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1.
Optica ; 11(4): 569-576, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-39006164

RESUMO

With histopathology results typically taking several days, the ability to stage tumors during interventions could provide a step change in various cancer interventions. X-ray technology has advanced significantly in recent years with the introduction of phase-based imaging methods. These have been adapted for use in standard labs rather than specialized facilities such as synchrotrons, and approaches that enable fast 3D scans with conventional x-ray sources have been developed. This opens the possibility to produce 3D images with enhanced soft tissue contrast at a level of detail comparable to histopathology, in times sufficiently short to be compatible with use during surgical interventions. In this paper we discuss the application of one such approach to human esophagi obtained from esophagectomy interventions. We demonstrate that the image quality is sufficiently high to enable tumor T staging based on the x-ray datasets alone. Alongside detection of involved margins with potentially life-saving implications, staging tumors intra-operatively has the potential to change patient pathways, facilitating optimization of therapeutic interventions during the procedure itself. Besides a prospective intra-operative use, the availability of high-quality 3D images of entire esophageal tumors can support histopathological characterization, from enabling "right slice first time" approaches to understanding the histopathology in the full 3D context of the surrounding tumor environment.

2.
Clin Ter ; 174(6): 509-517, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38048114

RESUMO

Introduction: utism spectrum disorder (ASD) is a heterogeneous clinical condition, and its genetic basis is widely confirmed. The chromosomal microarray analysis (CMA) is a first-line diagnostic test that identifies copy number variants (CNVs). Some of these genomic rearrangements are associated with ASD, but the meaning of most of them is still unknown. Materials and methods: We performed a comparative genome hybridization (array-CGH) analysis in 130 children with confirmed ASD. Genetic results were analyzed and compared to clinical phenotype. Results and discussion.: 61/130 children carry CNVs, 44 presenting variants of unknown significance (u-CNVs), and 17 with susceptibility-CNVs (c-CNVs). Clinical evaluation showed no differences in cognitive abilities, language and EEG abnormalities, ASD symptoms among CNVs group and other patients. Finally, we highlight the role of GPHN, IMMP2L and ZMYND11, as ASD susceptibility genes. Conclusions: Our findings underscore the importance of array-CGH in ASD children since new CNVs and emerging genes appear to be associated with different clinical pictures.


Assuntos
Transtorno do Espectro Autista , Humanos , Criança , Transtorno do Espectro Autista/genética , Hibridização Genômica Comparativa , Cognição , Idioma , Proteínas de Ligação a DNA , Proteínas de Ciclo Celular , Proteínas Correpressoras
3.
Virchows Arch ; 479(6): 1111-1118, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34480612

RESUMO

The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33-0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23-0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58-0.70) for roundness to κ 0.26 (95%-CI 0.12-0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.


Assuntos
Extensão Extranodal/patologia , Patologistas , Neoplasias Retais/patologia , Biópsia , Competência Clínica , Ensaios Clínicos como Assunto , Inglaterra , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Variações Dependentes do Observador , Valor Preditivo dos Testes , Neoplasias Retais/classificação , Reprodutibilidade dos Testes , Estudos Retrospectivos
4.
ESMO Open ; 6(4): 100222, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34352702

RESUMO

BACKGROUND: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). PATIENTS AND METHODS: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. RESULTS: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). CONCLUSIONS: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.


Assuntos
Tumores do Estroma Gastrointestinal , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Estudos Retrospectivos
5.
Br J Surg ; 108(1): 74-79, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33640940

RESUMO

BACKGROUND: Histopathological outcomes, such as lymph node yield and margin positivity, are used to benchmark and assess surgical centre quality, and are reported annually by the National Oesophago-Gastric Cancer Audit (NOGCA) in England and Wales. The variation in pathological specimen assessment and how this affects these outcomes is not known. METHODS: A survey of practice was circulated to all tertiary oesophagogastric cancer centres across England and Wales. Questions captured demographic data, and information on how specimens were prepared and analysed. National performance data were retrieved from the NOGCA. Survey results were compared for tertiles of lymph node yield, and circumferential and longitudinal margins. RESULTS: Survey responses were received from 32 of 37 units (86 per cent response rate), accounting for 93.1 per cent of the total oesophagectomy volume in England and Wales. Only 5 of 32 units met or exceeded current guidelines on specimen preparation according to the Royal College of Pathologists guidelines. There was wide variation in how centres defined positive (R1) margins, and how margins and lymph nodes were assessed. Centres with the highest nodal yield were more likely to use systematic fat blocking, and to re-examine specimens when the initial load was low. Systematic blocking of lesser curve fat resulted in significantly higher rates of patients with at least 15 lymph nodes examined (91.4 versus 86.5 per cent; P = 0.027). CONCLUSION: Preparation and histopathological assessment of specimens varies significantly across institutions. This challenges the validity of currently used surgical quality metrics for oesophageal and other tumours.


