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2.
J Clin Med ; 9(11)2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33217963

RESUMO

Digital pathology is on the verge of becoming a mainstream option for routine diagnostics. Faster whole slide image scanning has paved the way for this development, but implementation on a large scale is challenging on technical, logistical, and financial levels. Comparative studies have published reassuring data on safety and feasibility, but implementation experiences highlight the need for training and the knowledge of pitfalls. Up to half of the pathologists are reluctant to sign out reports on only digital slides and are concerned about reporting without the tool that has represented their profession since its beginning. Guidelines by international pathology organizations aim to safeguard histology in the digital realm, from image acquisition over the setup of work-stations to long-term image archiving, but must be considered a starting point only. Cost-efficiency analyses and occupational health issues need to be addressed comprehensively. Image analysis is blended into the traditional work-flow, and the approval of artificial intelligence for routine diagnostics starts to challenge human evaluation as the gold standard. Here we discuss experiences from past digital pathology implementations, future possibilities through the addition of artificial intelligence, technical and occupational health challenges, and possible changes to the pathologist's profession.

3.
Br J Cancer ; 122(12): 1744-1746, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32336753

RESUMO

Inter-test concordance between the MammaPrint and the EndoPredict tests used to predict the risk of recurrence in breast cancer was evaluated in 94 oestrogen receptor-positive, HER2-negative breast cancers. We correlated histopathological data with clinical risk estimation as defined in the MINDACT trial. 42.6% (40/94) of cases were high-risk by MammaPrint, 44.7% (42/94) by EndoPredict (EPclin), and 45.7% (43/94) by clinical risk definition. Thirty-six percent of genomic risk predictions were discordant with a low inter-test correlation between EndoPredict and MammaPrint (p = 0.012; κ = 0.27, 95% CI [0.069, 0.46]). Clinical risk stratification did not correlate with MammaPrint (p = 0.476) but highly correlated with EndoPredict (p < 0.001). Consequently, clinically high-risk tumours (n = 43) were more frequently high-risk by EndoPredict than by MammaPrint (76.6% vs. 46.5%, p = 0.004), with 44% of cases discordantly classified and no significant association between genomic risk predictions (p = 0.294). Clinicians need to be aware that clinical pre-stratification can profoundly influence multigenomic test performance.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica/métodos , Testes Genéticos/métodos , Recidiva Local de Neoplasia/genética , Feminino , Humanos , Medição de Risco/métodos
4.
Eur J Surg Oncol ; 45(4): 538-543, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30366878

RESUMO

INTRODUCTION: Axillary ultrasound staging (AUS) is an important tool to guide clinical decisions in breast cancer therapy, especially regarding axillary surgery but also radiation therapy. It is unknown whether biological subtypes influence axillary staging using ultrasound (AUS). METHOD: This is a retrospective single center analysis. All patients with breast cancer, a preoperative axillary ultrasound and a complete surgical axillary staging were included between 1999 and 2014, except patients with neoadjuvant chemotherapy (NACT). The results of the AUS were compared with final pathological results. Biological subtypes were identified by immunohistochemistry. RESULTS: 583 women were included in the study. Sensitivity, Specificity, positive and negative predictive value for AUS were 39%, 96%, 91% and 83%. While sensitivity was significantly lower in Luminal A and B patients (25.0%; 39.8%) as compared to non Luminal breast cancer patients (TN 68.8%; Her2+ 71.4%; p = 0.0032), there were no significant differences between the groups with respect to specificity, PPV and NPV. CONCLUSION: Solely regarding sensitivity of AUS, our study could show significant differences between biological subtypes of breast cancer with lower sensitivity in Luminal patients. While PPV was excellent, standing for a low overtreatment rate using AUS for clinical decision making, sensitivity was poor overall, comparable to the results of other studies.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Ultrassonografia , Adulto , Idoso , Axila , Feminino , Humanos , Antígeno Ki-67/metabolismo , Linfonodos/cirurgia , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Adulto Jovem
6.
Arch Gynecol Obstet ; 295(4): 959-964, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28265757

