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1.
Ann Surg Oncol ; 28(2): 1167-1177, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32761330

RESUMO

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Prognóstico
2.
Neuroendocrinology ; 111(7): 609-630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32971521

RESUMO

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.


Assuntos
Consenso , Neoplasias Duodenais , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Pancreáticas , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/terapia , Humanos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia
3.
Mediators Inflamm ; 2021: 8854916, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708009

RESUMO

BACKGROUND: CARD15/NOD2 is the most significant genetic susceptibility in Crohn's disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. METHODS: 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. RESULTS: CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases (p < 0.05). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery (p = 0.0344). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine (p = 0.012), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. CONCLUSIONS: 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.


Assuntos
Doença de Crohn/genética , Doença de Crohn/cirurgia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Adulto Jovem
4.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919851

RESUMO

Pancreatic neuroendocrine tumors (pNETs) are a rare group of cancers accounting for about 1-2% of all pancreatic neoplasms. About 10% of pNETs arise within endocrine tumor syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1). pNETs affect 30-80% of MEN1 patients, manifesting prevalently as multiple microadenomas. pNETs in patients with MEN1 are particularly difficult to treat due to differences in their growth potential, their multiplicity, the frequent requirement of extensive surgery, the high rate of post-operative recurrences, and the concomitant development of other tumors. MEN1 syndrome is caused by germinal heterozygote inactivating mutation of the MEN1 gene, encoding the menin tumor suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin. Menin is a key regulator of endocrine cell plasticity and its loss in these cells is sufficient for tumor initiation. Somatic biallelic loss of wild-type menin in the neuroendocrine pancreas presumably alters the epigenetic control of gene expression, mediated by histone modifications and DNA hypermethylation, as a driver of MEN1-associated pNET tumorigenesis. In this light, epigenetic-based therapies aimed to correct the altered DNA methylation, and/or histone modifications might be a possible therapeutic strategy for MEN1 pNETs, for whom standard treatments fail.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Animais , Epigênese Genética , Humanos , Neoplasia Endócrina Múltipla Tipo 1/classificação , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Transdução de Sinais/genética
6.
Mod Pathol ; 33(7): 1398-1409, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32066859

RESUMO

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.


Assuntos
Adenocarcinoma/patologia , Antígeno B7-H1/metabolismo , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Adenocarcinoma/etiologia , Adenocarcinoma/imunologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Doença Celíaca/complicações , Doença de Crohn/complicações , Feminino , Humanos , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Int J Cancer ; 145(9): 2580-2593, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30973654

RESUMO

Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.


Assuntos
Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/genética , Proteínas Nucleares/genética , Idoso , Quimioterapia Adjuvante/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Prognóstico , Análise de Sequência de RNA/métodos , Transdução de Sinais/genética , Transcriptoma/genética , Regulação para Cima/genética
8.
World J Surg ; 41(9): 2312-2323, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28429092

RESUMO

BACKGROUND: The multiple endocrine neoplasia type 1 syndrome (MEN1) natural history is poorly evaluated, and few single-institution experiences about hereditary gastroenteropancreatic neuroendocrine tumors (GEP-NET) are reported. Our purpose is to analyze the role of GEP-NET in MEN1-related death, as well as the behavior of these lesions during follow-up. METHODS: The study population consists of 77 patients diagnosed with MEN1 GEP-NET, regularly followed up since 1990. Extensive clinical data were prospectively recorded. Statistical analysis was performed both on the whole population of 77 patients and on two subgroups including patients who, during the long lasting study period, underwent GEP-NET surgery (50 pts) and who did not (27 pts), respectively. RESULTS: Twenty-five males (32.5%) and 52 females (67.5%) were enrolled. Sixty-four patients had MEN1 family history (83.1%), and genetic mutation was detected in 67 cases (87%). The mean age at GEP-NET diagnosis was 41.4 years (SD = 13.6); 16 patients (20.8%) had GEP-NET diagnosed before age 30 and 12 cases (15.6%) before 1996. The mean interval time between MEN1 diagnosis and GEP-NET detection was 5.7 years (range -11/37; SD = 8.1 years). Overall, the mean follow-up time from MEN1 diagnosis was 15.8 years (SD = 9.7 years) and from GEP-NET diagnosis was 9.6 years (SD = 6.9 years). Gastrinoma was the most frequent functioning GEP-NET and pancreatoduodenectomy the most adopted surgery. GEP-NET progression affected 12 patients within the non-surgical group, while 18 subjects developed progression after surgery. CONCLUSIONS: Our single-center data provide information on epidemiologic, clinical and pathological features of GEP-NET in MEN1 making possible to clarify their natural history.


