RESUMO
BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal and genomic instability due to telomere dysfunction has been known to play an important role in the carcinogenesis of some organs. OBJECTIVES: The aim of this study was to examine the correlation between smoking and the telomere length of human bronchial epithelial cells in individuals with and without lung cancer. PATIENTS AND METHODS: We examined 68 non-lung cancer adult autopsy cases and 24 surgically resected cases of lung squamous cell carcinoma. Telomere lengths of the basal cells of bronchial epithelium were measured using the tissue quantitative fluorescence in situ hybridization method and were expressed in normalized telomere-to-centromere ratios (NTCRs). RESULTS: The autopsied individuals included 27 current smokers (CuS), 33 never-smokers (NeS), and 8 ex-smokers (ExS). The NTCRs in the central bronchi of CuS, NeS, and ExS were 1.515, 1.372, and 1.204, respectively. The bronchial epithelial telomeres of CuS were significantly longer than those of non-CuS (NeS + ExS). When the analysis was conducted separately for females and males, a significant difference between CuS and NeS + ExS was recognized only for males. The NTCRs of the bronchial epithelium of lung cancer cases and lung cancer tissue are 1.514 and 1.385, respectively. CONCLUSIONS: Our findings suggest that smoking causes telomeric elongation in the bronchial epithelium. Therefore, it appears that the mechanism of carcinogenesis in smoking-related carcinomas may differ from that of many other carcinomas in which genetic instability due to aging-related telomeric shortening is assumed to play a role.
Assuntos
Carcinoma Broncogênico/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Mucosa Respiratória/patologia , Homeostase do Telômero , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Estudos de Casos e Controles , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Fumar/patologiaRESUMO
We report a case in which renal biopsies were performed 4 years apart in a woman with a prolonged human parvovirus B19 (HPB19) infection. When she was 29 years old the first biopsy, performed because of microscopic hematuria and mild proteinuria, showed endocapillary and mesangial proliferative glomerulonephritis in light microscopy as well as deposits of immunoglobulins (Igs) and complement C3 on capillary walls. Mesangial, intramembranous, and subepithelial hump-like electron dense deposits were seen in electron microscopy. The principal differential diagnoses, acute poststreptococcal glomerulonephritis and lupus nephritis, were unlikely, and her serological positivity for IgM antibody for HPB19 made us diagnose acute glomerulonephritis associated with HPB19 infection. The second biopsy, performed 4 years later because of persistent proteinuria and prolonged positivity for IgM antibody for HPB19, showed membranoproliferative glomerulonephritis (MPGN) with mesangial interposition and with thickening and double contours of glomerular basement membrane. In tissues obtained in both biopsies, HPB19 DNA was detected by polymerase chain reaction. HPB19 infection has been widely known to cause various glomerular diseases. This case reveals that acute endocapillary proliferative glomerulonephritis can change into MPGN during prolonged HPB19 infection.
Assuntos
Glomerulonefrite Membranoproliferativa/virologia , Rim/virologia , Infecções por Parvoviridae/complicações , Parvovirus B19 Humano/isolamento & purificação , Adulto , Anticorpos Antivirais/sangue , Biópsia , DNA Viral/isolamento & purificação , Diagnóstico Diferencial , Progressão da Doença , Feminino , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/imunologia , Humanos , Imunoglobulina M/sangue , Rim/imunologia , Rim/patologia , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/virologia , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/imunologia , Valor Preditivo dos Testes , Fatores de TempoRESUMO
Pseudomonas aeruginosa is a common pathogen in nosocomial and/or healthcare-associated pneumonia, but is rare in community-acquired pneumonia. A 50-year-old previously healthy woman was taken to the emergency department because of rapidly progressing dyspnea. Chest radiograph showed consolidation of the entire right upper lobe, a finding suggestive of lobar pneumonia. The patient died of respiratory failure with bronchial bleeding, on the same day of admission. Autopsy revealed that the alveoli throughout the upper right lobe were filled with dense inflammatory cells mainly consisting of macrophages and neutrophils. Immunoreactive bacilli by using an anti-P. aeruginosa antibody were localized within macrophages accumulated in the alveoli as well in the vessel walls. Lobar pneumonia composed of dense neutrophils and bacteria-laden macrophages with total lung congestion and edema may be characteristic for community-acquired P. aeruginosa pneumonia in a healthy adult.