Assuntos
Esofagectomia/normas , Esôfago/patologia , Indicadores de Qualidade em Assistência à Saúde , Inglaterra , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esôfago/cirurgia , Humanos , Excisão de Linfonodo , Margens de Excisão , Inquéritos e Questionários , País de Gales
6.
J Eur Acad Dermatol Venereol ; 35(3): 658-668, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32997839

RESUMO

BACKGROUND: Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. OBJECTIVES: The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. METHODS: Retrospective analysis of clinical data and histopathological features by an expert panel. RESULTS: Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. CONCLUSIONS: Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.


Assuntos
Linfoma Cutâneo de Células T , Linfoma de Células T Periférico , Neoplasias Cutâneas , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/terapia
7.
Dig Dis Sci ; 64(10): 2815-2822, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30982210

RESUMO

BACKGROUND: The endoscopic detection of esophageal cancer is suboptimal in both patients referred with dyspeptic symptoms and those enrolled in Barrett's surveillance programs. MCM5 expression in cells collected from gastric fluid may be correlated with the presence of dysplasia or adenocarcinoma. Analysis of this biomarker may improve the detection of cancer. METHODS: Sixty-one patients were enrolled at a single UK referral center. From each patient, 5-10 ml of gastric fluid was aspirated endoscopically. Patients were categorized according to their histology, normal, non-dysplastic Barrett's (NDBE), high-grade dysplastic Barrett's (HGD), and esophageal adenocarcinoma (EAC). All histology was confirmed by Seattle protocol biopsies or endoscopic mucosal resection. Samples were centrifuged, and the cell pellet was lysed. MCM5 expression levels were quantified using a proprietary immunoassay. The mean MCM5 expression was compared between groups by Kruskal-Wallis test. ROC curves were also used to assess diagnostic utility. RESULTS: The mean expression of MCM5 increases as patients progress from a normal esophagus to NDBE, HGD, and EAC (14.4; 49.8; 112.3; and 154.1, respectively). There was a significant difference in the MCM5 expression of patients with a normal esophagus compared to those with EAC (p = 0.04). There was a trend toward higher MCM5 expression in patients with EAC compared to those with NDBE (p = 0.34). MCM5 expression was a fair discriminator (AUC 0.70 [95% CI 0.57-0.83]) between patients without neoplasia (normal and NDBE) and those with early neoplasia (HGD and EAC). CONCLUSION: MCM5 expression in gastric fluid samples can differentiate patients with a histologically normal esophagus compared to those with early adenocarcinoma. Larger, powered studies are needed to assess whether it can be used to differentiate those with HGD from NDBE.


Assuntos
Adenocarcinoma , Esôfago de Barrett , Proteínas de Ciclo Celular/análise , Neoplasias Esofágicas , Suco Gástrico/metabolismo , Lesões Pré-Cancerosas , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Biomarcadores/análise , Biópsia/métodos , Replicação do DNA , Progressão da Doença , Detecção Precoce de Câncer/métodos , Endoscopia do Sistema Digestório/métodos , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia
9.
Ann Oncol ; 29(3): 616-623, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29293881

RESUMO

Background: We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods: DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results: Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13-2.77) and HR = 2.95 (95% CI: 1.73-5.03), P < 0.001]. Conclusion: A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/classificação , Intervalo Livre de Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ploidias , Prognóstico , Estudos Retrospectivos , Microambiente Tumoral
11.
J Eur Acad Dermatol Venereol ; 30(4): 624-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25809796

