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BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Inestabilidad de Microsatélites , Mutación , Paclitaxel , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Anciano , Carboplatino/administración & dosificación , Carboplatino/farmacología , Carboplatino/uso terapéutico , Inmunoterapia/métodos , Fosfohidrolasa PTEN/genética , Adulto , Supervivencia sin Progresión , Biomarcadores de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Proteínas de Unión al ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Factores de Transcripción , Fosfatidilinositol 3-Quinasa Clase IRESUMEN
The National Institute for Health and Care Excellence (NICE) defines febrile neutropenia or "neutropenic sepsis" as a patient with an absolute neutrophil count (ANC) less than 0.5 x 109/L and temperature >38°C or signs and symptoms of sepsis.
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Biomarcadores/sangre , Neutropenia Febril/sangre , Neoplasias/sangre , Sepsis/diagnóstico , Niño , Humanos , Recuento de Leucocitos , Sepsis/sangreRESUMEN
BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.
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Antineoplásicos Alquilantes/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Dioxoles/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Tetrahidroisoquinolinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Dioxoles/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Compuestos de Platino/uso terapéutico , Estudios Prospectivos , Tetrahidroisoquinolinas/efectos adversos , TrabectedinaRESUMEN
BACKGROUND: Endothelial function in psoriatic patients has been mainly evaluated through a high-resolution ultrasound measurement of flow-mediated vasodilation in the brachial artery, which is an operator-dependent and technically demanding technique: this characteristic, together with different patient selection criteria, could account for the conflicting results emerging from different studies. Recently, Circulating Endothelial Cells (CECs) level has been suggested as a novel biomarker of vascular injury. METHODS: The number of CECs was determined by a semi-automated immunomagnetic system (CellSearch system) in peripheral blood of psoriatic patients (n = 48) and healthy subjects (n = 50). In 15 patients, CEC level was also evaluated after 6 months of treatment with an anti-TNF-alpha agent, Etanercept. The plasma levels of high-sensitivity C-reactive Protein (CRP), E-selectin, VEGF and PAI-1 were measured by ELISA. The psoriasis severity was assessed by PASI score. RESULTS: A statistically significant difference (P = 0.001) was found between CEC level in psoriatic patients (10.6 ± 9.4 cells/mL) vs. the control group (3.9 ± 0.9 cells/mL). This count inversely correlated with sE-selectin levels (r(2) = 0.16; P = 0.03). After 6 months of therapy, patients experienced a significant (P < 0.05) decrease in CEC levels (3.4 ± 1.3 cells/mL) and in PASI score (from 11.7 ± 8.1 to 2.1 ± 4.0). CONCLUSIONS: The elevated CECs level that we found in a sample of high selected psoriatic patients could be expression of endothelial damage. Lowering of CECs count after treatment with Etanercept support the hypothesis that an effective systemic therapy of psoriasis may also improve the endothelial function.
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Células Endoteliales , Inmunoglobulina G/uso terapéutico , Psoriasis/sangre , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Estudios de Casos y Controles , Etanercept , Femenino , Humanos , Inmunoglobulina G/farmacología , Separación Inmunomagnética , Masculino , Persona de Mediana Edad , Psoriasis/tratamiento farmacológicoRESUMEN
Objectives. In a previous randomized clinical trial (Falsini et al. (2010)), it was shown that short-term Saffron supplementation improves retinal flicker sensitivity in early age-related macular degeneration (AMD). The aim of this study was to evaluate whether the observed functional benefits from Saffron supplementation may extend over a longer follow-up duration. Design. Longitudinal, interventional open-label study. Setting. Outpatient ophthalmology setting. Participants. Twenty-nine early AMD patients (age range: 55-85 years) with a baseline visual acuity >0.3. Intervention. Saffron oral supplementation (20 mg/day) over an average period of treatment of 14 (±2) months. Measurements. Clinical examination and focal-electroretinogram-(fERG-) derived macular (18°) flicker sensitivity estimate (Falsini et al. (2010)) every three months over a followup of 14 (±2) months. Retinal sensitivity, the reciprocal value of the estimated fERG amplitude threshold, was the main outcome measure. Results. After three months of supplementation, mean fERG sensitivity improved by 0.3 log units compared to baseline values (P < 0.01), and mean visual acuity improved by two Snellen lines compared to baseline values (0.75 to 0.9, P < 0.01). These changes remained stable over the follow-up period. Conclusion. These results indicate that in early AMD Saffron supplementation induces macular function improvements from baseline that are extended over a long-term followup.