RESUMO

PURPOSE: To evaluate a one-stop clinical assessment of risk for assessing endometrial pathologies (OSCAR-Endo), consisting of a fast-track protocol with hysteroscopy, dilation and curettage (D&C) with intraoperative frozen section analysis of the removed tissue in cases of hysteroscopic suspicion of malignancy. METHODS: In this prospective clinical trial, a total of 304 consecutive women with sonographically suspected endometrial hyperplasia and/or postmenopausal bleeding, underwent D&C with intraoperative frozen section analysis between May 2013 and September 2015. Based on the results of the hysteroscopy and/or frozen section, the OSCAR-Endo score was reported: negative, when no frozen section was regarded necessary or the frozen section yielded a negative result; equivocal, when the frozen section reported an equivocal result; positive, when frozen section reported either complex hyperplasia with atypia or cancer. RESULTS: Frozen sections were required by the surgeons in 59 (19.4%) of cases. When compared with the final histology after D&C, frozen section showed a sensitivity, specificity, PPV, NPV, and overall test accuracy of 91.3, 100, 100, 94.1, and 96.3% for predicting malignant disease, respectively. The OSCAR-Endo score showed a sensitivity, specificity, PPV, NPV, and overall test accuracy of 84, 100, 100, 98.6, and 98.7% for predicting malignant disease, respectively. CONCLUSION: The OSCAR-Endo protocol is easy to perform in daily clinical practice reaching an excellent test accuracy. It helps in immediate postoperative counseling of affected patients. Clinical Trial Registration http://www.clinicaltrials.gov ; NCT01961102.


Assuntos
Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Adulto , Idoso , Dilatação e Curetagem , Hiperplasia Endometrial/diagnóstico por imagem , Hiperplasia Endometrial/cirurgia , Neoplasias do Endométrio/cirurgia , Feminino , Secções Congeladas , Humanos , Histeroscopia , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Sensibilidade e Especificidade , Ultrassonografia
7.
Clin Cancer Res ; 23(5): 1274-1285, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28232476

RESUMO

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.


Assuntos
Leiomiossarcoma/tratamento farmacológico , Proteína S6 Ribossômica/genética , Serina-Treonina Quinases TOR/genética , Neoplasias Uterinas/tratamento farmacológico , Animais , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Camundongos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Clin Cancer Res ; 23(14): 3676-3683, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28143867

RESUMO

Purpose: To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.Experimental Design: 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by in situ hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is).Results: In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; P = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P = 0.002 and P < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90; P = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, P = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, P = 0.005; and ypT0/is: 87.5% vs. 28.0%, P < 0.001), and was largely absent in HR-negative tumors.Conclusions: An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. Clin Cancer Res; 23(14); 3676-83. ©2017 AACR.


Assuntos
Biomarcadores Farmacológicos , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Centrômero/genética , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Trastuzumab/efeitos adversos
9.
Mod Pathol ; 29(10): 1262-77, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27363490

RESUMO

Smooth muscle tumors of the uterus are a diagnostically challenging group of tumors. Molecular surrogate markers reliably distinguishing between benign and malignant tumors are not available. Therefore, the diagnosis is based on morphologic criteria. The aim was to investigate a well-characterized group of challenging uterine smooth muscle tumors consisting of 20 leiomyomas, 13 leiomyomas with bizarre nuclei, and 14 leiomyosarcomas for copy number alterations, MED12 mutations and FH deletions to search for potential diagnostically useful surrogate markers. MED12 mutations were detected in 47, 15, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. MED12 mutations in leiomyomas with bizarre nuclei were detected outside the hotspot region. FH-deletions were seen in 27, 30.8, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. By using copy number alteration profiling a clear separation of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas could not be observed. Copy number alterations revealed clear genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas. Leiomyosarcomas showed a similar pattern of gains and losses as leiomyomas with bizarre nuclei, with additional copy number alterations and more homozygous losses and high-level amplifications compared to leiomyomas with bizarre nuclei. In conclusion, this study demonstrates that known FH-deletions, a recurrent molecular change in leiomyomas, occur in morphologically challenging variants of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas. Although MED12 mutations are common in leiomyomas, they infrequently occur in leiomyomas with bizarre nuclei and leiomyosarcomas. The genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas raise the intriguing possibility that uterine leiomyomas with bizarre nuclei and leiomyosarcomas are closely related and challenge the traditional concept that leiomyoma with bizarre nuclei is a tumor with just marked 'degenerative' cellular changes. These findings support the hypothesis that tumor progression within uterine smooth muscle tumors might occur.


