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1.
Histochem Cell Biol ; 160(2): 113-125, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37284845

RESUMO

Mismatch repair (MMR) testing on all new cases of colorectal cancer (CRC) has customarily been preferably performed on surgical specimens, as more tissue is available; however, new clinical trials for the use of immune checkpoint inhibitors in the neoadjuvant setting require MMR testing on biopsy samples. This study aims at identifying advantages, disadvantages and any potential pitfalls in MMR evaluation on biopsy tissue and how to cope with them. The study is prospective-retrospective, recruiting 141 biopsies (86 proficient (p)MMR and 55 deficient (d)MMR) and 97 paired surgical specimens (48 pMMR; 49 dMMR). In biopsy specimens, a high number of indeterminate stains was observed, in particular for MLH1 (31 cases, 56.4%). The main reasons were a punctate nuclear expression of MLH1, relatively weak MLH1 nuclear expression compared to internal controls, or both (making MLH1 loss difficult to interpret), which was solved by reducing primary incubation times for MLH1. A mean of  ≥ 5 biopsies had adequate immunostains, compared to ≤ 3 biopsies in inadequate cases. Conversely, surgical specimens rarely suffered from indeterminate reactions, while weaker staining intensity (p < 0.007) for MLH1 and PMS2 and increased patchiness grade (p < 0.0001) were seen. Central artefacts were almost exclusive to surgical specimens. MMR status classification was possible in 92/97 matched biopsy/resection specimen cases, and all of these were concordant (47 pMMR and 45 dMMR). Evaluation of MMR status on CRC biopsy samples is feasible, if pitfalls in interpretation are known, making laboratory-specific appropriate staining protocols fundamental for high-quality diagnoses.


Assuntos
Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias Colorretais/genética , Biópsia
2.
Breast Cancer Res Treat ; 137(1): 167-74, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23129173

RESUMO

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.


Assuntos
Antineoplásicos/uso terapêutico , Aromatase/genética , Neoplasias da Mama/genética , Estrona/análogos & derivados , Nitrilas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Ensaios Clínicos como Assunto , Estrona/sangue , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Letrozol , Pessoa de Meia-Idade , Nitrilas/farmacologia , Estudos Prospectivos , Triazóis/farmacologia
3.
Cancer Invest ; 31(5): 336-45, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23641913

RESUMO

CTLA-4 blockade with monoclonal antibodies can lead to cancer regression in patients with metastatic melanoma (MM). CTLA-4 gene polymorphisms may influence the response to anti-CTLA-4 antibodies although few data are available regarding this issue. We analyzed six CTLA-4 single nucleotide polymorphisms (-1661A > G, -1577G > A, -658C > T, -319C > T, +49A > G, and CT60G > A) in 14 Italian MM patients and 45 healthy subjects. We found a significant association between the -1577G/A and CT60G/A genotypes and improved overall survival (Pc < 0.006, Bonferroni corrected), further confirmed by the diplotype analysis (-1577 & CT60 GG-AA diplotype, p < 0.001). A positive trend toward an association between these genotypes and response to therapy was also observed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/genética , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Autoimunidade , Sequência de Bases , Antígeno CTLA-4/antagonistas & inibidores , Estudos de Casos e Controles , Ensaios Clínicos Fase II como Assunto , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Ipilimumab , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Projetos Piloto , Análise de Sequência de DNA , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Resultado do Tratamento
4.
Tissue Antigens ; 80(4): 322-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22803950

RESUMO

Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoietic disorder characterized by expansion of phosphatidylinositol glycan-A-defective progenitor(s). Immune-dependent mechanisms, likely involving a deranged T cell-dependent autoimmune response, have been consistently associated with the selection/dominance of PNH precursors. Natural killer (NK) lymphocytes might participate in PNH pathogenesis, but their role is still controversial. NK activity is dependent on the balance between activating and inhibiting signals. Key component in such regulatory network is represented by killer immunoglobulin-like receptors (KIR). KIR are also involved in the regulation of adaptive cytotoxic T cell response and associated with autoimmunity. This study investigated on the frequency of KIR genes and their known human leukocyte antigen (HLA) ligands in 53 PNH Italian patients. We observed increased frequency of genotypes characterized by ≤2 activating KIR as well as by the presence of an inhibitory/activating gene ratio ≥3.5. In addition, an increased matching between KIR-3DL1 and its ligand HLA-Bw4 was found. These genotypes might be associated with lower NK-dependent recognition of stress-related self molecules; this is conceivable with the hypothesis that an increased availability of specific T cell targets, not cleared by NK cells, could be involved in PNH pathogenesis. These data may provide new insights into autoimmune PNH pathogenesis.


Assuntos
Antígenos HLA-B/genética , Hemoglobinúria Paroxística/genética , Células Matadoras Naturais/imunologia , Receptores KIR3DL1/genética , Linfócitos T/imunologia , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Expressão Gênica , Frequência do Gene , Antígenos HLA-B/imunologia , Haplótipos , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Humanos , Itália , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Ligantes , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Receptores KIR3DL1/imunologia , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia
5.
Int J Cancer ; 85(5): 667-73, 2000 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10699947

RESUMO

The growth and differentiation of normal and neoplastic epithelial cells may be regulated by the presence of adjacent normal tissues and cells, particularly stromal fibroblasts. However, the influence of normal fibroblast-tumor cell interactions on the response of malignant epithelial cells to radiation has not been adequately investigated nor has the possible role played by a 3-D environment in such modulation. We addressed this question by embedding MCF-7 mammary carcinoma cells into a collagen lattice, alone or mixed with HSF human dermal fibroblasts, and kept the gels anchored to the plastic surface or suspended in the culture medium. Some gels served as controls and others were irradiated with 6 MV photons fractionated into 3 daily doses totaling 5 or 10 Gy. After 2 or 7 days from the last treatment (7 or 12 days in culture, respectively), gels were processed in 1 of 2 ways: overall cell survival was determined by the MTT assay, while the survival of MCF-7 cells was selectively detected by a clonogenicity assay. Under these experimental conditions, we found that, in the presence of HSF fibroblasts, the growth of MCF-7 cells was restrained and radiosensitivity increased compared with MCF-7 cells cultured alone. For example, while the average number of MCF-7 foci/gel recovered from control gels with MCF-7 cells alone was 2,460 on day 7 and 3, 290 on day 12 of culture, it was 4 to 5 times lower (p < 0.001) in control gels with mixed MCF-7 and HSF cells. Radiation affected severely the survival of MCF-7 cells in all experimental groups but not sufficiently to mask the differences. For example, following exposure to the low dose of 5 Gy, the average number of MCF-7 foci/gel recovered from MCF-7-containing gels was 590 on day 7 and 329 on day 12 of culture, whereas numbers from the gels containing mixed MCF-7 and HSF cells were only 218 and 73, respectively (p < 0. 003 in both cases). HSF fibroblasts did not grow in our system, but they contracted strongly anchored and floating gels.


Assuntos
Sobrevivência Celular/efeitos da radiação , Colágeno , Fibroblastos/fisiologia , Tolerância a Radiação , Neoplasias da Mama , Divisão Celular/efeitos da radiação , Linhagem Celular , Técnicas de Cocultura , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos da radiação , Humanos , Lactente , Cinética , Pele/citologia , Fatores de Tempo , Células Tumorais Cultivadas
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