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Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.
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Neoplasias Ováricas , Neoplasias Pancreáticas , Neoplasias de la Próstata , Femenino , Humanos , Italia , Masculino , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Sociedades CientíficasRESUMEN
BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.
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Mangifera , Neoplasias Ováricas , Femenino , Humanos , Bevacizumab/uso terapéutico , Carboplatino/uso terapéutico , Recombinación Homóloga , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Paclitaxel/uso terapéutico , Platino (Metal)/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts' opinions, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.
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Células Neoplásicas Circulantes , Sociedades Científicas , Biomarcadores de Tumor/genética , Humanos , Italia , Biopsia LíquidaRESUMEN
OBJECTIVE: This study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated. METHODS: This retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS). RESULTS: As of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively. Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS. CONCLUSIONS: In the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients.
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Carcinoma Epitelial de Ovario/cirugía , Genes BRCA1 , Genes BRCA2 , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia/cirugía , Neoplasias Ováricas/cirugía , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Ca-125/sangre , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/secundario , Quimioterapia Adyuvante , Procedimientos Quirúrgicos de Citorreducción , Femenino , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Metástasis Linfática , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Compuestos de Platino/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Supervivencia sin Progresión , Estudios Retrospectivos , Terapia Recuperativa , Factores de Tiempo , Carga TumoralRESUMEN
Patency of the ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD) development represent severe affections for premature newborns, therefore the research of early markers for these two conditions is really important. The aim of this study is to analyze epithelial lining fluid (ELF) Neutrophil-gelatinase-associated lipocalin (NGAL) levels for prediction of lung injury or possible involvement of this molecule in PDA. Only scarce and contrasting results have previously been published in this field. In contrast, this molecule, included in a large macromolecular complex together with matrix metalloproteinase-9 (MMP-9), is considered an acceptable marker of infectious/inflammatory processes, cancer monitoring and induction of apoptotic pathway. NGAL was detected in 28 pre-term newborns by means of a commercially available kit in bronchoalveolar lavage fluid (BALF). The results have been corrected to ELF levels, by the urea method, to eliminate bias due to BALF collection. ELF NGAL levels were found significantly increased both in infants developing BPD or in those affected by PDA. By means of multivariate logistic regression analysis the significances were confirmed after adjusting for possible interfering variables such as gestational age and concomitant presence of both PDA and BPD. Our results stress the involvement of NGAL in the mechanisms leading to BPD and also suggest a possible association with PDA, which is often linked to prematurity and BPD development, probably due to the involvement of inflammatory and angiogenetic processes in both pathologies.
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Proteínas de Fase Aguda/análisis , Líquido del Lavado Bronquioalveolar/química , Displasia Broncopulmonar/metabolismo , Conducto Arterioso Permeable/metabolismo , Lipocalinas/análisis , Proteínas Proto-Oncogénicas/análisis , Biomarcadores , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Lipocalina 2 , Modelos Logísticos , Masculino , Metaloproteinasa 9 de la Matriz/análisisRESUMEN
BACKGROUND: Vitamin D receptor (VDR) mediates the effects of vitamin D. Our paper evaluates the FokI and BsmI VDR genotypes in 246 Caucasian (Italian from Lazio Region) T1DM patients compared with 246 Caucasian healthy controls, sharing age and gender and regional provenience with the patients. In addition, T1DM patients without complications were compared with those carrying three complications. METHODS: Genotyping has been obtained by RFLP-PCR technique. RESULTS: A slight significant association of T1DM with FokI homozygous "f" genotype was observed. No association was observed with the presence of multiple complications by a multivariate analysis. CONCLUSION: T1DM patients showed slightly increased prevalence of "ff" VDR genotype.