RESUMO

BACKGROUND: The discovery, from 2007, of eight new human polyomaviruses (HPyVs) has revived interest in the Polyomaviridae family and their association with human diseases and cancer. In particular, HPyV6 and HPyV7 were discovered in skin swabs of healthy donors and TSPyV was discovered in a heart transplant recipient affected by virus-associated Trichodysplasia Spinulosa (TS), a rare skin disease, exclusively found in immunocompromised patients. OBJECTIVE: The presence of HPyV6, HPyV7 and TSPyV DNA in skin biopsies from patients affected by different skin diseases (cancers and inflammatory disorders) has been evaluated to confirm their skin tropism and the possible pathological association. METHODS: DNA extracted was amplified with HPyV6, HPyV7 and TSPyV specific PCR real time on Taqman platform with standard profile. RESULTS: HPyV7 and TSPyV sequences were not found in any skin specimen analysed. HPyV6, on the other hand, was detected in 30% of samples from healthy subjects vs. 14.3% of skin cancer patients and 2.9% of inflammatory disorders. HPyV6 sequences have been detected in primary cutaneous T-cell lymphoma (CTCL) patients (in 18.6% out of Mycosis Fungoides (MF) patients and in 16.7% out of CTCL not MF/SS(Sèzary syndrome) but have not been detected in primary cutaneous B-cell lymphoma (CBCL) patients. CONCLUSION: Our preliminary data suggest that these three novel human polyomaviruses seem not to play a significant role neither in the pathogenesis of cutaneous malignancies nor in that of inflammatory disorders but, according to literature, can inhabit the skin. On the basis of our data regarding the HPyV6 DNA presence with decreasing percentages in healthy subjects, skin cancer and inflammatory disorders patients, it could be an intriguing matter to study if the activated innate immune response in inflammatory disorders can suppress the virus. Further investigations are needed to better understand their relationship with the human host and its innate immune system.


Assuntos
DNA Viral/genética , Polyomavirus/genética , Dermatopatias/virologia , Estudos de Casos e Controles , Humanos , Dermatopatias/genética
12.
J Eur Acad Dermatol Venereol ; 30(4): 655-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25809919

RESUMO

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).


Assuntos
Pioderma Gangrenoso/imunologia , Subpopulações de Linfócitos T , Adolescente , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Pioderma Gangrenoso/sangue , Pioderma Gangrenoso/patologia , Adulto Jovem
13.
Int J Obes (Lond) ; 39(9): 1339-48, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25971926

RESUMO

BACKGROUND: Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD. METHODS: Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months. RESULTS: We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators. CONCLUSIONS: These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Ritmo Circadiano , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos , Metilação de DNA , Modelos Animais de Doenças , Feminino , Lactação , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Circadianas Period/metabolismo , Gravidez
14.
Gut ; 64(8): 1192-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25539672

RESUMO

BACKGROUND: Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. METHODS: We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008-2010 and 2011-2013). Durability of successful treatment and progression to OAC were also evaluated. RESULTS: 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). CONCLUSIONS: Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2-4% at 1 year in these high-risk patients. TRIAL REGISTRATION NUMBER: ISRCTN93069556.


Assuntos
Adenocarcinoma/cirurgia , Esôfago de Barrett/cirurgia , Ablação por Cateter/métodos , Neoplasias Esofágicas/cirurgia , Esofagoscopia/métodos , Lesões Pré-Cancerosas , Sistema de Registros , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Reino Unido
15.
Br J Cancer ; 110(8): 2159-64, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24642618

RESUMO

BACKGROUND: The prognostic impact of an indication of chromosomal instability (CIN) is evaluated in a consecutive series of 952 colorectal cancer patients treated at Aker University Hospital, Norway, during 1993-2003. Microsatellite instability (MSI) in this case series has recently been reported and made it possible to find the co-occurrence and compare the prognostic significance of CIN and MSI. METHODS: Data sets for overall survival (OS; n=855) and time to recurrence (TTR; n=579) were studied. To reveal CIN we used automated image cytometry (ICM). Non-diploid histograms were taken as indicative of the presence of CIN. PCR-based measures of MSI in this material have already been described. RESULTS: As with MSI, CIN was found to be an independent predictor of early relapse and death among stage II patients (TTR: n=278: HR 2.19 (95% CI: 1.35-3.55), P=0.002). Of the MSI tumours (16%), 71% were found to be DNA diploid, 21% were DNA tetraploid and 8% were DNA aneuploid. Among microsatellite stable tumours, 24% were DNA diploid, 15% were DNA tetraploid and 61% were DNA aneuploid. CONCLUSION: For patients presenting with stage II disease, genomic instability as detected by DNA image cytometry has the potential to provide a useful biomarker for relapse and cancer-related death following surgery with curative intent.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Noruega
16.
Br J Cancer ; 110(7): 1698-704, 2014 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-24569464