Assuntos
Leiomioma/genética , Leiomiossarcoma/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Núcleo Celular/patologia , Aberrações Cromossômicas , Feminino , Humanos , Leiomioma/patologia , Leiomiossarcoma/patologia , Pessoa de Meia-Idade , Neoplasias Uterinas/patologia
10.
Virchows Arch ; 469(3): 285-95, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27287269

RESUMO

Benign apocrine metaplasia (AM) of the adult breast is a very common, but enigmatic lesion. It has been speculated that AM might be a precursor of malignancy or an indicator of a susceptibility of the breast tissue to develop neoplasia, mainly based on comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. Studies using comparative genomic hybridization have supported this by showing similar molecular alterations in benign and malignant apocrine lesions [2]. Few studies, however, have compared expression of biomarkers involved in tumor progression in AM and progressively more advanced atypical apocrine lesions. The expression of C-KIT, COX2, CD24, and CD44s was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded material of 9 AM, 20 apocrine ductal intraepithelial neoplasia (DIN1c-3) and 40 atypical apocrine lesions (not qualifying for DIN1c-3) and compared to expression of the same biomarkers in adjacent normal ductal epithelium. Of the 66 apocrine lesions, 62 (94 %) did not express C-KIT compared to 4/63 (6 %) of the normal glands (Fisher's exact, p < 0.001). COX2 was expressed in a significantly higher proportion of apocrine lesions than of normal glands (49 vs. 14 %, p < 0.001), and the number of apocrine lesions positive for CD24 was found to be higher with increasing aggressiveness of the lesions (Spearman, p < 0.001). In conclusion, benign and non-invasive proliferative apocrine lesions of the breast display immuno-phenotypical characteristics previously ascribed mainly to malignant transformation. This could lend support to the theory that AM is an early step towards malignant transformation, albeit associated with slow progression to carcinoma.


Assuntos
Neoplasias da Mama/metabolismo , Ciclo-Oxigenase 2/metabolismo , Receptores de Hialuronatos/metabolismo , Metaplasia/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Hibridização Genômica Comparativa/métodos , Células Epiteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Metaplasia/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem
11.
Am J Pathol ; 186(1): 15-23, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26718977

RESUMO

Usual ductal hyperplasia (UDH) of the breast is generally regarded as a nonneoplastic proliferation, albeit loss of heterozygosity has long been reported in a part of these lesions. To gain deeper insights into the molecular drivers of these lesions, an extended mutation profiling was performed. The coding regions of 409 cancer-related genes were investigated by next-generation sequencing in 16 cases of UDH, nine unassociated with neoplasia (classic) and seven arising within papillomas. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) activation was investigated by phosphorylated AKT, mTOR, and S6 immunohistochemistry. Of 16 lesions, 10 (63%) were mutated; 56% of classic lesions were unassociated with neoplasia, and 71% of lesions arose in papillomas. Fourteen missense mutations were detected: PIK3CA [6 (43%) of 14], AKT1 [2 (14%) of 14], as well as GNAS, MTOR, PIK3R1, LPHN3, LRP1B, and IGF2R [each 1 (7%) of 14]. Phosphorylated mTOR was seen in 83% and phosphorylated S6 in 86% of evaluable lesions (phospho-AKT staining was technically uninterpretable). In conclusion, UDH displays mutations of the phosphatidylinositol 3-kinase/AKT/mTOR axis at different levels, with PIK3R1, MTOR, and GNAS mutations not previously described. Specifically, oncogenic G-protein activation represents a yet unrecognized route to proliferation in UDH. On the basis of evidence of activating mutations, loss of heterozygosity, and a mass forming proliferation, we propose that UDH is most appropriately viewed as an early neoplastic intraductal proliferation.