Assuntos
Infecções Comunitárias Adquiridas/microbiologia , Pneumonia/microbiologia , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosa , Autopsia , Infecções Comunitárias Adquiridas/diagnóstico , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Pessoa de Meia-Idade , Pneumonia/diagnóstico , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/isolamento & purificaçãoRESUMO
BACKGROUND: The therapeutic effect of tonsillectomy for immunoglobulin A nephropathy (IgAN) has been widely recognized, but the mechanism by which tonsillar immunity leads to glomerulonephritis has been unclear. We investigated subtypes and localization of dendritic cells (DCs) in tonsils and looked for relationships between the tonsillar DCs and the clinical features and renal histological changes of patients with IgAN. METHODS: We examined tonsils from 33 IgAN patients, using as control tonsillar specimens from subjects without glomerulonephritis. Five distinct markers of DCs (CD303, CD1c, CD209, CD208 and CD1a) were analyzed by immunohistochemistry and flow cytometry. The mRNA levels of these DC markers were evaluated using real-time polymerase chain reaction. The clinical data and histological results obtained evaluating renal biopsy tissues were statistically compared with immunological data. RESULTS: Of the five subtypes of DCs, CD208(+) DCs were significantly increased in the tonsils of IgAN patients compared with that of controls. Furthermore, the number of CD208(+) DCs in the tonsils was positively and linearly correlated with the proportion of crescentic glomeruli in renal biopsy tissues and with the urinary protein level. Only few CD208(+) cells, however, were found in the kidney biopsy specimens of IgAN patients. CONCLUSIONS: These observations suggest that increased CD208(+) DCs in tonsils may play a directive role in the pathogenesis of IgAN. The present results support the therapeutic significance of tonsillectomy for IgAN patients.
Assuntos
Células Dendríticas/imunologia , Glomerulonefrite por IGA/imunologia , Proteínas de Membrana Lisossomal/metabolismo , Proteínas de Neoplasias/metabolismo , Tonsila Palatina/imunologia , Adulto , Western Blotting , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Citometria de Fluxo , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/cirurgia , Humanos , Técnicas Imunoenzimáticas , Rim/imunologia , Rim/metabolismo , Rim/patologia , Masculino , Tonsila Palatina/metabolismo , Tonsila Palatina/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TonsilectomiaRESUMO
Our previous study demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. This study was conducted to address how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. We histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases, and selected 11 tumors with synchronous endometriosis and 2 tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed (ie, non-atypical endometrioses and the benign CCAFs) were negative for MET gain. However, low-level (≥3 MET copies in ≥10% and ≥4 MET copies in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in ≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components, wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). These results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive the development and progression of the MET amplification-positive ovarian clear-cell adenocarcinoma.
Assuntos
Adenocarcinoma de Células Claras/genética , Adenofibroma/genética , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Endometriose/genética , Amplificação de Genes , Dosagem de Genes , Neoplasias Ovarianas/genética , Lesões Pré-Cancerosas/genética , Proteínas Proto-Oncogênicas c-met/genética , Adenocarcinoma de Células Claras/química , Adenocarcinoma de Células Claras/patologia , Adenofibroma/metabolismo , Adenofibroma/patologia , Biomarcadores Tumorais/análise , Diferenciação Celular , Transformação Celular Neoplásica/química , Transformação Celular Neoplásica/patologia , Distribuição de Qui-Quadrado , Progressão da Doença , Endometriose/metabolismo , Endometriose/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Japão , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Lesões Pré-Cancerosas/química , Lesões Pré-Cancerosas/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-met/análiseRESUMO
ARID1A is a recently identified tumor suppressor gene that is mutated in â¼50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations. A total of 42 clear-cell carcinoma cases with adjacent putative precursor lesions (endometriosis-associated carcinoma cases (n=28) and (clear-cell) adenofibroma-associated carcinoma cases (n=14)) were selected and subjected to immunohistochemical analysis for ARID1A protein expression and direct genomic DNA sequencing of exons 9 and 20 of the PIK3CA gene. ARID1A immunoreactivity was deficient in 17 (61%) of the 28 endometriosis-associated carcinomas and 6 (43%) of the 14 adenofibroma-associated carcinomas. Among the precursor lesions adjacent to the 23 ARID1A-deficient carcinomas, 86% of the non-atypical endometriosis (12 of 14) and 100% of the atypical endometriosis (14 of 14), benign (3 of 3), and borderline (6 of 6) clear-cell adenofibroma components were found to be ARID1A deficient. In contrast, in the 19 patients with ARID1A-intact carcinomas, all of the adjacent precursor lesions retained ARID1A expression regardless of their types and cytological atypia. Analysis of 22 solitary endometrioses and 10 endometrioses distant from ARID1A-deficient carcinomas showed that all of these lesions were diffusely immunoreactive for ARID1A. Among the 42 clear-cell carcinomas, somatic mutations of PIK3CA were detected in 17 (40%) tumors and majority (71%) of these were ARID1A-deficient carcinomas. These results suggest that loss of ARID1A protein expression occurs as a very early event in ovarian clear-cell carcinoma development, similar to the pattern of PIK3CA mutation recently reported by our group, and frequently coexists (not mutually exclusive) with PIK3CA mutations.
Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma/química , Carcinoma/genética , Mutação , Proteínas Nucleares/análise , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Fosfatidilinositol 3-Quinases/genética , Fatores de Transcrição/análise , Adenofibroma/química , Adenofibroma/genética , Adenofibroma/patologia , Carcinoma/patologia , Transformação Celular Neoplásica/química , Transformação Celular Neoplásica/genética , Distribuição de Qui-Quadrado , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Progressão da Doença , Regulação para Baixo , Endometriose/genética , Endometriose/metabolismo , Éxons , Feminino , Humanos , Imuno-Histoquímica , Japão , Invasividade Neoplásica , Neoplasias Ovarianas/patologia , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: This study was designed to clarify retrospectively the clinical significance of occult metastases in both sentinel lymph nodes (SLNs) and non-SLNs in patients with early breast cancer. METHODS: A total of 109 (80.1%) of 136 women with breast cancer who had consecutively undergone SLN biopsy (176 lymph nodes) were intraoperatively diagnosed as being free of SLN involvement. SLNs were routinely examined by hematoxylin-eosin (HE) staining of one to four frozen sections per node. Sixty-four (58.7%) of these patients also underwent backup axillary dissection. For the 109 patients, all formalin-fixed, paraffin-embedded tissues of SLNs and non-SLNs were entirely cut into 5-µm-thick sections. All serial step sections at 85-µm intervals were stained with HE and immunohistochemistry with pancytokeratin. RESULTS: Occult metastases in SLNs and non-SLNs were detected in 25 (23%) and 10 (16%) patients, respectively. The presence of occult SLN metastasis was marginally correlated with T-factor (P=0.06), and predictive factors for occult non-SLN metastases were tumor nuclear grade (P=0.039). With a median follow-up of 86 months, disease-free survival (P=0.3) or overall survival (P=0.8) did not differ between the patients with and without occult SLN metastases, regardless of backup axillary lymph node dissection. CONCLUSIONS: SLN or non-SLN occult metastases detected by serial step sections at 85-µm intervals did not have significant prognostic implications.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/patologia , Carcinoma Lobular/secundário , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Análise de SobrevidaRESUMO
AIMS: Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs). METHODS AND RESULTS: Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology. CONCLUSION: Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.
Assuntos
Actinina/genética , Actinina/metabolismo , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Amplificação de Genes , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/etiologia , Adenocarcinoma de Células Claras/metabolismo , Adenofibroma/genética , Adenofibroma/metabolismo , Adenofibroma/patologia , Adulto , Idoso , Progressão da Doença , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/metabolismo , Regulação para CimaRESUMO
Clear cell adenocarcinoma (CCA), a highly lethal histological subtype of ovarian carcinoma, is a type of human cancer with a high frequency of activating mutations in the PIK3CA gene. In this study, we aimed to determine how these mutations contribute to tumour development of CCAs. Exons 9 and 20 of the PIK3CA gene were analysed by direct genomic DNA sequencing of 23 CCAs with synchronous putative precursor lesions (ie endometriosis adjacent to carcinoma, with or without cytological atypia) and their mutational statuses were compared. Somatic mutations of the PIK3CA gene were detected in 10/23 (43%) carcinomas and in all cases the type of mutation was H1047R in the kinase domain. The identical H1047R mutation was also detected in the coexisting endometriotic epithelium, adjacent to the CCAs, in nine of ten (90%) cases. Moreover, in six of the nine lesions, the H1047R mutation was identified even in the endometrioses lacking cytological atypia. These findings provide evidence that mutations of the PIK3CA gene occur in the putative precursor lesions of CCA, strongly suggesting that they are very early events in tumourigenesis, probably initiating the malignant transformation of endometriosis. A specific kinase inhibitor to mutated PIK3CA may potentially be an effective therapeutic reagent against these carcinomas.