RESUMO

BACKGROUND: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. METHODS: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg(-1) verteporfin. After 60-90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. RESULTS: In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm(3) at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy. CONCLUSIONS: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Progressão da Doença , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fotoquimioterapia/efeitos adversos , Verteporfina
17.
J Eur Acad Dermatol Venereol ; 28(2): 222-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23331964

RESUMO

BACKGROUND: Although regulatory T cells (Tregs) are affected in several autoimmune skin diseases, only two studies have been performed in patients with bullous pemphigoid (BP) with contrasting results. OBJECTIVE: To characterize Tregs and to determine the serum levels of regulatory cytokines in patients with BP. METHODS: In BP lesional skin, immunohistochemistry and confocal microscopy were performed for CD4(+) , CD25(+) , forkhead/winged helix transcription factor (FOXP3)(+) , transforming growth factor (TGF)-ß(+) and interleukin (IL)-10(+) cells. In addition, the number of CD4(+) CD25(++) FOXP3(+) Tregs in peripheral blood was assessed by flow cytometry, and the levels of TGF-ß and IL-10 were determined in serum samples by enzyme-linked immunosorbent assay before and after steroid therapy. Controls included patients with psoriasis, atopic dermatitis (AD) and healthy donors. RESULTS: The frequency of FOXP3(+) cells was significantly reduced in skin lesions from patients with BP (P < 0.001) compared with psoriasis and AD. Moreover, the number of IL-10(+) cells was lower in BP than in psoriasis (P < 0.001) and AD (P = 0.002), while no differences were observed in the number of TGF-ß(+) cells. CD4(+) CD25(++) FOXP3(+) Treg in the peripheral blood of patients with BP was significantly reduced compared with healthy controls (P < 0.001), and augmented significantly after steroid therapy (P = 0.001). Finally, TGF-ß and IL-10 serum levels were similar in patients with BP compared with healthy controls. However, after therapy, BP patients showed significantly higher IL-10 serum levels than before therapy (P = 0.01). CONCLUSIONS: These data suggest that the depletion of Tregs and of IL-10 in patients with BP may be an important factor in the pathogenesis of the disease.


Assuntos
Penfigoide Bolhoso/sangue , Penfigoide Bolhoso/patologia , Linfócitos T Reguladores/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/análise , Contagem de Linfócito CD4 , Dermatite Atópica/sangue , Dermatite Atópica/patologia , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Interleucina-10/análise , Subunidade alfa de Receptor de Interleucina-2/análise , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/tratamento farmacológico , Psoríase/sangue , Psoríase/patologia , Fator de Crescimento Transformador beta/análise , Adulto Jovem
18.
Photodiagnosis Photodyn Ther ; 10(4): 566-74, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24284113

RESUMO

BACKGROUND: Anal Intraepithelial Neoplasia (AIN), a pre-cursor of anal squamous carcinoma, is increasingly detected in individuals with impaired immune function. However, choices for effective, low morbidity treatment are limited. Photodynamic Therapy (PDT) is promising as it is known to ablate more proximal gastrointestinal mucosa with safe healing, without damage to underlying muscle. It can also ablate skin with safe healing and minimal scarring. METHODS: Pharmacokinetics: Normal rats were sensitised with 200mg/kg 5-aminolaevulinic acid (ALA) and killed 1-8h later. Anal tissues were examined by fluorescence microscopy to quantify the concentration of PPIX (protoporphyrin IX, the active derivative of ALA) in anal mucosa and in the underlying sphincter. PDT: Normal rats were sensitised similarly 3h later, laser light (635 nm) was delivered. Anal canal: 50-150 J/cm using 1cm diffuser fibre; for peri-anal skin, 50-200 J/cm(2), using microlens fibre. In each group, 2 rats were killed 3, 7, 14 and 28 days later and the anal region removed for histological examination. RESULTS: Pharmacokinetics: Peak concentration of PPIX in mucosa was at 3h, peak ratio mucosa: muscle, 6, seen at same time. PDT. Anal canal 50 J/cm: complete mucosal ablation by 3 days, complete regeneration by 28 days. Higher energies caused muscle damage with scarring. Peri-anal skin: 200 J/cm(2); complete ablation of skin, including appendages, complete healing by 28 days. Minimal effect with lower energy. CONCLUSION: ALA-PDT can ablate anal mucosa and peri-anal skin with safe healing and no underlying damage. However, over treatment can damage the sphincters. This technique is ready to undergo clinical trials.


