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1.
J Card Surg ; 37(6): 1613-1622, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35343608

RESUMO

BACKGROUND: The pathogenesis of mitral valve insufficiency is not yet fully understood. Several studies stressed the role of matrix metalloproteinases (MMPs) in the emergence of valvular pathologies. The primary objective of the present study is to analyze the role of selected MMPs and their inhibitors in mitral valve insufficiency. PATIENTS AND METHODS: Eighty patients (33 female/47 male, mean age 67 years) underwent cardiopulmonary bypass surgery for mitral valve reconstruction between 2007 and 2015. All patients suffered from mitral insufficiency (MI) Stages iii and iv. When tissue resection was acquired specimens were taken immediately frozen and used for histological examination. Expression of MMP-1, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 was examined immunohistochemically and distribution was analyzed in regard to preoperative clinical, echocardiographic, and histopathological findings. RESULTS: A clear correlation between the MMP expression and the MI degree of severity could be shown. The expression of MMPs proved to be high in relation to mild insufficiencies and relatively weak in the case of severe ones. Additionally, the etiology of the MI was considered in the analysis and a significant difference in the expression of MMPs between the mitral valves with endocarditis and the ones featuring a degenerative disease could be shown. Within the group of valves with degenerative diseases, no significant difference could be established between the subgroups (myxoid and sclerosed valves). CONCLUSION: The increased expression of MMPs and their inhibitors in mild insufficiencies could prove that the molecular changes in the valve precede the macroscopical and thus the echocardiographically diagnosable changes. Hence, new options for early diagnosis and therapy of MIs should be examined in further studies, respectively. Herein, the correlation of the MMP blood levels with MMP tissue expression should be addressed for surgical therapeutical decisions.


Assuntos
Insuficiência da Valva Mitral , Idoso , Feminino , Humanos , Masculino , Metaloproteinase 1 da Matriz , Metaloproteinase 9 da Matriz , Metaloproteinases da Matriz/metabolismo , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/cirurgia , Inibidor Tecidual de Metaloproteinase-1 , Inibidor Tecidual de Metaloproteinase-2 , Inibidores Teciduais de Metaloproteinases/metabolismo
2.
ScientificWorldJournal ; 2020: 6845413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231466

RESUMO

BACKGROUND: In China, the incidence of cancer has significantly decreased over the last two decades. In contrast, the incidence of gastric carcinoma (GC) has risen in young patients. METHODS: We reevaluated the histopathological results of 4,353 endoscopic gastroscopies from the Department of Pathology at No 1 Hospital of Liangshan. The ethnic groups Han and Yi were almost equally distributed in this cohort. Over a five-year period, 1407 GC were diagnosed. RESULTS: In 171 of these cases (12%), the patients were ≤40 years old (early-onset GC, EOGC). Out of this cohort, 9 patients were aged ≤25 years. 54% of these patients were male and showed marked predominance (92%) of the Yi-minority. Using the classification of Lauren, 103 GC (60%) were of diffuse type, 27 (16%) of intestinal type, and 41 (24%) of mixed type. In the remaining 1,236 cases of patients ≥41 years (88%), 1,014 patients (82%) belonged to the Yi-minority. Helicobacter pylori (HP) were found in 46% of all cases. Familial clustering was found in 14 patients (18%; in first degree relatives, 12%, and in second degree relatives, 6%). Follow-up was not possible. CONCLUSION: This study demonstrates the unequal manifestation of EOGC within the two ethnic groups of Han and Yi. However, familial clustering was infrequent. Further investigations are necessary to discover relevant risk factors apart from hereditary predisposition.


Assuntos
Neoplasias Gástricas/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Biópsia , China/epidemiologia , Detecção Precoce de Câncer , Feminino , Gastroscopia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prevalência , Vigilância em Saúde Pública , Neoplasias Gástricas/patologia , Adulto Jovem
3.
Int J Cancer ; 143(7): 1806-1816, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29696624

RESUMO

Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Ácido Clodrônico/uso terapêutico , Insulinoma/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sunitinibe/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/uso terapêutico , Sinergismo Farmacológico , Feminino , Humanos , Lipossomos/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Adulto Jovem
4.
J Ultrasound Med ; 37(12): 2943-2947, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29732588

