identify MUC13 as a potential tumour cell marker in PMP. CONCLUSIONS: In sum, our results demonstrate that this protein isolation protocol from mucin will have a high impact, allowing the oncology research community to more rapidly advance in the knowledge of PMP and other mucinous neoplasms, as well as develop new and effective therapeutic strategies.
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Pseudomyxoma peritonei (PMP) is a rare disease characterized by a massive accumulation of mucus in the peritoneal cavity. The only effective treatment is aggressive surgery, aimed at removing all visible tumors. However, a high percentage of patients relapse, with subsequent progression and death. Recently, there has been an increase in therapies that target mutated oncogenic proteins. In this sense, KRAS has been reported to be highly mutated in PMP, with KRASG12D being the most common subtype. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in a high-grade PMP xenograft mouse model carrying a KRASG12D mutation. The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRASG12D-PMP tumors and provide a rationale for clinical trials.
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BACKGROUND: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis â¼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells. METHODS: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin. FINDINGS: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFß-pathways). Interestingly, an enrichment analysis uncovered a TGFß-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)]. INTERPRETATION: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans. FUNDING: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality).
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Glioblastoma , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Humanos , Camundongos , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Proto-Oncogênicas c-akt , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Retrospectivos , Fator de Crescimento Transformador beta/farmacologia , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
Introduction: Pseudomyxoma peritonei (PMP) is a rare malignant disease characterized by a massive multifocal accumulation of mucin within the peritoneal cavity. The current treatment option is based on complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, the recurrence is frequent with subsequent progression and death. To date, most of the studies published in PMP are related to histological and genomic analyses. Thus, the need for further studies unveiling the underlying PMP molecular mechanisms is urgent. In this regard, hypoxia and oxidative stress have been extensively related to tumoral pathologies, although their contribution to PMP has not been elucidated. Methods: In this manuscript, we have evaluated, for the first time, the intratumoral real-time oxygen microtension (pO2mt) in the tumor (soft and hard mucin) and surrounding healthy tissue from five PMP patients during surgery. In addition, we measured hypoxia (Hypoxia Inducible Factor-1a; HIF-1α) and oxidative stress (catalase; CAT) markers in soft and hard mucin from the same five PMP patient samples and in five control samples. Results: The results showed low intratumoral oxygen levels, which were associated with increased HIF-1α protein levels, suggesting the presence of a hypoxic environment in these tumors. We also found a significant reduction in CAT activity levels in soft and hard mucin compared with healthy tissue samples. Discussion: In conclusion, our study provides the first evidence of low intratumoral oxygen levels in PMP patients associated with hypoxia and oxidative stress markers. However, further investigation is required to understand the potential role of oxidative stress in PMP in order to find new therapeutic strategies.
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Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n = 13) and minor spliceosome (n = 4) and associated splicing factors (n = 27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently, in vivo and in vitro models were applied to explore the pathophysiological role of NOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.
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Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Proteínas de Ligação a RNA/genética , Proliferação de Células/genética , Fatores de Processamento de RNA/genética , Neoplasias Pancreáticas/patologia , Antígeno Neuro-Oncológico VentralRESUMO
BACKGROUND: The treatment of ovarian carcinomatosis with cytoreductive surgery and HIPEC is still controversial. The effect and pharmacokinetics of the chemotherapeutics used (especially taxanes) are currently under consideration. METHODS: A phase II, simple blind and randomized controlled trial (NTC02739698) was performed. The trial included 32 patients with primary or recurrent ovarian carcinomatosis undergoing cytoreductive surgery (CRS) and intraoperative intraperitoneal chemotherapy with paclitaxel (PTX): 16 in hyperthermic (42-43 °C) and 16 in normothermic (37 °C) conditions. Tissue, serum and plasma samples were taken in every patient before and after intraperitoneal chemotherapy to measure the concentration of PTX. To analyze the immunohistochemical profile of p53, p27, p21, ki67, PCNA and caspase-3 and the pathological response, a scale of intensity and percentage of expression and a grouped Miller and Payne system were used, respectively. Perioperative characteristics and morbi-mortality were also analyzed. RESULTS: The main characteristics of patients, surgical morbidity, hemotoxicity and nephrotoxicity were similar in both groups. The concentration of paclitaxel in the tissue was higher than that observed in plasma and serum, although no statistically significant differences were found between the two groups. No statistically significant association regarding pathological response and apoptosis (caspase-3) between both groups was proved. There were no statistically significant differences between the normothermic and the hyperthermic group for pathological response and apoptosis. CONCLUSIONS: The use of intraperitoneal PTX has proven adequate pharmacokinetics with reduction of cell cycle and proliferation markers globally without finding statistically significant differences between its administration under hyperthermia versus normothermia conditions.