Assuntos
Doenças Mamárias/genética , Doenças Mamárias/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Adulto , Idoso , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Imuno-Histoquímica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Adulto Jovem
12.
Exp Mol Pathol ; 98(3): 367-74, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25758203

RESUMO

INTRODUCTION: The endometrial stromal sarcoma (ESS) is a very rare uterine sarcoma, counting for 1-3% of all gynecologic malignancies. ESS represents 0.2-8% of all uterine malignant tumors and accounts for about 10% of all uterine sarcomas. With regard to chromosomal aberrations, very little is known about benign and malignant endometrial stromal tumors. METHODS: 30 tumors, consisting of 4 cases of benign endometrial stromal nodule (ESN), 22 cases of low-grade ESS and 4 cases of undifferentiated endometrial sarcoma (UES), were analyzed by array-comparative genomic hybridization (aCGH). RESULTS: ESN did not show many copy number changes (CNCs) by aCGH. Frequent losses could be identified on chromosomes 7p and 19, and gains on chromosomes 1q, 6p and 8q. Low-grade ESS presented as a very heterogeneous group. 90% (20/22) of cases displayed aberrations. Most frequent changes were losses on chromosomes 7 and 22, and gains on chromosome 1q or 11. UES showed a high number of chromosomal aberrations and on every chromosome CNCs were detected. Most frequent changes were losses on chromosomes 1q, 2q (3/4, 75%) and 13, and gains on chromosomes 1q and 17p. CONCLUSION: Our data shows an increasing number of CNCs from ESN to low-grade ESS and to UES. However, the chromosomal aberrations differ considerably between the investigated ESN-, low-grade ESS- and UES cases and thus, a linear tumor progression seems to be unlikely.


Assuntos
Variações do Número de Cópias de DNA , Tumores do Estroma Endometrial/genética , Genoma Humano , Sarcoma/genética , Cromossomos/genética , Hibridização Genômica Comparativa , Tumores do Estroma Endometrial/patologia , Feminino , Humanos , Sarcoma/patologia
13.
Diagn Pathol ; 9: 203, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25420931

RESUMO

BACKGROUND: Tumour-to-tumour metastasis (TTM) occurs when one tumour metastasises to a separate tumour within the same individual. TTM is observed frequently in breast cancer but has not been described in male breast cancer. In addition reports describing solitary fibrous tumours (SFT) of the pleura hosting other neoplasms' metastases are limited. We report an exceptional case of male breast cancer metastasising to an extrapleural SFT, occurring in the subcutaneous tissue of the back of a 68-year old Caucasian patient. CASE PRESENTATION: A 68-year old male was diagnosed with a metastasising ductal breast cancer. He was treated by mastectomy of the right breast and axillary lymph-adenectomy. Further staging revealed an increasing subcutaneous expansion located on the patient's back. Excision biopsy confirmed a SFT hosting a breast cancer metastasis. The patient received palliative chemotherapy but died of disease seven years after initial diagnosis. CONCLUSIONS: The abundance of blood vessels within these lesions might predispose SFTs for an involvement in TTM. This case describes the possibility of concurrent rare occurrences and reminds clinicians, as well as pathologists, to be open-minded and fastidious about their differential diagnoses, sampling and examination of histological specimens. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_203.


Assuntos
Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/secundário , Neoplasias Primárias Múltiplas , Neoplasias de Tecidos Moles/patologia , Tumores Fibrosos Solitários/patologia , Tela Subcutânea/patologia , Idoso , Antineoplásicos/uso terapêutico , Dorso , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Mama Masculina/química , Neoplasias da Mama Masculina/terapia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/terapia , Evolução Fatal , Humanos , Imuno-Histoquímica , Excisão de Linfonodo , Masculino , Mastectomia , Estadiamento de Neoplasias , Cuidados Paliativos , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/terapia , Tumores Fibrosos Solitários/química , Tumores Fibrosos Solitários/terapia , Tela Subcutânea/química , Fatores de Tempo , Resultado do Tratamento
14.
PLoS One ; 9(10): e108457, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25302712

RESUMO

INTRODUCTION: Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed. METHODS: Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist's neoplasia grades with the predicted groups obtained by fractal methods. RESULTS: Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist's grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia. CONCLUSION: Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Colo do Útero/patologia , Fractais , Neoplasias do Colo do Útero/diagnóstico , Feminino , Humanos , Processamento de Imagem Assistida por Computador
15.
Cancer Lett ; 354(1): 21-7, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25128649

RESUMO

Endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) are very rare gynecologic malignancies. Due to the rarity and heterogeneity of these tumors, little is known about their epidemiology, pathogenesis, and molecular pathology. Our previous studies have described deregulation of histone deacetylases expression in ESS/UES samples. Some of these enzymes can be inhibited by substances which are already approved for treatment of cutaneous T-cell lymphoma. On the basis of published data, they may also provide a therapeutic option for ESS/UES patients. Our review focuses on molecular mechanisms of ESS/UES. It describes various aspects with special emphasis on alteration of histone deacetylation and its possible relevance for novel therapies.