Assuntos
Gastrinoma/diagnóstico , Neoplasias Intestinais , Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Adulto , Progressão da Doença , Feminino , Seguimentos , Gastrinoma/genética , Gastrinoma/mortalidade , Gastrinoma/cirurgia , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/genética , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/mortalidade , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Mutação , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
9.
Langenbecks Arch Surg ; 402(7): 1071-1078, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27534867

RESUMO

PURPOSE: The jejunum is a relatively uncommon localization of Crohn's disease (CD) compared to the terminal ileum or the large bowel. The type of surgery and the short and long-term results after surgery have not been extensively investigated. A review of patients who underwent surgery for jejunal CD in our center was examined. METHODS: Between 1986 and 2011, 110 patients underwent surgery for jejunal CD. Thirty patients (27.3 %) were surgically treated with resection, 29 patients (26.4 %) with one or more strictureplasties, and 51 patients (46.3 %) with both a resection and one or more strictureplasties. RESULTS: There was no statistical difference in terms of short-term postoperative complications between patients operated with three different options (p = 0.72). Patients were followed up for a period ranging from 2 to 18 years (mean 11 years). During this period, 42 patients had no CD recurrence, 11 patients had medical recurrences only, while 57 patients had surgical recurrences, too. There was no statistical difference in terms of medical and surgical recurrence between the three types of surgical procedures employed (p = 0.24) and between smokers and non-smokers. The recurrent CD was prevalently treated with strictureplasty. CONCLUSIONS: The most frequently employed surgery for the treatment of jejunal CD is a combined type of treatment, i.e., resection of the most affected tract and strictureplasty of the residual strictures. This approach does not imply an increased risk of postoperative complications and recurrence and can reduce the risk of the short bowel syndrome.


Assuntos
Doença de Crohn/terapia , Doenças do Jejuno/terapia , Complicações Pós-Operatórias/etiologia , Adolescente , Adulto , Idoso , Terapia Combinada , Doença de Crohn/patologia , Feminino , Humanos , Doenças do Jejuno/patologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
10.
Dig Surg ; 34(5): 380-386, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28099957

RESUMO

BACKGROUND AND AIM: Chemoradiotherapy (CRT) is the gold standard treatment for anal cancer, which permits the maintenance of the anal function. However, about 30-40% of patients develop local disease progression, for which surgery represents a good salvage therapy. The aim of this study is to evaluate survival and morbidity rate in patients who undergo salvage surgery in our single institution, with an overview of the literature. METHODS: A retrospective study was carried out on patients who underwent surgical treatment of anal canal cancer after failure of CRT. We evaluated overall survival at 1, 3, and 5 years and postoperative morbidity rate. RESULTS: Twenty patients who underwent radical surgery with abdominoperineal resection were included in the study. The survival rates at 1, 3, and 5 years were 75, 60, and 37.4%; with a disease-free survival of 67, 53, and 35%, respectively. There was no postoperative mortality. The morbidity rate was 35%. CONCLUSION: Surgery represents the recommended therapy for persistent or recurrent anal canal cancer after CRT, with a good survival rate and an acceptable morbidity.


Assuntos
Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/cirurgia , Complicações Pós-Operatórias/etiologia , Terapia de Salvação , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Falha de Tratamento
11.
Exp Cell Res ; 323(1): 77-86, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24583398

RESUMO

Matrix metalloproteinases (MMPs) play a critical role in inflammation and ulcerations in gut of Crohn׳s disease (CD) patients. Intestinal subepithelial myofibroblasts (ISEMFs) secrete MMPs in response to inflammatory stimuli. Previous data showed in CD-ISEMFs increased oxidative status. The aim of this study was to investigate the role of ISEMFs in modulating the production of MMP-3 and TIMP-1, an inhibitor of MMPs activity. A relationship among oxidative stress, activity of antioxidants and MMP-3/TIMP-1 was also studied. ISEMFs isolated from CD patient colon and human colonic cell line of myofibroblasts (18Co) were used. Oxidative state was modulated by buthionine sulfoximine, an inhibitor of glutathione (GSH) synthesis, and N-acetylcysteine (NAC), GSH precursor. An up-regulation of MMP-3 due to increased oxidative state was found in CD-ISEMFs. Stimulation by tumor necrosis factor (TNF)α increased further MMP-3 levels. On the contrary, no change in TIMP-1 production was determined. NAC treatment decreased MMP-3 production in CD-ISMEFs and removed the enhancement due to TNFα. Similar effects were observed in 18Co cells treated with curcumin, antioxidant with anti-inflammatory properties. The involvement of MAPKs on MMP-3 redox regulation was also shown. This study demonstrates the involvement of ISEMFs and high oxidative state in the increased MMP-3 production found in intestinal mucosa of CD patients. NAC and curcumin normalize MMP-3 levels mainly in TNFα stimulated cells. A modulation of MMP-3 production by NAC and curcumin due to their direct action on transcriptional factors has been also suggested. Therefore, they could have a therapeutic use for the prevention and treatment of fistulaes in CD.