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Our aim was to investigate the role of left atrial longitudinal strain (LALS) in the non-invasive diagnosis of acute cellular rejection (ACR) episodes in heart transplant (HTx) recipients. Methods: We performed successive echocardiographic exams in 18 consecutive adult HTx recipients in their first year after HTx within 3 h of the routine surveillance endomyocardial biopsies (EMB) in a single center. LALS parameters were analyzed with two different software. We investigated LALS association with ACR presence, as well as inter-vendor variability in comparable LALS values. Results: A total of 147 pairs of EMB and echo exams were carried out. Lower values of LALS were significantly associated with any grade of ACR presence. Peak atrial longitudinal strain (PALS) offered the best diagnostic value for any grade of ACR, with a C statistic of 0.77 using one software (95% CI 0.68−0.84, p < 0.0005) and 0.64 with the other (95% CI 0.54−0.73, p = 0.013) (p = 0.02 for comparison between both curves). Reproducibility between comparable LALS parameters was poor (intraclass correlation coefficients were 0.60 for PALS, 95% CI 0.42−0.73, p < 0.0005; and 0.42 for PALS rate, 95% CI −0.13−0.68, p < 0.0005). Conclusions: LALS variables might be a sensitive marker of ACR in HTx recipients, principally discriminating between those studies without rejection and those with any grade of ACR. Inter-vendor variability was significant.
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OBJECTIVES: The main objective is to establish the overall survival and disease-free survival profiles regarding the patients with retroperitoneal liposarcoma, making a comparison based on the well-differentiated and dedifferentiated histological subtypes. The secondary objectives are to descriptively analyze the clinical characteristics of said patients and to identify and analyze other independent variables that might modify these survival profiles significantly. METHODS: An observational and analytical study was performed using a retrospective historical cohort that was followed prospectively. The inclusion criteria consisted of: the procedure of liposarcoma located in the retroperitoneum, the well-differentiated and dedifferentiated histological subtypes, between January of 2002 and May of 2019. As a result, 32 patients took part in this study's sample. Kaplan-Meier estimator was used to summarise the results and log-rank test was used in the comparative analysis. RESULTS: The overall survival at 5 years was around 59%. No differences were found between the patients with a well-differentiated subtype compared to the dedifferentiated ones (p = 0.834). The disease-free survival at 2 years was 59% regarding the well-differentiated and 26% regarding the dedifferentiated, with these differences being statistically significant (p = 0.005). None of the other studied variables modified these survival profiles significantly. CONCLUSIONS: Dedifferentiated retroperitoneal liposarcomas show less disease-free survival than well-differentiated liposarcomas. However, regarding overall survival no differences can be claimed.
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Lipossarcoma , Neoplasias Retroperitoneais , Humanos , Lipossarcoma/patologia , Lipossarcoma/cirurgia , Prognóstico , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignancy, classified according to the Peritoneal Surface Oncology Group International (PSOGI) classification, whose response to treatment remains highly heterogeneous within the high-grade (HG) category. Molecular profiling of PMP cases might help to better categorize patients and predict treatment responses. METHODS: We studied the Ki-67 proliferation rate and P53 overexpression in tissue samples from our historical cohort of HG-PMP patients. We established as cut-off levels the third quartile of each marker to perform univariate and multivariate Cox regression survival analyses. According to these results, the HG-PMP category was divided into subcategories and a new survival analysis was performed. RESULTS: A total of 90/117 patients with PMP undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) were selected for secondary analysis. The survival analysis of the HG-PMP category for preoperative variables showed that a proliferation index defined by Ki-67 >15% is a bad prognostic factor, with a hazard ratio (HR) of 3.20 (95% confidence interval [CI] 1.24-8.25). Accordingly, the HG-PMP group was divided using the Ki-67 15% cut-off. The new PSOGI/Ki-67 variable was an independent prognostic factor for overall survival (OS), with an HR of 3.74 (95% CI 1.88-7.47), and disease-free survival (DFS), with an HR of 4.184 (95% CI 1.79-9.75). The estimated 5-year OS rate was 100%, 70% and 24% for the LG-PMP, HG-PMP ≤15% and HG-PMP >15% groups, respectively (p = 0.0001), while the 5-year DFS rate was 90%, 44% and 0%, respectively (p = 0.0001). CONCLUSION: Division of the HG-PMP category of the PSOGI classification, according to the Ki-67 proliferation index, provides two well-defined subcategories, with significant differences in terms of OS and DFS, and hence high prognostic value.