Assuntos
Ácido Aminolevulínico/administração & dosagem , Neoplasias do Ânus/tratamento farmacológico , Carcinoma in Situ/tratamento farmacológico , Mucosa Intestinal/efeitos da radiação , Fotoquimioterapia/métodos , Pele/efeitos da radiação , Ácido Aminolevulínico/efeitos adversos , Animais , Feminino , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/lesões , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/efeitos adversos , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/lesões , Resultado do Tratamento
19.
Chemosphere ; 93(8): 1447-55, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24050715

RESUMO

The aim of this research was to investigate the mechanism(s) underlying the acute toxicity of dioxin in pancreatic beta cells and to evaluate the protective effects of epigallocatechin-3-gallate (EGCG), the most abundant of the green tea's catechins and a powerful inhibitor of the aryl hydrocarbon receptor (AhR). Using the insulin-secreting INS-1E cell line we have explored the effect of 1h exposure to different concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alone or in the presence of EGCG, on: (a) cell survival; (b) cellular ultrastructure; (c) intracellular calcium levels; (d) mitochondrial membrane potential; (e) glucose-stimulated insulin secretion and (f) activation of MAP kinases. Our results demonstrate that TCDD is highly toxic for INS-1E cells, suggesting that pancreatic beta cells should be considered a relevant and sensitive target for dioxin acute toxicity. EGCG significantly protects INS-1E cells against TCDD-induced toxicity in terms of both cell survival and preservation of cellular ultrastructure. The mechanism of this protective effect seems to be related to: (a) the ability of EGCG to preserve the mitochondrial function and thus to prevent the TCDD-induced inhibition of glucose-stimulated insulin secretion and (b) the ability of EGCG to inhibit the TCDD-induced activation of selected kinases, such as e.g. ERK 1/2 and JNK. Our results clearly show that EGCG is able to protect pancreatic beta cells against dioxin acute toxicity and indicate the mitochondrion as the most likely target for this beneficial effect.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Catequina/farmacologia , Linhagem Celular , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Receptores de Hidrocarboneto Arílico/metabolismo
20.
G Ital Dermatol Venereol ; 148(2): 197-201, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23588145

RESUMO

Regulatory T cells (Tregs) play a crucial role by maintaining the peripheral tolerance and inhibiting autoimmunity. In recent years, numerous autoimmune and immune-mediated diseases have been shown to present significant number depletion and/or function impairment of this subset. In the present study, we present a brief overview of the results obtained by our group in association with the centers belonging to the Italian Immunopathology Group, as to the expression levels and biological significance of circulating regulatory CD4+CD25+brightFOXP3+ T cells in a variety of immune-mediated skin diseases (such as psoriasis, scleroderma, bullous pemphigoid and GvHD), together with preliminary results achieved in patients with inflammatory bowel disease-related dermatoses. This review shows that this series of different cutaneous diseases characterised by an immune-mediated pathogenesis, share a significant down-regulation of circulating FOXP3+ Treg cells, whilst the treatment and the achievement of clinical response are generally associated with an opposite phenomenon with up-regulation of Treg cells. Future studies are mandatory to identify the effective role of these modifications in the disease pathogenesis as well as its relationship with the clinical response.


Assuntos
Dermatite Herpetiforme/imunologia , Citometria de Fluxo , Linfócitos T Reguladores/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Dermatite Herpetiforme/genética , Dermatite Herpetiforme/metabolismo , Dermatite Herpetiforme/patologia , Regulação para Baixo/genética , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/genética , Humanos , Penfigoide Bolhoso/imunologia , Psoríase/imunologia , Escleroderma Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Regulação para Cima/genética
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