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1.
Br J Haematol ; 202(5): 953-959, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37357817

RESUMO

We explored the relevance of genomic microarrays (GM) in the refinement of prognosis in newly diagnosed low-risk chronic lymphocytic leukaemia (CLL) patients as defined by isolated del(13q) or no lesions by a standard 4 probe fluorescence in situ hybridization (FISH) analysis. Compared to FISH, additional lesions were detected by GM in 27 of the 119 patients (22.7%). The concordance rate between FISH and GM was 87.4%. Discordant results between cytogenetic banding analysis (CBA) and GM were observed in 45/119 cases (37.8%) and were mainly due to the intrinsic characteristics of each technique. The presence of additional lesions by GM was associated with age > 65 years (p = 0.047), advanced Binet stage (p = 0.001), CLL-IPI score (p < 0.001), a complex karyotype (p = 0.004) and a worse time-to-first treatment in multivariate analysis (p = 0.009). Additional lesions by GM were also significantly associated with a worse time-to-first treatment in the subset of patients with wild-type TP53 and mutated IGHV (p = 0.025). In CLL patients with low-risk features, the presence of additional lesions identified by GM helps to identify a subset of patients with a worse outcome that could be proposed for a risk-adapted follow-up and for early treatment including targeted agents within clinical trials.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Hibridização in Situ Fluorescente , Prognóstico , Fatores de Risco , Genômica
2.
Int J Mol Sci ; 23(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955679

RESUMO

Liquid biopsy has advantages over tissue biopsy, but also some technical limitations that hinder its wide use in clinical applications. In this study, we aimed to evaluate the usefulness of liquid biopsy for the clinical management of patients with advanced-stage oncogene-addicted non-small-cell lung adenocarcinomas. The investigation was conducted on a series of cases-641 plasma samples from 57 patients-collected in a prospective consecutive manner, which allowed us to assess the benefits and limitations of the approach in a real-world clinical context. Thirteen samples were collected at diagnosis, and the additional samples during the periodic follow-up visits. At diagnosis, we detected mutations in ctDNA in 10 of the 13 cases (77%). During follow-up, 36 patients progressed. In this subset of patients, molecular analyses of plasma DNA/RNA at progression revealed the appearance of mutations in 29 patients (80.6%). Mutations in ctDNA/RNA were typically detected an average of 80 days earlier than disease progression assessed by RECIST or clinical evaluations. Among the cases positive for mutations, we observed 13 de novo mutations, responsible for the development of resistance to therapy. This study allowed us to highlight the advantages and disadvantages of liquid biopsy, which led to suggesting algorithms for the use of liquid biopsy analyses at diagnosis and during monitoring of therapy response.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Mutação , Oncogenes , Estudos Prospectivos , RNA
3.
Br J Haematol ; 192(6): 1068-1072, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32578873

RESUMO

In a series of 349 patients with chronic lymphocytic leukaemia (CLL), we found lower levels of signalling lymphocytic activation molecule family member 1 (SLAMF1) expression in cases with highly complex karyotypes, as defined by the presence of five or more chromosomal abnormalities (CK5; P < 0·001) and with major chromosomal structural abnormalities (P < 0·001). SLAMF1 downregulation was significantly associated with advanced Binet Stage (P = 0·001), CD38 positivity (P < 0·001), high ß2 -microglobulin levels (P < 0·001), immunoglobulin heavy chain variable region gene (IGHV) unmutated status (P < 0·001), 11q deletion (P < 0·001), tumour protein p53 (TP53) disruption (P = 0·011) and higher risk CLL International Prognostic Index categories (P < 0·001). Multivariate analysis showed that downregulated SLAMF1 levels had independent negative prognostic impact on time-to-first treatment (P < 0·001) and overall survival (P < 0·001).


Assuntos
Aberrações Cromossômicas , Leucemia Linfocítica Crônica de Células B , Proteínas de Neoplasias , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Valor Preditivo dos Testes , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Taxa de Sobrevida
4.
Br J Haematol ; 181(2): 229-233, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29611195

RESUMO

Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high-risk CLL patients with distinct clinical and biological characteristics.