Assuntos
Adenocarcinoma de Células Claras/genética , Endometriose/genética , Mutação , Neoplasias Ovarianas/genética , Fosfatidilinositol 3-Quinases/genética , Lesões Pré-Cancerosas/genética , Adenocarcinoma de Células Claras/etiologia , Adulto , Classe I de Fosfatidilinositol 3-Quinases , Endometriose/complicações , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/etiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A 70-year-old Japanese woman who was treated for interstitial pneumonia (IP) with steroid therapy developed cholecystitis. A serial computed-tomography (CT) imaging showed irregular thickness of the fundus wall of the gallbladder and two rapidly enlarged lymph nodes (LNs): number (no.) 12 and no. 8a. Positron-emission tomography-computed tomography (PET-CT) scan showed an abnormal uptake at the site of the gallbladder tumor and those LNs. We subsequently performed open radical cholecystectomy and LN dissection of the no. 12 and 8a LNs, following complete remission of IP. The histology showed gallbladder adenocarcinoma, with a single focus of neuroendocrine carcinoma (NEC) component of less than 30%; Ki-67 index > 80%, synaptophysin (Syn) (+), chromogranin A (CgA) (+), and clusters of differentiation (CD) 56 (+) (T2bN1M0, Stage IIIB). LN no. 8a was diffusely metastatic with NEC components. LN no. 12c, which was adjacent to the cystic duct, revealed necrosis without apparent tumor cells, but was highly suspicious for tumor necrosis. The final diagnosis was adenocarcinoma of the gallbladder with focal NEC (< 30%), which did not meet the criteria for mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). Postoperatively, she completed 4 cycles of adjuvant chemotherapy for NEC (Cisplatin plus Etoposide), and no recurrence was observed after 12 months.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Neoplasias da Vesícula Biliar , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Idoso , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Feminino , Vesícula Biliar , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Metástase Linfática , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
The aim of this study was to assess protein overexpression and gene copy number alterations of MET in ovarian clear-cell adenocarcinoma, and to assess its potential as a novel therapeutic target. Ninety cases of clear-cell adenocarcinoma were analyzed for MET protein overexpression and copy number alterations of the MET gene by immunohistochemistry and brightfield double in situ hybridization, respectively. In addition, 101 cases of the non-clear-cell type ovarian carcinomas at advanced stages were also evaluated for comparison. MET overexpression was assigned when complete membrane staining with moderate or strong intensity was observed in at least 10% of the tumor cells examined. Double in situ hybridization was determined as positive when the tumor exhibited high-level polysomy (≥4 copies in ≥40% of tumor cells) or MET gene amplification. MET overexpression was detected in 20 of 90 clear-cell adenocarcinomas (22%) and none of 111 non-clear-cell type ovarian carcinomas. Double in situ hybridization was positive in 21 of 89 informative clear-cell adenocarcinomas (24%) and only 3 non-clear-cell type ovarian carcinomas (3%). In the whole population, true amplification of the MET gene was detected only in the clear-cell adenocarcinoma histology (five cases, 6%). In clear-cell adenocarcinomas, double in situ hybridization positivity was highly correlated with the presence of MET overexpression and a poorly differentiated histology of tumors (P=0.0105 and 0.00038, respectively). For the patients with clear-cell adenocarcinomas, MET overexpression, as well as advanced clinical stage and the poorly differentiated histology of tumors, was identified as an independent unfavorable prognostic factor for overall survival. In conclusion, among ovarian carcinomas, the amplification of the MET proto-oncogene is highly selective and commonly occurs in clear-cell adenocarcinoma. MET could serve as a biomarker for the prognostication of patients with clear-cell adenocarcinoma and tumor progression, and has potential as a novel therapeutic target for this carcinoma.