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Neoplasias Peritoneais , Pseudomixoma Peritoneal , Proliferação de Células , Humanos , Antígeno Ki-67 , Neoplasias Peritoneais/terapia , Pseudomixoma Peritoneal/terapiaRESUMO
OBJECTIVES: The main objective is to establish the overall survival and disease-free survival profiles regarding the patients with retroperitoneal liposarcoma, making a comparison based on the well-differentiated and dedifferentiated histological subtypes. The secondary objectives are to descriptively analyze the clinical characteristics of said patients and to identify and analyze other independent variables that might modify these survival profiles significantly. METHODS: An observational and analytical study was performed using a retrospective historical cohort that was followed prospectively. The inclusion criteria consisted of: the procedure of liposarcoma located in the retroperitoneum, the well-differentiated and dedifferentiated histological subtypes, between January 2002 and May 2019. As a result, 32 patients took part in this study's sample. Kaplan-Meier estimator was used to summarize the results and log-rank test was used in the comparative analysis. RESULTS: The overall survival at 5 years was around 59%. No differences were found between the patients with a well-differentiated subtype compared to the dedifferentiated ones (p=0.834). The disease-free survival at 2 years was 59% regarding the well-differentiated and 26% regarding the dedifferentiated, with these differences being statistically significant (p=0.005). None of the other studied variables modified these survival profiles significantly. CONCLUSIONS: Dedifferentiated retroperitoneal liposarcomas show less disease-free survival than well-differentiated liposarcomas. However, regarding overall survival no differences can be claimed.
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BACKGROUND: Several classifications have been used for pseudomyxoma peritonei (PMP), and among these, the Ronnett classification is the most commonly used. However, a new consensual Peritoneal Surface Oncology Group International (PSOGI) classification has recently been proposed. Nonetheless, to date, the ability of the PSOGI classification to predict survival based on its different disease histologic categories has not been validated. METHODS: This study enrolled 117 patients with PMP who had undergone cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) between 1997 and 2020. Cox proportional hazards regression models and time-dependent curve receiver operating characteristic (ROC) analyses were used to assess the predictive capacity of both classification systems for the overall survival (OS) and disease-free survival (DFS) of these patients. RESULTS: Significant differences in the 5-year OS rate were found for the different histologic grades according to each of the classifications. The completeness of cytoreduction score (CCS) was identified as a factor that predicted patient OS prognosis (p = 0.006). According to the time-dependent ROC curves at the "100" time point, adjusted by the CCS and DFS, the capacity to predict OS was optimal and achieved an area under the curve (AUC) of about 69% for OS and approximately 62% for DFS. CONCLUSIONS: Both the Ronnett and PSOGI classifications were able to predict survival optimally for this patient cohort. However, when the classifications were adjusted by the CCS, the predictive availability for OS was better with the PSOGI classification than with the Ronnett classification.
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Hipertermia Induzida , Neoplasias Peritoneais , Pseudomixoma Peritoneal , Procedimentos Cirúrgicos de Citorredução , Humanos , Neoplasias Peritoneais/terapia , Modelos de Riscos Proporcionais , Pseudomixoma Peritoneal/cirurgia , Estudos RetrospectivosRESUMO
To investigate the value of tissue Doppler velocities for ruling out treatment-requiring acute cellular rejection (TR-ACR), in the context of myocardial deformation analysis performed by means of speckle tracking echocardiography. We performed serial echocardiograms in 37 heart transplant recipients in their first year post-transplantation within 3 h of the routine surveillance endomyocardial biopsies (EMB). The association of the sum of lateral mitral annulus systolic (s') and early diastolic (e') velocities, in absolute values, measured by tissue Doppler echocardiography (s'+ e'), with TR-ACR (ACR grade ≥ 2R) was investigated by multivariate analysis, including classic echocardiographic parameters and myocardial deformation variables. A total of 251 pairs of EMB and echo exams were performed, 35 (14%) with rejection grade ≥ 2R (TR-ACR). s' + e' was independently associated to TR-ACR (OR 0.80, 95%CI 0.72-0.89, p < 0.0005), with a C statistic of 0.79 (95%CI 0.71-0.87, p < 0.0005) by ROC curve analysis. An s'+ e' value ≥ 23 cm/s, present in 43% of studies, had a negative predictive value of 98% for ruling out TR-ACR. Moreover, in the same patients, s'+ e' significantly decreased when TR-ACR occurred after a study without this condition (- 3.7 ± 3.3 cm/s, p = 0.003), but it was similar when rejection status was the same in the present versus the previous study. A drop in s'+ e' value < 2.7 cm/s from the previous echocardiogram, had a 99% negative predictive value for ruling out TR-ACR. Tissue Doppler velocities, a widely available echo parameter, were found to be a valuable marker for ruling out TR-ACR in this multivariate study which included myocardial deformation variables.