Assuntos
Aberrações Cromossômicas , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B , RNA Mensageiro , RNA Neoplásico , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Taxa de Sobrevida
5.
Clin Exp Rheumatol ; 35(1): 113-121, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27749230

RESUMO

OBJECTIVES: To evaluate the micro-RNA (miRNA) expression profile in patients with early psoriatic arthritis (PsA) in order to assess the role of miRNAs as potential PsA biomarkers. METHODS: The expression of 723 mature miRNAs in peripheral blood mononuclear cells of early PsA patients in comparison with early-rheumatoid arthritis (ERA) patients and healthy controls (HC) was evaluated using a miRNA microarray. All patients had active disease and were naïve from treatment. The results were validated for a specific miRNA (miR-21-5p) in the entire series of patients plus an additional group of early PsA, ERA and HC using droplet digital PCR. RESULTS: In PsA, microarray analysis revealed a distinct pattern of 19 (vs. HC) and 48 (vs. ERA) deregulated miRNAs (p<0.05). The significant up-regulation of miR-21-5p both in early PsA and in ERA in comparison with HC was validated and confirmed. In PsA, miR-21-5p was found significantly down regulated after 12 weeks of therapy, which significantly correlated with the reduction of DAPSA score. CONCLUSIONS: In early PsA, a 19- (vs. HC) and 48- (vs. ERA) miRNA signature was identified. A differential expression of miRNAs in patients with active disease makes them attractive biomarkers of psoriatic disease. MiR-21-5p was found up-regulated both in early PsA and ERA, a finding which highlights its role in the inflammatory process in general and its potential role as a therapeutic target in different inflammatory disorders. A potential role of miR-21-5p as a response to treatment biomarker in early PsA has been identified.


Assuntos
Artrite Psoriásica/metabolismo , Leucócitos Mononucleares/metabolismo , MicroRNAs/metabolismo , Adulto , Artrite Psoriásica/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade
6.
Genes Chromosomes Cancer ; 54(12): 818-26, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26355802

RESUMO

To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis.


Assuntos
Deleção Cromossômica , Interleucina-2/farmacologia , Cariotipagem , Leucemia Linfocítica Crônica de Células B/genética , Mitógenos/farmacologia , Oligonucleotídeos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 17/genética , Citogenética , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA , Receptor Notch1/genética , Proteínas Recombinantes/farmacologia , Ribonucleoproteína Nuclear Pequena U2/genética , Tempo para o Tratamento , Proteína Supressora de Tumor p53/genética
8.
Blood ; 119(10): 2310-3, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22246039

RESUMO

It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with "normal" FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = < .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features.


Assuntos
Aberrações Cromossômicas , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Interleucina-2/farmacologia , Cariótipo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Metáfase/efeitos dos fármacos , Metáfase/genética , Pessoa de Meia-Idade , Mitógenos/farmacologia , Oligonucleotídeos/farmacologia , Prognóstico , Análise de Sobrevida
9.
Mol Cancer ; 9: 123, 2010 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-20504344

RESUMO

BACKGROUND: Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. RESULTS: By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. CONCLUSIONS: This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , MicroRNAs/genética , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , Vidarabina/uso terapêutico
10.
Am J Med Qual ; 35(3): 265-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31271037

RESUMO

In the Local Health Authority (LHA) of Parma, Emilia Romagna, Italy, 16 medical homes were established between 2011 and 2014. The authors implemented a 1-year (January 1, 2015, to December 31, 2015) cross-sectional population-based design to compare utilization and processes of care between medical homes and comparison practices using the Parma LHA administrative health care database. Residents (n = 372 396) attributed to a primary care physician practicing in a medical home as of January 1, 2015, were considered exposed to medical homes. Adjusted rates of emergency department (ED) use (incidence rate ratio [IRR] = 0.86; 95% CI = 0.82-0.90), potentially avoidable ED use (IRR = 0.78; 95% CI = 0.72-0.84), and hospitalization for chronic ambulatory care sensitive conditions (ACSCs; IRR = 0.87, 95% CI = 0.78-0.97) were lower among patients in medical homes. Performance on process of care measures favored the medical home group; however, associations were generally weak. Receipt of care in medical homes in Parma LHA was associated with lower rates of avoidable ED visits and hospitalizations for chronic ACSCs.