Assuntos
Acetilcisteína/farmacologia , Doença de Crohn/enzimologia , Curcumina/farmacologia , Metaloproteinase 3 da Matriz/metabolismo , Miofibroblastos/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Adulto , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Butionina Sulfoximina/farmacologia , Células Cultivadas , Colo/citologia , Colo/metabolismo , Doença de Crohn/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Glutationa/biossíntese , Humanos , Peróxido de Hidrogênio/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Metaloproteinase 3 da Matriz/biossíntese , Pessoa de Meia-Idade , Miofibroblastos/citologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Adulto Jovem
12.
Clin Mol Allergy ; 13(1): 12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26203298

RESUMO

BACKGROUND: Crohn's disease (CD) and Hidradenitis suppurativa (HS) are both chronic inflammatory diseases. The pathogenesis of these diseases is multifactorial, due to the interaction of genetic and environmental factors leading to a deregulated local immune response where T lymphocytes play a major role. To the best of our knowledge, no previous study has clarified whether the pathogenetic mechanism of perianal CD and HS is the same. We therefore analyzed the cellular expression pattern and the cytokine repertoire in three patients suffering from both perianal CD and HS. METHODS: We evaluated three patients affected by concurrent HS and CD with fistulizing perianal disease. Surgical specimens have been fixed and embedded in paraffin prior to sectioning for histological examination. Inflammatory tissue curettages have been recovered during intervention from perianal fistulas and HS lesions in order to analyze the phenotypic and functional characteristics of infiltrating T cells. In particular we evaluated T cells, by flow cytometry, for cytokine production profile and expression of surface markers. Moreover, analysis of the T cell repertoire was performed by means of spectratyping, in only one patient. RESULTS: A higher frequency of CD4+ CD161+ T lymphocytes has been detected in CD fistulas and in HS lesions than in peripheral blood (PB) samples. In the patient in whom we derived enough cells from the three sources, we found higher frequency of CD4+ IL-17- producing cells in HS lesion and fistula lesion compared to PB. It is noteworthy that the same clonotypes were expanded in this patient in T cells derived from both HS lesion and fistula lesion. CONCLUSION: The presence of numerous CD4+ CD161+ lymphocytes in fistula and HS lesion curettages suggests that these cells may play a pathogenic role, and candidates CD161 as a possible biological target for medical treatment.

13.
Nutr Cancer ; 66(7): 1228-36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25207387

RESUMO

The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular diseases, and some types of cancer. Recent interest has been focused on the biological activity of phenolic compounds present in extra virgin olive oils (EVOOs). Both in vivo and in vitro studies have shown that EVOO components have positive effects on metabolic parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet function, and antimicrobial activity. We have investigated the possible interactions between 2 extracts of extra virgin olive oil and estrogen receptor ß (ERß) in an in vitro model of colon cancer. The qualification and quantification of the components of the 2 samples tested showed that phenolic compounds-hydroxytyrosol, secoiridoids, and lignans-are the major represented compounds. EVOO extracts were tested on a colon cancer cell line engineered to overexpress ERß (HCT8-ß8). By using custom made Oligo microarray, gene expression profiles of colon cancer cells challenged with EVOO-T extracts when compared with those of cells exposed to 17ß-estradiol (17ß-E2). This study demonstrated that the EVOO extracts tested showed an antiproliferative effect on colon cancer cells through the interaction with estrogen-dependent signals involved in tumor cell growth. Specifically, the ability of EVOO extracts to inhibit cell proliferation was superimposable to the activation of the ERß receptor, similar to what was observed after 17ß-E2 challenge.