Assuntos
Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-met/biossíntese , Adenocarcinoma de Células Claras/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Progressão da Doença , Feminino , Amplificação de Genes , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Prognóstico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-met/genética , Análise Serial de Tecidos , Regulação para CimaRESUMO
Little is known about the pathologic significance of epidermal growth factor receptor (EGFR) expression in malignant testicular germ cell tumors (TGCTs) in adults. From the primary tumor sites of a cohort of 110 TGCT cases, we obtained 209 histologically distinct components: 53 intratubular germ cell neoplasia unclassified (IGCNU) lesions, 83 seminomas (66 pure-form seminomas and 17 seminoma components in the mixed-form with nonseminomatous TGCTs), 27 embryonal carcinomas, eight choriocarcinomas, 18 yolk sac tumors, and 20 immature teratomas. Samples were analyzed for expression of EGFR protein and EGFR gene amplification by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Overexpression of the EGFR protein was detected in 28% of seminomas (27% in the pure-form and 29% in the mixed-form), 11% of embryonal carcinomas, 88% of choriocarcinomas, 44% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas. A higher copy number (≥4 copies per cell) and amplification of the EGFR gene were detected in 20% and 10% of seminomas, 13% and 0% of embryonal carcinomas, 71% and 60% of choriocarcinomas, 15% and 8% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas, respectively. Both higher copy number and amplification of the EGFR gene were positively correlated with immunohistochemical overexpression of EGFR protein (each P < 0.0001). These results suggest that overexpression of EGFR protein and increased copy number or amplification of the EGFR gene occur relatively frequently in primary TGCTs, and may play roles in the formation of invasive cancer and in the progression, especially morphological evolution, of tumors.
Assuntos
Receptores ErbB/genética , Amplificação de Genes , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Idoso , Distribuição de Qui-Quadrado , Progressão da Doença , Receptores ErbB/metabolismo , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Análise Serial de Tecidos , Carga Tumoral , Adulto JovemRESUMO
UNLABELLED: Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL)-12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS-induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate. CONCLUSION: CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved.
Assuntos
Proteína C-Reativa/fisiologia , Hepatite/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Células de Kupffer/imunologia , Fígado/imunologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
AIMS: To identify the key cell-cycle dysregulations in the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA). METHODS AND RESULTS: Expression of p27(Kip1)-interacting cell-cycle regulators, such as p27(Kip1) itself, Skp2, cyclin-dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell-cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down-regulated (p27(Kip1), P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell-cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA. CONCLUSIONS: Alteration of the p27(Kip1)-interacting cell-cycle regulators appeared strongly involved in the progression of endometriosis-associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.
Assuntos
Adenocarcinoma de Células Claras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Endometriose/complicações , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Ovarianas/metabolismo , Adenocarcinoma de Células Claras/etiologia , Adenocarcinoma de Células Claras/patologia , Quinases relacionadas a CDC2 e CDC28 , Proteínas de Transporte/metabolismo , Ciclina A/metabolismo , Inibidor de Quinase Dependente de Ciclina p27 , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo , Endometriose/genética , Endometriose/patologia , Feminino , Humanos , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/patologia , Proteínas Quinases Associadas a Fase S/metabolismoRESUMO
We report a case of massive intra-abdominal undifferentiated carcinoma derived from a tiny well-differentiated endometrioid adenocarcinoma of the ovary. The patient, a 56-year-old woman, who presented with a large intra-abdominal mass, underwent cytoreductive surgery with hysterectomy and bilateral salpingo-oophorectomy. Macroscopically, the intra-abdominal mass was composed of fragile and solid tumor components with extensive necro-hemorrhagic areas, mimicking a primary peritoneal tumor. Both ovaries were apparently normal in size, but a cut section of the right ovary revealed a 2-cm solid and cystic tumor showing focal rupture to the peritoneal surface. The intra-abdominal tumor consisted of pleomorphic cells without specific differentiation, showing diffuse sheet-like proliferation. The right ovarian tumor was a histologically well-differentiated endometrioid adenocarcinoma. Both the intra-abdominal undifferentiated tumor and the ovarian adenocarcinoma cells were immunohistochemically positive for keratin AE1/3, Ber-EP4, and CD10. Epithelial membrane antigen was positive only in the ovarian adenocarcinoma component, and vimentin was diffusely positive only in the intra-abdominal undifferentiated tumor component. Calretinin was negative in both tumor components. Allelotype analysis using 24 polymorphic markers located on 12 chromosomal arms showed that the intra-abdominal undifferentiated carcinoma and ovarian adenocarcinoma components had a high concordance rate (88%) of allelic patterns including identical allelic loss patterns at 7 chromosomal loci, suggesting a common genetic lineage. These data suggest that ovarian endometrioid adenocarcinoma, even when small in size, can give rise to a massive undifferentiated carcinoma filling the peritoneal cavity.