Assuntos
Assistência Ambulatorial/organização & administração , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Assistência Centrada no Paciente/organização & administração , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Pesquisa sobre Serviços de Saúde , Hospitalização/estatística & dados numéricos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Avaliação de Processos em Cuidados de Saúde , Indicadores de Qualidade em Assistência à Saúde , Características de Residência , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
11.
Mol Oncol ; 14(9): 2163-2175, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32441866

RESUMO

Cytopathological analyses of bronchial washings (BWs) collected during fibre-optic bronchoscopy are often inconclusive for lung cancer diagnosis. To address this issue, we assessed the suitability of conducting molecular analyses on BWs, with the aim to improve the diagnosis and outcome prediction of lung cancer. The methylation status of RASSF1A, CDH1, DLC1 and PRPH was analysed in BW samples from 91 lung cancer patients and 31 controls, using a novel two-colour droplet digital methylation-specific PCR (ddMSP) technique. Mutations in ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1 and TP53 and gene fusions of ALK, RET and ROS1 were also investigated, using next-generation sequencing on 73 lung cancer patients and 14 tumour-free individuals. Our four-gene methylation panel had significant diagnostic power, with 97% sensitivity and 74% specificity (relative risk, 7.3; odds ratio, 6.1; 95% confidence interval, 12.7-127). In contrast, gene mutation analysis had a remarkable value for predictive, but not for diagnostic, purposes. Actionable mutations in EGFR, HER2 and ROS1 as well as in other cancer genes (KRAS, PIK3CA and TP53) were detected. Concordance with gene mutations uncovered in tumour biopsies was higher than 90%. In addition, bronchial-washing analyses permitted complete patient coverage and the detection of additional actionable mutations. In conclusion, BWs are a useful material on which to perform molecular tests based on gene panels: aberrant gene methylation and mutation analyses could be performed as approaches accompanying current diagnostic and predictive assays during the initial workup phase. This study establishes the grounds for further prospective investigation.


Assuntos
Lavagem Broncoalveolar , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Técnicas de Diagnóstico Molecular , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Metilação de DNA/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética
12.
Mediterr J Hematol Infect Dis ; 11(1): e2019057, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31528323

RESUMO

In 2014 a 66-year-old woman presented with anemia and an IgAk monoclonal spike. Bone marrow (BM) biopsy showed 80% lymphocytes and lymphoplasmacytoid cells. Computed Tomography (CT) scan documented neither adenopathy nor splenomegaly. Diagnosis of IgA lymphoplasmacytic lymphoma was made. After three lines of treatment, progressive disease with adenopathies, splenomegaly, and ascites were documented on a CT scan. Our patient developed thrombocytopenia, transfusion-dependent anemia, and clinical deterioration. We performed genetic studies of peripheral blood lymphocytes with the NGS approach. Given the identification of MYD88 L265P mutation, in February 2018 our patient started ibrutinib off-label. Hb and PLT improved from day +35. In July 2018 no ascites and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019 the patient was still on ibrutinib with transfusion independence and good performance status.

13.
Epigenomics ; 11(6): 587-604, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066579

RESUMO

Aim: To investigate the genome-wide methylation of genetically characterized colorectal cancer stem cell (CR-CSC) lines. Materials & methods: Eight CR-CSC lines were isolated from primary colorectal cancer (CRC) tissues, cultured and characterized for aneuploidy, mutational status of CRC-related genes and microsatellite instability (MSI). Genome-wide DNA methylation was assessed by MethylationEPIC microarray. Results: We describe a distinctive methylation pattern that is maintained following in vivo passages in immune-compromised mice. We identified an epigenetic CR-CSC signature associated with MSI. We noticed that the preponderance of the differentially methylated positions do not reside at CpG islands, but spread to shelf and open sea regions. Conclusion: Given that CRCs with MSI-high status have a lower metastatic potential, the identification of a MSI-related methylation signature could provide new insights and possible targets into metastatic CRC.