Assuntos
Neoplasias do Colo/patologia , Óleos de Plantas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Humanos , Lignanas/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Azeite de Oliva , Polifenóis/farmacologia , Transcriptoma
14.
Endocr J ; 61(3): 239-47, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24317294

RESUMO

Some published criteria for intraoperative monitoring of PTH serum concentrations may cause misleading results, since the timing of samples measured between the pre-incision and pre-excision phase of surgery is often unrecorded. In our opinion this information is critical, as the time of an intermediate sample during surgical manipulation may represent the "true" beginning of the PTH decay. We modified the usual criterion of monitoring (cut-off at 10 minutes after clamping) proposing a further check at manipulation in case the primary check at clamping produces an apparently negative result. On the basis of a mathematical model, false negative curves were simulated by means of a time shift. This shift was assumed to be the interval between manipulation and clamping. Analysing the decay curve, we used the 50% cut-off at 10 minutes after the supposed "true" origin (clamping or manipulation). Using a rapid immunochemiluminometric assay (ICMA), data were collected from 22 patients successfully operated for parathyroid adenoma. The check at clamping correctly diagnosed 13 patients. Among the 9 false negative cases, 6 were correctly diagnosed considering the manipulation as the baseline value. In the remaining 3 patients, diagnosis required prolonged observation of the curves. In case the iPTH decay does not follow the expected curve, it can be useful to check the decay normalising to a pre-excision value. The advantages of our criterion are both the prompt recognition of false negative results and the construction of a "true" decay curve for each patient, supporting the surgeon during the excision of hyperfunctioning parathyroid tissue.


Assuntos
Hiperparatireoidismo Primário/cirurgia , Monitorização Intraoperatória/métodos , Hormônio Paratireóideo/sangue , Adulto , Idoso , Reações Falso-Negativas , Feminino , Humanos , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/cirurgia , Neoplasias das Paratireoides/cirurgia
15.
Endocr J ; 61(8): 781-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24882518

RESUMO

Renal tumors are exceedingly rare in Multiple Endocrine Neoplasia type 1 (MEN1), a pleyotropic hereditary cancer disorder affecting the endocrine system. Herein we report a unique case of renal sarcomatoid carcinoma with concomitant ipsilateral non-secreting adrenal adenoma occurring in a young male MEN1 patient, previously operated for hyperparathyroidism and multiple pancreatic neuroendocrine neoplasms. Molecular analysis in the MEN1 locus at 11q13 showed loss of heterozygosity in the adrenal lesion, while kidney cancer was unrelated to MEN1 syndrome.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Proteínas Proto-Oncogênicas/genética , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/genética , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/genética , Análise Mutacional de DNA , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Masculino , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética
16.
Pharmaceutics ; 16(5)2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38794302

RESUMO

Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the ß subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.

17.
J Exp Med ; 204(8): 1849-61, 2007 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-17635957

RESUMO

T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-gamma (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor ROR gamma t, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of ROR gamma t and the production of IL-17, but induced IFN-gamma. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17-producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Proliferação de Células , Clonagem Molecular , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Microscopia Confocal , Modelos Biológicos , Receptores CCR6 , Receptores de Quimiocinas/metabolismo , Receptores de Interleucina/metabolismo
18.
Int Arch Allergy Immunol ; 161(1): 81-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23257766

RESUMO

BACKGROUND: Crohn's disease (CD) is an idiopathic inflammatory bowel disease (IBD) in the pathogenesis of which both Th1 and Th17 lymphocytes have been described as being involved. The NK-associated molecule CD161 has recently been described as a marker of IL-17-producing lymphocytes. In this work we assessed the presence and the functional features of CD161 T helper lymphocytes infiltrating CD-associated perianal fistulas, both before and after inoculation of anti-TNF-α mAbs along the fistula. METHODS: In a group of 9 CD patients with fistulizing perianal disease, we evaluated phenotypic and functional features of T cells recovered from the fistula, comparing them with peripheral blood (PB) T lymphocytes. Moreover, the effects anti-TNF-α mAbs injections along the fistula in terms of ability to reduce the inflammatory infiltrate and to determine fistula disappearance were assessed. RESULTS: In CD patients with fistulizing disease there is an accumulation of CD161+ T helper lymphocytes, with higher frequencies of Th1, Th17 and Th17/Th1 cells in the fistula than in PB. Local anti-TNF-α administration is associated with fistula resolution in the majority of patients with disappearance of infiltrating T lymphocytes, without any systemic effect in circulating effector T cells. CONCLUSIONS: These findings suggest that CD4+CD161+ T cells with Th17, Th17/Th1 and Th1 phenotype accumulate in CD perianal fistulas, and indicate local anti-TNF-α mAbs administration along the fistula as a promising tool for the treatment of these patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Fístula Retal/tratamento farmacológico , Fístula Retal/imunologia , Adalimumab , Adulto , Anti-Inflamatórios/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Doença de Crohn/sangue , Doença de Crohn/patologia , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Fístula Retal/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
19.
Int J Colorectal Dis ; 28(7): 915-24, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23271497