Assuntos
Carcinoma Endometrioide/secundário , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Alelos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Calbindina 2 , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/cirurgia , DNA de Neoplasias/química , DNA de Neoplasias/genética , Feminino , Humanos , Queratinas Específicas do Cabelo/metabolismo , Pessoa de Meia-Idade , Mucina-1/metabolismo , Neprilisina/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/cirurgia , Reação em Cadeia da Polimerase , Proteína G de Ligação ao Cálcio S100/metabolismo , Vimentina/metabolismoRESUMO
The purpose of this study was to clarify the characteristics of improved ischemic tolerance induced by severe, short-term food restriction in isolated, perfused rat hearts. Male Wistar (8 week-old) rats were given a food intake equivalent to a 70% reduction on the food intake of ad-libitum fed rats for 11 days (FR group and AL group, respectively). After this period, hearts were isolated and perfused in the Langendorff mode, and subjected to 20 min of global ischemia followed by 30 min of reperfusion. Although the coronary flow rate in the FR group (63.0 +/- 3.1 ml/min/g dry weight) was higher than that in the AL group (47.1 +/- 1.3 ml/min/g dry weight) during preischemic perfusion, the lactate release into the coronary effluent and absolute values of +dP/dt and -dP/dt in the FR group (2422 +/- 161 and -1282 +/- 51) were inversely lower than in the AL group (2971 +/- 156 and -1538 +/- 74, respectively). An increase in ischemic contracture was suppressed in the FR group. Following reperfusion, cardiac function, high-energy phosphate content, and intracellular pH, as measured by 31P-nuclear magnetic resonance spectroscopy, had recovered to a much greater degree in the FR group than in the AL group. The serum T3 level was significantly lower in the FR group (2.7 +/- 0.1 pg/ml) than in the AL group (3.6 +/- 0.1 pg/ml), and the levels of triglycerides, free fatty acids, insulin, and glucose were also significantly lower in the FR group than in the AL group. The protein expressions of myocyte enhancer factor 2A, Na(+), K(+)-ATPase, and phospholamban in the cardiac tissue were higher in the FR group than in the AL group. These results suggested that severe, short-term food restriction improves ischemic tolerance in rat hearts via altered expression of functional proteins induced by low serum T3 levels, decreased coronary conductance, and change in metabolic flux.
Assuntos
Restrição Calórica , Metabolismo Energético , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Função Ventricular Esquerda , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Concentração de Íons de Hidrogênio , Insulina/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , Perfusão , Ratos , Ratos Wistar , Fatores de Tempo , Triglicerídeos/metabolismo , Tri-Iodotironina/metabolismo , Pressão VentricularRESUMO
Actinin-4, an isoform of non-muscular alpha-actinin, enhances cell motility by bundling the actin cytoskeleton. We previously reported a prognostic implication of high immunohistochemical expression of actinin-4 protein in ovarian cancers. Chromosomal gain or amplification of the 19q12-q13 region has been reported in ovarian cancer. We hypothesized that the actinin-4 (ACTN4) gene might be a target of the 19q12-q13 amplicon and play an essential role of ovarian cancer progression. In total, 136 advanced-stage ovarian cancers were investigated for the copy number of the ACTN4 gene on chromosome 19q13, using fluorescence in situ hybridization, and the correlation of the ACTN4 copy number with actinin-4 protein immunoreactivity and major clinicopathological factors was investigated. A higher copy number (> or =4 copies) of the ACTN4 gene was detected in 29 (21%) cases and was highly associated with the intensity of actinin-4 immunoreactivity (P<0.0001), a high histological tumor grade (P=0.030), a clear-cell adenocarcinoma histology (P=0.012), resistance to first-line chemotherapies (P=0.028), and poor patient outcome (P=0.0011). Univariate analyses using the Cox regression model showed that a higher ACTN4 gene copy number was able to predict patient outcome more accurately than high actinin-4 immunoreactivity (relative risk: 2.48 vs 1.55). Multivariate analysis showed that a higher copy number of the ACTN4 gene and the degree of residual disease were independent prognostic factors for overall patient survival. The actinin-4 gene may be a target of the 19q amplicon, acting as a candidate oncogene, and serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers.