Assuntos
Neoplasias do Endométrio/genética , Tumores do Estroma Endometrial/genética , Regulação Neoplásica da Expressão Gênica , Sarcoma do Estroma Endometrial/genética , Acetilação , Diferenciação Celular , Neoplasias do Endométrio/metabolismo , Tumores do Estroma Endometrial/metabolismo , Feminino , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Histonas/química , Humanos , Linfoma Cutâneo de Células T/metabolismo , Sarcoma do Estroma Endometrial/metabolismo , Resultado do Tratamento , Proteínas Wnt/metabolismo
16.
Carcinogenesis ; 35(11): 2447-51, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24997853

RESUMO

Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERß. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Estetrol/administração & dosagem , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Receptor alfa de Estrogênio/genética , Feminino , Hormônio Foliculoestimulante/biossíntese , Terapia de Reposição Hormonal , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Antígeno Ki-67/biossíntese , Pessoa de Meia-Idade , Período Pré-Operatório
17.
Anticancer Res ; 34(6): 2883-97, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24922651

RESUMO

AIM: Endometrial stromal sarcoma (ESS) is a rare gynecological mesenchymal malignancy with only few therapeutic options. This study aimed to investigate the efficacy of the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) combined with inhibitors of the phosphoinositid-3-Kinase (PI3K) pathway in ESS therapy. MATERIALS AND METHODS: The effects of SAHA combined with inhibitor of PI3K (LY294002, LY), mammalian target of rapamycin mTOR (rapamycin), and their combination on cell growth and the PI3K pathway in two ESS cell lines (ESS-1 and MES-SA) and one non-neoplastic cell line HESC, were investigated. RESULTS: SAHA reduced growth of the three cell lines by inhibiting protein kinase B AKT and mTOR/p70S6K cascade activation. SAHA combined with LY or rapamycin, or both, synergistically reduced p-p70S6K and p-4E-BP1 levels. SAHA combined with LY and rapamycin led to the strongest growth inhibition and slowest growth recovery among the combination treatments. CONCLUSION: SAHA combined with inhibition of PI3K and mTOR could represent an efficient therapy option for patients with ESS.


Assuntos
Neoplasias do Endométrio/metabolismo , Histona Desacetilases/química , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sarcoma do Estroma Endometrial/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Inibidores Enzimáticos/farmacologia , Feminino , Imunofluorescência , Histona Desacetilases/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sarcoma do Estroma Endometrial/tratamento farmacológico , Sarcoma do Estroma Endometrial/patologia , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
18.
Anticancer Res ; 34(2): 819-27, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24511018

RESUMO

INTRODUCTION: Ependymomas are glial neoplasms that arise at or close to the inner ependymal surface of the ventricular system. They are most frequently located intraventricularly, but they may also occur in the spinal cord or, very seldom, at extraneural sites. Here we report a case of an ectopic ependymoma, arising in the pelvic cavity. CASE REPORT: A 35 year-old female patient was diagnosed with a suspect tumor mass in the rectovaginal space, infiltrating the perirectal adipose tissue and the vagina. Three years later, liver and peritoneal metastases of the same tumor were diagnosed. Two years after that, the patient experienced a recidive in the left adnexa. Histological analysis revealed an anaplastic tumor of dual nature, comprising of mesenchymal and epithelial features. There were ependymoma-like rosettes and pseudorosettes, indicating an ependymal differentiation. Immunohistochemically, the tumor was positive for epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP). Accordingly, the diagnosis "grade 3 ependymoma, i.e. ependymoblastoma" was made. REVIEW: Ependymomas are most frequently located in the ventricular system, but may also occur in the spinal cord or rarely at extraneural sites. Extraneural ependymomas represent a diagnostic challenge, since they can mimic other tumor types and the immunohistochemical profile may be non-specific. The most important features of ependymal differentiation are rosette- or pseudorosette formation. Extraneural ependymomas can be located in the ovary or elsewhere in the pelvic cavity. Locations in the lung, liver and the small bowel have also been described. In the present article we review several reported cases of ectopic, extraneural ependymomas. DISCUSSION: The origin of extraneural ependymomas is not completely clarified. They probably arise from glial tissue that is a residue from the embryonic development, pinched-off from the neural tube during its closure. We propose, that extraneural ependymoma should be considered in differential diagnosis for anaplastic tumors of the pelvic cavity.