RESUMO

PURPOSE: Intestinal subepithelial myofibroblasts (ISEMFs)(1) are the predominant source of matrix metalloproteinase-2 (MMP-2) in gut, and a decrease in glutathione/oxidized glutathione (GSH/GSSG) ratio, intracellular redox state index, occurs in the ISEMFs of patients with Crohn's disease (CD). The aim of this study is to demonstrate a relationship between MMP-2 secretion and activation and changes of GSH/GSSG ratio in ISEMFs stimulated or not with tumor necrosis factor alpha (TNFα). METHODS: ISEMFs were isolated from ill and healthy colon mucosa of patients with active CD. Buthionine sulfoximine, GSH synthesis inhibitor, and N-acetylcysteine (NAC), precursor of GSH synthesis, were used to modulate GSH/GSSG ratio. GSH and GSSG were measured by HPLC and MMP-2 by ELISA Kit. RESULTS: In cells, stimulated or not with TNFα, a significant increase in MMP-2 secretion and activation, related to increased oxidative stress, due to low GSH/GSSG ratio, was detected. NAC treatment, increasing this ratio, reduced MMP-2 secretion and exhibited a direct effect on the secreted MMP-2 activity. In NAC-treated and TNFα-stimulated ISEMFs of CD patients' MMP-2 activity were restored to physiological value. The involvement of c-Jun N-terminal kinase pathway on redox regulation of MMP-2 secretion has been demonstrated. CONCLUSION: For the first time, in CD patient ISEMFs, a redox regulation of MMP-2 secretion and activation related to GSH/GSSG ratio and inflammatory state have been demonstrated. This study suggests that compounds able to maintain GSH/GSSG ratio to physiological values can be useful to restore normal MMP-2 levels reducing in CD patient intestine the dysfunction of epithelial barrier.


Assuntos
Acetilcisteína/metabolismo , Doença de Crohn/enzimologia , Doença de Crohn/patologia , Glutationa/metabolismo , Intestinos/patologia , Metaloproteinase 2 da Matriz/metabolismo , Miofibroblastos/enzimologia , Adulto , Butionina Sulfoximina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Dissulfeto de Glutationa/metabolismo , Humanos , Espaço Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Oxirredução/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Adulto Jovem
20.
World J Surg ; 37(4): 902-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23381673

RESUMO

BACKGROUND: The relation between Crohn's colitis (CC) and colorectal cancer is still controversial. Several case reports and retrospective studies have shown that patients with Crohn's disease (CD) have a 6- to 20-fold higher risk to develop CRC than does the normal population. The extent of disease (extensive colitis), presence of anal fistula, age > 40 years, strictures, and length of disease >10 years may be important determinants for increasing risk. Despite this evidence, other population-based studies have shown no increased risk of colon or rectal cancer. The aim of this study was to investigate retrospectively factors that may predict the development of cancer. METHODS: We searched the histopathologic database of the Digestive Surgery Unit at Careggi University Hospital for CC patients (January 1987 to September 2011) and identified 313 patients with CC who underwent surgery. RESULTS: There are 11 (3.5 %) of adenocarcinomas. Multivariate analysis showed disease duration (p = 0.001), age at CD diagnosis (p = 0.002), distal localization (p = 0.045), and penetrating disease (p = 0.041) to be risk factors. Multivariate analysis showed that 40 patients who had undergone previous immunosuppressive therapy had a significant risk of developing CRC (p = 0.026). CONCLUSIONS: Crohn's colitis patients who require surgery are at higher risk for developing CRC, particularly those whose disease duration is >10 years, have distal localization, age at diagnosis was <40 years, and have penetrating disease. Previous immunosuppressive therapy should be better investigated. We recommend surgery for any patient presenting with colonic strictures.


Assuntos
Adenocarcinoma/etiologia , Colite/complicações , Neoplasias Colorretais/etiologia , Doença de Crohn/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Colite/cirurgia , Doença de Crohn/cirurgia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
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