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Ecocardiografia Doppler , Rejeição de Enxerto/diagnóstico por imagem , Transplante de Coração/efeitos adversos , Ventrículos do Coração/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Doença Aguda , Adulto , Idoso , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Ventrículos do Coração/imunologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Valva Mitral/imunologia , Valva Mitral/fisiopatologia , Análise Multivariada , Miocárdio/imunologia , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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Tumores Neuroendócrinos/tratamento farmacológico , Peptídeos/farmacologia , Neoplasias Hipofisárias/tratamento farmacológico , Receptores de Somatostatina/agonistas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Peptídeos/química , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Transdução de Sinais , Células Tumorais Cultivadas , Adulto JovemRESUMO
INTRODUCTION AND OBJECTIVES: Ovarian tumours are rare in childhood, and account for 1-5% of all tumours. The aim of this study is to determine the epidemiological features, histological subtypes, and therapeutic management of ovarian solid ovarian tumours of the paediatric population of the province of Cordoba, in Spain. MATERIAL AND METHODS: A retrospective, descriptive, observational and institutional study was conducted in which a review was made of the clinical histories of patients younger than 14years-old diagnosed with ovarian tumours, excluding secondary tumours in a University Hospital between 1994 and 2017. A review was carried out on the age, clinical presentation, laterality, diagnostic methodology, treatment, histopathology, and evolution of these tumours. RESULTS: A total of 37 ovarian tumours were reviewed in 31 patients, 6 of them being bilateral. The mean age was 10.3 (0-14) years, with 58% presenting as a palpable mass. There was no predominance of laterality. The tumour markers were negative. Conservative surgery was performed in 29.7% and adnexectomy in 70.3%. Only one case required post-operative adjuvant chemotherapy treatment (stageI immature teratoma with peritoneal gliomatosis). The histological study shows a predominance of germ cell tumours (65%) against those of epithelial lineage (22%). There were 3 stromal tumours that corresponded to fibroma (Gorlin syndrome), and bilateral gonadoblastoma associated with Frasier syndrome. The most frequent type of tumour was mature cystic teratoma (35.1%). There were no complications in the follow-up. CONCLUSIONS: Given that most childhood ovarian tumours are benign, conservative surgery is considered as the first choice, being even more important in bilateral tumours. If there is a family history, it is essential to carry out molecular genetic studies, to rule out associated syndromes.
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Neoplasias Ovarianas/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Fibroma/patologia , Gonadoblastoma/patologia , Humanos , Lactente , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/terapia , Estudos Retrospectivos , Espanha , Teratoma/patologiaRESUMO
El síndrome hemofagocítico es una condición clínica e histológica grave, secundaria a diferentes procesos. La glomerulonefritis colapsante es una podocitopatía proliferativa, generalmente de pronóstico desfavorable para la función renal. Se presenta un caso en el que las dos condiciones aparecieron asociadas, lo cual es una forma infrecuente de presentación del linfoma hepatoesplénico de células T. Se discute, asimismo, el papel de los marcadores de desdiferenciación podocitaria en esta glomerulopatía, y se revisan la fisiopatología y el tratamiento.
The hemophagocytic syndrome is a serious clinical-histological entity secondary to different diseases. Collapsing glomerulonephritis is a proliferative podocytopathy that usually has an unfavorable renal prognosis. We present a case in which both entities were associated, which is an infrequent form of hepatosplenic T-cell lymphoma. In addition, we review the role of the markers of podocyte dedifferentiation in this glomerulopathy and its pathophysiology and treatment.
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Linfo-Histiocitose Hemofagocítica , Glomerulonefrite , Antígenos de Diferenciação , Insuficiência Renal , Linfoma , Transtornos LinfoproliferativosRESUMO
The hemophagocytic syndrome is a serious clinical-histological entity secondary to different diseases. Collapsing glomerulonephritis is a proliferative podocytopathy that usually has an unfavorable renal prognosis. We present a case in which both entities were associated, which is an infrequent form of hepatosplenic T-cell lymphoma. In addition, we review the role of the markers of podocyte dedifferentiation in this glomerulopathy and its pathophysiology and treatment.