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Desoxirribonucleasas de Localización Especificada Tipo II/genética , Complicaciones de la Diabetes/genética , Diabetes Mellitus Tipo 1/genética , Polimorfismo Genético , Adulto , Factores de Edad , Estudios de Casos y Controles , Nefropatías Diabéticas/genética , Neuropatías Diabéticas/genética , Retinopatía Diabética/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Análisis de RegresiónRESUMEN
UNLABELLED: Insulin-like growth factor-1 (IGF-1) is involved in regulating the Th-1/Th-2 balance, favoring the development of the Th-2 compartment which enhances fibrosis, one of the main characteristics of Chronic Lung Disease (CLD) in premature newborns. Limited data is available concerning a possible association between early epithelial lining fluid (ELF) concentrations of IGF-1 (total and free forms), IGF-binding protein-3 (IGFBP-3), beta2-microglobulin and subsequent development of CLD in preterm neonates. If neutropenic, preterm neonates are frequently treated with recombinant human granulocyte colony stimulating factor (rhG-CSF). The objective of the study was to correlate ELF concentrations of IGF-1 and beta2 microglobulin during the first week of life both in non-neutropenic and in rhGCSF-treated neutropenic preterm neonates, with subsequent development in CLD. Thirty preterm neonates with Respiratory Distress Syndrome (6 with neutropenia) were studied. Eleven out of 24 non-neutropenic preterm infants (46%) and all of the six neutropenic subjects (100%) developed CLD. With the exception of first day values, there was a clear similarity in the behaviors of assayed molecules between non-neutropenic and neutropenic patients developing CLD. Non-neutropenic patients without CLD showed significantly lower values of free IGF-1 and beta2M both on days 1 and 3. Total IGF-I and cell counts were different only on the 3rd day. CONCLUSIONS: 1) the mechanisms leading to CLD might be mediated by high levels of IGF-family molecules soon after birth 2) beta2M could be a marker of increased bronchoalveolar lavage fluid cellularity with potential inflammatory properties 3) G-CSF treatment induces an increased synthesis of IGF-1 molecules by cells recruited in the lung, with possible enhancement of the fibrogenic mechanisms.
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Células Epiteliales/metabolismo , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Recien Nacido Prematuro/metabolismo , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Microglobulina beta-2/biosíntesis , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Infecciones por Chlamydia/tratamiento farmacológico , Infecciones por Chlamydia/microbiología , Enfermedad Crónica , Células Epiteliales/efectos de los fármacos , Humanos , Recién Nacido , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Neutropenia/tratamiento farmacológico , Neutropenia/patología , Fibrosis Pulmonar/microbiología , Proteínas Recombinantes , Infecciones por Ureaplasma/tratamiento farmacológico , Infecciones por Ureaplasma/microbiología , Ureaplasma urealyticumRESUMEN
Oncogenes are important regulators of cancer growth and progression and their action may be modulated by proteins of the growth factor family, such as angiogenic cytokines, known to be strongly involved in neoplastic evolution. Reciprocal interactions between oncogenes and angiogenic modulators may represent, in haematological neoplasms, including multiple myeloma (MM), a possible mechanism of drug resistance. The aim of this work is to investigate in vitro and in vivo whether or not c-myc deregulation is involved in the melphalan resistance elicited by myeloma patients and consequently to clarify the role of the angiogenic factor PDGF-BB in modulating c-myc protein expression. Fifty-one MM patients on chemotherapy with melphalan were analyzed for structural alterations of the c-myc gene, c-Myc protein expression, as well as for serum PDGF-BB release. For the in vitro study, two M14-derived established cell clones, differing for the c-Myc protein expression (c-Myc low -expressing or constitutively expressing clones) were used. Our results show that PDGF-BB is able to up-regulate Myc expression and reduce melphalan sensitivity of tumor cell clones, constitutively expressing c-myc gene product. In addition, down-regulation of c-Myc protein induces the expression of PDGF-beta receptor molecules and reduces PDGF-BB release. In agreement with these results, in vivo data show that melphalan-resistant MM patients present overexpressed c-Myc protein and higher serum PDGF-BB receptor levels compared to minor responding patients.
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Antineoplásicos Alquilantes/farmacología , Melfalán/farmacología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Factor de Crecimiento Derivado de Plaquetas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Becaplermina , Southern Blotting , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN de Neoplasias/biosíntesis , Resistencia a Antineoplásicos , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-sis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacosRESUMEN
BACKGROUND: Several studies have reported predictors for loss of mobility and impairments of physical performance among frail elderly people. AIM: To evaluate the relationship between lifetime occupation and physical function in persons aged 80 years or older. METHODS: Data are from baseline evaluation of 364 subjects enrolled in the ilSIRENTE study (a prospective cohort study performed in a mountain community in Central Italy). Physical performance was assessed using the physical performance battery score, which is based on three timed tests: 4-metre walking speed, balance, and chair stand tests. Muscle strength was measured by hand grip strength. Lifetime occupation was categorised as manual or non-manual work. RESULTS: Mean age of participants was 85.9 (SD 4.9) years. Of the total sample, 273 subjects (75%) had a history of manual work and 91 subjects (25%) a history of non-manual work. Manual workers had significant lower grip strength and physical performance battery score (indicating worse performance) than non-manual workers. After adjustment for potential confounders (including age, gender, education, depression, cognitive performance scale score, physical activity, number of diseases, hearing impairment, history of alcohol abuse, smoking habit, and haemoglobin level), manual workers had significantly worse physical function (hand grip strength: non-manual workers 32.5 kg, SE 1.4, manual workers 28.2 kg, SE 0.8; physical performance battery score: non-manual workers 7.1, SE 0.4, manual workers 6.1, SE 0.2). CONCLUSIONS: A history of manual work, especially when associated with high physical stress, is independently associated with low physical function and muscle strength in older persons.