Assuntos
Neoplasias do Colo/genética , Metilação de DNA , Instabilidade de Microssatélites , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias do Colo/patologia , Ilhas de CpG/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Xenoenxertos , Humanos , Camundongos
14.
J Hematol Oncol ; 12(1): 114, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744508

RESUMO

Clonal evolution of chronic lymphocytic leukemia (CLL) often follows chemotherapy and is associated with adverse outcome, but also occurs in untreated patients, in which case its predictive role is debated. We investigated whether the selection and expansion of CLL clone(s) precede an aggressive disease shift. We found that clonal evolution occurs in all CLL patients, irrespective of the clinical outcome, but is faster during disease progression. In particular, changes in the frequency of nucleotide variants (NVs) in specific CLL-related genes may represent an indicator of poor clinical outcome.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Evolução Clonal , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Mutação , Progressão da Doença , Humanos , Estudos Longitudinais , Prognóstico , Taxa de Sobrevida
15.
Oncotarget ; 9(76): 34398-34412, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30344950

RESUMO

The complex karyotype (CK) is an established negative prognostic marker in a number of haematological malignancies. After the introduction of effective mitogens, a growing body of evidence has suggested that the presence of 3 or more aberrations by conventional banding analysis (CBA) is associated with an unfavorable outcome in chronic lymphocytic leukemia (CLL). Thus, the importance of CBA was recognized by the 2018 guidelines of the International Workshop on CLL, which proposed the introduction of CBA in clinical trials to validate the value of karyotype aberrations. Indeed, a number of observational studies showed that cytogenetic aberrations and, particularly, the CK may have a negative independent impact on objective outcome measures (i.e. time to first treatment, progression free survival, time to chemorefractoriness and overall survival) both in patients treated with chemoimmunotherapy and, possibly, in patients receiving novel mechanism-based treatment. Here, we set out to present the scientific evidence supporting the significance of CK as a prognostic marker in CLL and to discuss the biological basis showing that the CK is a consequence of genomic instability.

16.
Oncotarget ; 8(17): 28008-28020, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28427204

RESUMO

We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.


Assuntos
Aberrações Cromossômicas , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
17.
Ann Ist Super Sanita ; 52(1): 70-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27033621

RESUMO

BACKGROUND: The Comunity Health Centre (CHC) primary care model is a team-based health care delivery model intended to provide comprehensive and continuous medical care to patients within a defined community. The CHC, Case della Salute in Italian, model was introduced in the Emilia-Romagna Region in 2010. METHODS: We present updated data on the implementation on the CHC Case della Salute primary care model in the Emilia-Romagna Region. RESULTS: There are 67 operating CHCs in Emilia-Romagna (update March 2015); 26 small (39%), 24 medium (36%) and 17 large (25%). Since 2011 the number of operating CHCs has increased by 60%, reaching 55% of the target planned CHCs (n. = 122). There is, on average, one running CHC per 66.524 inhabitants. 16% of total general practitioners (GPs) and 8.4% of total family paediatricians working in Emilia-Romagna have their practice in CHCs. CHCs offer primary and specialist integrated care, prevention services, health education and social care. DISCUSSION: Although preliminary results suggest CHCs have fostered primary care's quality and efficiency, more research is needed to assess their impact on improving clinical, social and economic outcomes.


Assuntos
Centros Comunitários de Saúde/organização & administração , Atenção à Saúde/métodos , Atenção Primária à Saúde/métodos , Medicina de Família e Comunidade , Clínicos Gerais , Tamanho das Instituições de Saúde , Humanos , Itália , Regionalização da Saúde , Recursos Humanos
18.
J Hematol Oncol ; 9(1): 88, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27633522