Assuntos
Actinina/genética , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Ovarianas/genética , Actinina/biossíntese , Feminino , Amplificação de Genes , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Oncogenes , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Análise Serial de TecidosRESUMO
BACKGROUND: Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated. DESIGN: A prospective, randomized, open-label trial. METHODS: We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemic patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated. RESULTS: The 20-mg dose markedly reduced LDL-cholesterol levels (-47%) versus 5-mg (-35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (-15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (-14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (-1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64). CONCLUSION: Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment.
Assuntos
Aorta Abdominal/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aortografia/métodos , Aterosclerose/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Angiografia por Ressonância Magnética , Pirróis/uso terapêutico , Idoso , Aorta Abdominal/patologia , Aorta Torácica/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Atorvastatina , LDL-Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Cancer invasion and metastasis are critical events for patient prognosis; however, the most important step in the whole process of lymph node (LN) metastasis in gastric cancer remains obscure. In this study, the significance of cancer cell behaviors, such as cell detachment, stromal invasion and lymphatic invasion on regional LN metastasis in gastric cancer was investigated by comprehensive immunohistochemistry. METHODS: A total of 210 cases with gastric cancer were selected. These consisted of 105 cases with regional LN metastasis (LN[+] group) and 105 cases without LN metastasis (LN[-] group). Both groups exhibited the same depth of invasion. Cancer tissues were subjected to immunohistochemistry with antibodies against claudin-3, claudin-4, beta-catenin, matrix metalloproteinase (MMP)-1, and MMP-2, as well as endothelial markers of lymphatic vessel endothelial hyaluronan receptor-1 and von Willebrand factor for the objective discrimination between lymphatics and blood vessels. The expression of each protein as well as the histopathological parameters were compared between LN(+) and LN(-) groups. RESULTS: Along with lymphatic invasion by cancer cells and gross tumor size, MMP-1 expression in cancer cells at the invasive front of the primary tumor was a significant, independent predictor of LN metastasis. The expression of claudins and beta-catenin was associated with the histopathological type of cancer, but not with LN status. CONCLUSION: Among the cancer invasion-related proteins examined, MMP-1 plays a vital role in LN metastasis of gastric cancer. Tumor size, lymphatic invasion and MMP-1 expression level at the invasive front were the predictive factors of LN metastasis of gastric cancer.
Assuntos
Biomarcadores Tumorais/análise , Vasos Linfáticos/patologia , Metaloproteinase 1 da Matriz/análise , Neoplasias Gástricas/secundário , Neoplasias Gástricas/cirurgia , Idoso , Estudos de Casos e Controles , Claudina-3 , Claudina-4 , Feminino , Gastrectomia , Humanos , Imuno-Histoquímica , Metástase Linfática , Vasos Linfáticos/química , Masculino , Metaloproteinase 2 da Matriz/análise , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Gástricas/química , Resultado do Tratamento , Proteínas de Transporte Vesicular/análise , beta Catenina/análise , Fator de von Willebrand/análiseRESUMO
Carcinoma with a large central acellular zone (central acellular carcinoma, CAC) and matrix-producing carcinoma (MPC) have been recently noted as basal-like-type breast cancers, but the two entities are often confused. To clarify their histological differences, the histopathological sections of 15 CAC and seven MPC were examined and the following features were compared by reviewing slides: (i) mode of invasion; (ii) alteration of cancer cell adhesion in the transitional area between cellular and acellular zones; (iii) staining of the stromal matrix; (iv) lymphocyte infiltration; and (v) tumor grade. Complete agreement was required between two observers for the assessments of these features. All CAC had relatively sharp margins but showed infiltrative growth accompanied by eosinophilic intercellular matrix. In CAC there was abrupt transition between peripheral cellular and central acellular zones without alteration of cancer cell adhesion. In contrast, all MPC showed expansive growth with a well circumscribed margin, accompanied by basophilic and myxoid intercellular matrix. In MPC there was gradual transition from cellular to acellular areas with gradual loss of cancer cell adhesion. Histological grade 3 and peripheral lymphocyte infiltration were common features. It is suggested that CAC and MPC are histologically distinct entities, and that the aforementioned features are helpful for differential diagnosis.