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Personas con Discapacidad , Anciano Frágil , Fuerza de la Mano/fisiología , Exposición Profesional , Estrés Mecánico , Anciano de 80 o más Años , Estudios de Cohortes , Evaluación de la Discapacidad , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Clase Social , CaminataRESUMEN
BACKGROUND: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. RESULTS: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. CONCLUSION: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.
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Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Interleucina-8/genética , Óxido Nítrico Sintasa de Tipo III/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Estudios de Asociación Genética , Humanos , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
SETTING: Little information is available regarding the relationship between the fibrotic evolution of pulmonary tuberculosis (PTB) and cytokine levels in human bronchoalveolar lavage fluid (BALF) and serum. OBJECTIVE: To evaluate correlations between profibrotic cytokine levels and post-treatment lung fibrotic evolution. DESIGN: BALF and serum amounts of pro- or anti-inflammatory cytokines were obtained by ELISA before and 6 months after the start of anti-tuberculosis chemotherapy in 13 subjects with PTB. BALF levels were recalculated as ELF (epithelial lining fluid) levels by the urea method. High resolution computed tomography (HRCT) of both lungs was performed at the same time. RESULTS: When comparing pre- and post-treatment radiological data, the scores for 2-10 mm nodules, consolidation and fibrosis presented significant differences (P < 0.05). Concomitantly, pre-treatment vs. 6 month concentrations of ELF IFN-gamma and TNF-alpha were decreased (P < 0.05), while those of IL-4 and IL-10 were increased (P < 0.012). At serum level, IFN-gamma decreased, as did TNF-alpha, TGF-beta1 and PDGF-BB (P < 0.05). When the patients were subdivided into two groups, 1) stable or 2) increasing HRCT fibrosis score, significant increases in the second group were observed for ELF/ serum values of TGF-beta1 and ELF PDGF-BB (P < 0.05) at 6 months post-treatment. Only serum TGF-beta1 values were significantly associated with the same group before treatment.
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Antituberculosos/uso terapéutico , Citocinas/sangre , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/inmunología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/inmunología , Adulto , Lavado Broncoalveolar , Citocinas/análisis , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To report a new family belonging to a previously non-investigated geographic are a with a rare form of lattice corneal dystrophy (LCD). METHODS: Detailed ophthalmologic analysis was carried out on a Bulgarian woman, enrolled for perforating keratoplasty. In order to obtain a final diagnosis both histology and genetic analysis were performed. RESULTS: Upon transplantation, histologic analysis of the dystrophic cornea revealed the typical staining pattern and amyloid deposits of lattice corneal dystrophies. Genetic analysis of the subject and her daughter confirmed the presence of an autosomal dominant R124C mutation within exon 4 of the BIGH3 gene, encoding for keratoepithelin, while showing no abnormalities in her son. CONCLUSIONS: The identification of this mutation allows the unambiguous classification of this corneal dystrophy as LCD type I. A first case of LCD I in a family from Eastern Europe could help to better clarify the molecular epidemiology of the disease.
Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Proteínas de la Matriz Extracelular/genética , Factor de Crecimiento Transformador beta/genética , Adolescente , Adulto , Amiloide/metabolismo , Bulgaria/epidemiología , Distrofias Hereditarias de la Córnea/etnología , Distrofias Hereditarias de la Córnea/metabolismo , Análisis Mutacional de ADN , Exones/genética , Femenino , Genes Dominantes , Humanos , Masculino , Epidemiología Molecular , Linaje , Mutación PuntualRESUMEN
Peripheral blood progenitor cells (PBPC) mobilized by granulocyte colony-stimulating factor (G-CSF) promptly engraft allogeneic recipients after myeloablative chemotherapy for hematologic malignancies. Surprisingly, no exacerbation of acute graft-vs-host disease has been observed despite a 10-fold higher T-cell content in PBPC compared with bone marrow allografts. Because G-CSF can suppress T-cell proliferation in response to mitogens and enhance their activation-induced apoptosis, we examined the molecular mechanisms underlying G-CSF-induced immune dysfunction. Normal allogeneic lymphocytes were challenged with phytohemagglutinin in the presence of serum collected after G-CSF administration (postG) to healthy PBPC donors, and the expression of key components of the cell cycle and apoptotic machineries was investigated by flow cytometry and Western blotting. Lymphocyte stimulation was associated with collapse of mitochondrial transmembrane potential, hypergeneration of reactive oxygen intermediates, and activation of caspase-3 and DNA fragmentation. Lymphocytes were arrested in a G(1)-like phase of the cell cycle, as measured by G(1)-phase cyclin expression and bromodeoxyuridine (BrdUrd) incorporation. Cell tracking experiments confirmed the occurrence of a lower number of population doublings in postG compared with preG cultures. Unexpectedly, the phosphorylation state of the protein encoded by the retinoblastoma susceptibility gene (pRB) was unaltered in postG cultures, and the inhibition of cell cycle progression occurred without the recruitment of the cyclin-dependent kinase inhibitors p15(INK4B), p16(INK4A), and p27(Kip1). We eventually evaluated the ability of antioxidant/cytoprotectant agents to prevent the G-CSF-induced mitochondrial dysfunction and inhibition of cell cycle progression. Of interest, both N-acetylcysteine and amifostine reduced apoptotic cell death by 45% on average, inhibited the activation/processing of caspase-3, and increased BrdUrd incorporation in postG cultures. Based on these experimental findings, a model is proposed in which T-cell activation in the presence of serum immunoregulatory factor(s) induced by G-CSF is associated with a molecular phenotype mimicking the G(1)-S transition and consisting of pRB phosphorylation, lack of CDKI recruitment, and reduced cyclin-E expression. The putative relationship between lymphocyte mitogenic unresponsiveness and apoptosis induction would occur at the level of key molecules shared by the cell cycle and apoptotic machineries. Whether the G-CSF-mediated modulation of lymphocyte functions in vitro is beneficial in transplantation medicine remains to be determined.
Asunto(s)
Apoptosis , Proteínas de Ciclo Celular , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Expresión Génica , Factor Estimulante de Colonias de Granulocitos/farmacología , Proteína de Retinoblastoma/metabolismo , Linfocitos T/fisiología , Proteínas Supresoras de Tumor , Acetilcisteína/farmacología , Adulto , Amifostina/farmacología , Antioxidantes/farmacología , Proteínas Portadoras/genética , Caspasa 3 , Caspasas/metabolismo , División Celular , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Fragmentación del ADN , Inhibidores Enzimáticos , Femenino , Fase G1 , Humanos , Recuento de Linfocitos , Masculino , Proteínas Asociadas a Microtúbulos/genética , Mitocondrias/fisiología , Mitocondrias/ultraestructura , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Linfocitos T/ultraestructuraRESUMEN
BACKGROUND: Malignant melanoma is the most malignant tumours of skin and mucous membranes mainly due to its aggressive biological behaviour and tendency to generate early metastases. Unfortunately, the mechanisms underlying the development, progression and the expression of an aggressive melanoma phenotype still remain largely unknown. OBJECTIVES: The purpose of this study was to determine whether a multi-panel of molecular transcripts can be predictive for risk of recurrent disease in malignant melanoma patients. RESULTS: Peripheral blood was collected from 31 malignant melanoma patients in follow-up for melanoma and from 30 healthy volunteers randomly selected. Each specimen was examined by qRT-PCR analysis for the expression of six markers: PAX3d, TYR, MITFm, MCAM, TGFß2 and ABCB5. Malignant melanoma patients expressed an important number of markers, with a median value of four markers. Only PAX3d displayed a trend in terms of differences when the levels of gene expression were made in function of Breslow index. Furthermore, PAX3d showed the best diagnostic capacity among the remaining residual markers or in combination with TGFß2 and MTIF. CONCLUSIONS: We demonstrated the usefulness of multimarker qRT-PCR to detect circulating melanoma cells in blood and to potentially assessing patient disease status or progression, especially when PAX3d was used in combination with MTIFm and TGFß2.