RESUMO

BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression. The genomic DNA from peripheral blood samples of 200 consecutive CLL patients was analyzed using Ion Torrent Personal Genome Machine, a NGS platform that uses semiconductor sequencing technology. Karyotype analysis was performed using efficient mitogens. RESULTS: Mutations were detected in 42.0 % of cases with 42.8 % of mutated patients presenting 2 or more mutations. The presence of mutations by NGS was associated with unmutated IGHV gene (p = 0.009), CD38 positivity (p = 0.010), risk stratification by fluorescence in situ hybridization (FISH) (p < 0.001), and the complex karyotype (p = 0.003). A high risk as assessed by FISH analysis was associated with mutations affecting TP53 (p = 0.012), BIRC3 (p = 0.003), and FBXW7 (p = 0.003) while the complex karyotype was significantly associated with TP53, ATM, and MYD88 mutations (p = 0.003, 0.018, and 0.001, respectively). By multivariate analysis, the multi-hit profile (≥2 mutations by NGS) was independently associated with a shorter time to first treatment (p = 0.004) along with TP53 disruption (p = 0.040), IGHV unmutated status (p < 0.001), and advanced stage (p < 0.001). Advanced stage (p = 0.010), TP53 disruption (p < 0.001), IGHV unmutated status (p = 0.020), and the complex karyotype (p = 0.007) were independently associated with a shorter overall survival. CONCLUSIONS: At diagnosis, an extensive biologic characterization including NGS and karyotype analyses using novel mitogens may offer new perspectives for a better refinement of risk stratification that could be of help in the clinical management of CLL patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína 3 com Repetições IAP de Baculovírus/genética , Análise Mutacional de DNA , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteína Supressora de Tumor p53/genética
19.
Mediterr J Hematol Infect Dis ; 8(1): e2016047, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27872727

RESUMO

Chronic lymphocytic leukemia (CLL) displays an extremely variable clinical behaviour. Accurate prognostication and prediction of response to treatment are important in an era of effective first-line regimens and novel molecules for high risk patients. Because a plethora of prognostic biomarkers were identified, but few of them were validated by multivariable analysis in comprehensive prospective studies, we applied in this survey stringent criteria to select papers from the literature in order to identify the most reproducible prognostic/predictive markers. Each biomarker was analysed in terms of reproducibility across the different studies with respect to its impact on time to first treatment (TTFT), progression free survival (PFS), overall survival (OS) and response to treatment. We were able to identify the following biomarkers as the most reliable in guiding risk stratification in the daily clinical practice: 17p-/TP53 mutations, IGHV unmutated configuration, short telomeres and 11q-. However, the method for measuring telomere length was not validated yet and 11q- was predictive of inferior OS only in those patients who did not receive FCR-like combinations. Stage and lymphocytosis were predictive of shorter TTFT and age, high serum thymidine kinase levels and poor performance status were predictive of shorter OS. Using our criteria no parameter was found to independently predict for inferior response to treatment.

20.
Biomark Res ; 3: 12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26120471

RESUMO

BACKGROUND: Breast cancer circulating biomarkers include carcinoembryonic antigen and carbohydrate antigen 15-3, which are used for patient follow-up. Since sensitivity and specificity are low, novel and more useful biomarkers are needed. The presence of stable circulating microRNAs (miRNAs) in serum or plasma suggested a promising role for these tiny RNAs as cancer biomarkers. To acquire an absolute concentration of circulating miRNAs and reduce the impact of preanalytical and analytical variables, we used the droplet digital PCR (ddPCR) technique. RESULTS: We investigated a panel of five miRNAs in the sera of two independent cohorts of breast cancer patients and disease-free controls. The study showed that miR-148b-3p and miR-652-3p levels were significantly lower in the serum of breast cancer patients than that in controls in both cohorts. For these two miRNAs, the stratification of breast cancer patients versus controls was confirmed by receiver operating characteristic curve analyses. In addition, we showed that higher levels of serum miR-10b-5p were associated with clinicobiological markers of poor prognosis. CONCLUSIONS: The study revealed the usefulness of the ddPCR approach for the quantification of circulating miRNAs. The use of the ddPCR quantitative approach revealed very good agreement between two independent cohorts in terms of comparable absolute miRNA concentrations and consistent trends of dysregulation in breast cancer patients versus controls. Overall, this study supports the use of the quantitative ddPCR approach for monitoring the absolute levels of diagnostic and prognostic tumor-specific circulating miRNAs.

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