Assuntos
Tumores Neuroectodérmicos Primitivos/diagnóstico , Neoplasias Vaginais/diagnóstico , Adulto , Feminino , Humanos , Neoplasias Hepáticas/secundário , Tumores Neuroectodérmicos Primitivos/patologia , Tumores Neuroectodérmicos Primitivos/secundário , Neoplasias Peritoneais/secundário , Neoplasias Vaginais/patologia
19.
BMC Genomics ; 13: 594, 2012 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-23127113

RESUMO

BACKGROUND: Reports on common mutations in neuroendocrine tumors (NET) are rare and clonality of NET metastases has not been investigated in this tumor entity yet. We selected one NET and the corresponding lymph node and liver metastases as well as the derivative cell lines to screen for somatic mutations in the primary NET and to track the fate of genetic changes during metastasis and in vitro progression. RESULTS: Applying microarray based sequence capture resequencing including 4,935 Exons from of 203 cancer-associated genes and high-resolution copy number and genotype analysis identified multiple somatic mutations in the primary NET, affecting BRCA2, CTNNB1, ERCC5, HNF1A, KIT, MLL, RB1, ROS1, SMAD4, and TP53. All mutations were confirmed in the patients' lymph node and liver metastasis tissue as well as early cell line passages. In contrast to the tumor derived cell line, higher passages of the metastases derived cell lines lacked somatic mutations and chromosomal alterations, while expression of the classical NET marker serotonin was maintained. CONCLUSION: Our study reveals that both metastases have evolved from the same pair of genetically differing NET cell clones. In both metastases, the in vivo dominating "mutant" tumor cell clone has undergone negative selection in vitro being replaced by the "non-mutant" tumor cell population. This is the first report of a bi-clonal origin of NET derived metastases, indicating selective advantage of interclonal cooperation during metastasis. In addition, this study underscores the importance to monitor cell line integrity using high-resolution genome analysis tools.


Assuntos
Neoplasias Hepáticas/genética , Metástase Linfática/genética , Tumores Neuroendócrinos/genética , Linhagem Celular Tumoral , Cromossomos/genética , Cromossomos/metabolismo , Variações do Número de Cópias de DNA , Éxons , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Mutação , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Serotonina/genética , Serotonina/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
J Biophotonics ; 5(4): 345-66, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22232077

RESUMO

During the last 11 years, 5 molecular subtypes of breast carcinoma (luminal A, luminal B, Her2-positive, basal-like, and normal breast-like) have been characterized and intensively studied. As genomic research evolves, further subtypes of breast cancers into new "molecular entities" are expected to occur. For example, a new and rare breast cancer subtype, known as claudin-low, has been recently found in human carcinomas and in breast cancer cell lines. There is no doubt that global gene expression analyses using high-throughput biotechnologies have drastically improved our understanding of breast cancer as a heterogeneous disease. The main question is, however, whether new molecular techniques such as gene expression profiling (or signature) should be regarded as the gold standard for identifying breast cancer subtypes. A critical review of the literature clearly shows major problems with current molecular techniques and classification including poor definitions, lack of reproducibility, and lack of quality control. Therefore, the current molecular approaches cannot be incorporated into routine clinical practice and treatment decision making as they are immature or even can be misleading. This review particularly focuses on the "basal-like" breast cancer subtype that represents one of the most popular breast cancer "entities". It critically shows major problems and misconceptions with and about this subtype and challenges the common claim that it represents a "distinct entity". It concludes that the term "basal-like" is misleading and states that there is no evidence that expression of basal-type cytokeratins in a given breast cancer, regardless of other established prognostic factors, does have any impact on clinical outcome.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Classificação/métodos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , DNA Complementar/genética , Humanos , Biologia Molecular , Projetos de Pesquisa
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