El síndrome hemofagocítico es una condición clínica e histológica grave, secundaria a diferentes procesos. La glomerulonefritis colapsante es una podocitopatía proliferativa, generalmente de pronóstico desfavorable para la función renal. Se presenta un caso en el que las dos condiciones aparecieron asociadas, lo cual es una forma infrecuente de presentación del linfoma hepatoesplénico de células T. Se discute, asimismo, el papel de los marcadores de desdiferenciación podocitaria en esta glomerulopatía, y se revisan la fisiopatología y el tratamiento.
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Desdiferenciação Celular , Glomerulonefrite/patologia , Podócitos/patologia , Glomerulonefrite/complicações , Humanos , Neoplasias Hepáticas/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Linfoma de Células T/complicações , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/complicações , Neoplasias Esplênicas/complicaçõesRESUMO
PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a heterogeneous group of malignancies often presenting with metastasis at diagnosis and whose clinical outcome is difficult to predict. Somatostatin (SST) analogs (SSAs) provide a valuable pharmacological tool to palliate hormonal symptoms, and control progression in some NETs. However, many patients do not respond to SSAs or develop resistance, and there are many uncertainties regarding pathophysiology of SST and its receptors (sst1-sst5) in GEP-NETs. METHODS: The expression of SST system components in GEP-NETs was determined, compared with that of non-tumor adjacent and normal tissues and correlated with clinical and histological characteristics. Specifically, 58 patients with GEP-NETs and 14 normal samples were included. Cell viability in NET cell lines was determined in response to specific SSAs. RESULTS: Normal samples and non-tumor adjacent tissues presented a similar expression profile, with appreciable expression of sst2 and sst3, and a lower expression of the other receptors. In contrast, cortistatin, sst1, sst4, and sst5 were overexpressed in tumors, while sst3 and sst4 seemed overexpressed in less differentiated tumors. Some SST system components were related to vascular/nerve invasion and metastasis. In vitro, sst1 and sst3 agonists reduced viability in BON-1 cells, while they, similar to octreotide and pasireotide, increased viability in QGP-1 cells. CONCLUSIONS: These results provide novel information on SST system pathophysiology in GEP-NETs, including relevant associations with clinical-histological parameters, which might help to better understand the intrinsic heterogeneity of NETs and to identify novel biomarkers and/or targets with potential prognostic and/or therapeutic value for GEP-NETs patients.
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Neoplasias Intestinais/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologiaRESUMO
INTRODUCTION: Type iii extracapillary glomerulonephritis (PEGN) is a common cause of rapidly progressive glomerulonephritis and it is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent evidence points to complement activation as an important factor in the pathogenesis of PEGN. The aim of the present study was to assess the value of C3 deposits in the prognosis of PEGN. METHODS: All patients diagnosed of PEGN from 1995 to 2015 (n=72) were included in this study. Progression of renal disease in patients with positive staining for C3 by immunofluorescence was compared with those with negative staining. Mean follow up was 73 months. Progression to end-stage renal disease in relation to clinical and histological variables was analyzed. RESULTS: Positive staining for C3 was observed in 22 out of the 72 patients (30.5%). At the time of diagnosis, patients with C3 deposits had higher serum creatinine concentration than those without C3 staining (5.00 vs. 3.85mg/dl, P=0.050). Renal survival at 10 years was 36.9% in patients with positive C3 staining vs. 64.4% in patients with negative staining (P=0.005). Mortality at 10 years was higher in patients with C3 deposits than in patients without deposits (77 vs. 49.3%). CONCLUSIONS: Thus, our study shows that PEGN with deposits of C3 is associated with worse renal prognosis and greater mortality. These results would support the hypothesis that activation of the alternative pathway complement may play an important role in the generation of renal injury associated with PEGN.
Assuntos
Complemento C3/análise , Glomerulonefrite/imunologia , Idoso , Anticorpos Anticitoplasma de Neutrófilos/análise , Biomarcadores , Creatinina/sangue , Feminino , Glomerulonefrite/patologia , Humanos , Estimativa de Kaplan-Meier , Rim/química , Rim/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Diálise Renal , Estudos RetrospectivosRESUMO
BACKGROUND: The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). METHODS: In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). RESULTS: In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. CONCLUSIONS: Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.