RESUMO

Here, we describe the appearance and pattern of pulmonary lymphoma on B-mode imaging and with contrast-enhanced ultrasound (CEUS). From July 2009 to December 2015, 6 patients with histologically or cytologically confirmed lymphoma of the lung were examined by B-mode imaging, followed by CEUS. A retrospective analysis of the imaging data was performed with respect to the time to enhancement, pulmonary artery (PA) and bronchial artery, echogenicity (hypoechoic, isoechoic, or hyperechoic), and homogeneity (homogeneous or inhomogeneous) of the contrast enhancement. On B-mode imaging, all 6 pulmonary lymphoma lesions were hypoechoic. Five cases had PA enhancement, and 1 case had bronchial artery enhancement on CEUS imaging. Strikingly, all 6 patients had isoechoic arterial contrast enhancement. In the parenchymal phase, 3 of the lymphoma lesions showed hypoechoic contrast enhancement, and 3 showed isoechoic enhancement. Pulmonary lymphomas are hypoechoic on B-mode imaging. With CEUS, all patients had predominant PA contrast enhancement in the arterial phase with variable parenchymal contrast enhancement. Thus, definite differentiation from other malignant or benign pulmonary lesions cannot be achieved by CEUS.


Assuntos
Meios de Contraste , Aumento da Imagem/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Idoso , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Projetos Piloto , Reprodutibilidade dos Testes , Ultrassonografia/métodos
5.
Tumour Biol ; 39(10): 1010428317728417, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29017393

RESUMO

Typical and atypical carcinoid tumors belong to the neuroendocrine lung tumors. They have low recurrence and proliferation rate, lymph node, and distant metastases. Nevertheless, these tumors have shown a more aggressive behavior. In the last years, microRNAs were screened as new tumor markers for their potential diagnostic and therapeutic relevance. The expression of hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-222-3p, and their targets HMGA2 (high-mobility group A2) and CDKN1B (cyclin-dependent kynase inhibitor 1B, p27kip1) was evaluated in this rare small group of patients. We analyzed the clinical data of all typical and atypical carcinoid tumors of patients who underwent surgical operation at Marburg University Hospital (n = 18) from 2000. Quantitative reverse transcription polymerase chain reaction was performed in formalin-fixed paraffin-embedded tumor tissue versus four tumor-free lung tissue samples. HMGA2 was stable or downregulated; only one patient showed a significant overexpression. CDKN1B showed a significant overexpression or a stable level; it was downregulated in two samples only. Hsa-miR-222-3p resulted almost stable or overexpressed except for two samples (significantly downregulated). Hsa-let-7f-5p was stable or overexpressed in the majority of analyzed samples, whereas hsa-let-7b-5p was significantly downregulated. HMGA2 and CDKN1B are differently expressed between atypical and typical carcinoid tumors, thus representing valid biomarkers for the classification of the two tumor groups. Hsa-let-7f-5p and HMGA2 are inversely correlated. Hsa-miR-222-3p does not correlate with its predicted target CDKN1B.


Assuntos
Biomarcadores Tumorais/análise , Tumor Carcinoide/classificação , Tumor Carcinoide/patologia , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/patologia , Adulto , Idoso , Inibidor de Quinase Dependente de Ciclina p27/análise , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Feminino , Proteína HMGA2/análise , Proteína HMGA2/biossíntese , Humanos , Masculino , MicroRNAs/análise , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
6.
Lasers Med Sci ; 32(3): 557-562, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28110368

RESUMO

Lung metastases are often resected non-anatomically with a laser using a diode-pumped Nd:YAG laser at a wavelength of 1320 nm with a laser output of up to 60 W. Usually the removal of lesions is carried out in contact mode by means of a bare fibre. We compared the local effects of an Nd:YAG laser at a wavelength of 1064 nm with those at a wavelength of 1320 nm using a 600-µm bare fibre in contact mode in an experimental model. The investigations were carried out on porcine lungs freshly withdrawn at the abattoir. The 600-µm laser fibre was fixed vertically in contact with the lung surface on a fibre holder. The fibre holder was connected to a feeding device that advances the laser fibre at constant speeds (5, 10 or 20 mm/s). In each case, two laser powers were examined: 20 and 60 W. The lung lesions produced by the laser fibre were excised for histological examination. After haematoxylin-eosin staining, the depth of the vaporisation and coagulation zones (in µm) from the laser cuts was measured. For each setting, an average value was calculated. The individual groups were compared for significance using a non-parametric Mann-Whitney U test (p < 0.05). At a low speed of the bare fibre of 5 mm/s and a laser output of 20 W, the average depth of the vaporisation zone was 858 ± 3.3 µm (λ = 1064 nm) compared to 766.0 ± 7.5 µm (λ = 1320 nm) (p < 0.01). Upon faster movement (20 mm/s), the extension of the vaporisation zone decreased to 320.3 ± 7.1 µm (λ = 1064 nm). The depth of the vaporisation zone increased significantly at 60 W, both at λ = 1064 and 1320 nm with 1517.0 ± 1.7 µm and 1414.0 ± 4.9 µm, respectively. The extent of the coagulation zone was significantly smaller at 20 W and the low speed of 5 mm/s, namely, 200.4 ± 3.7 µm (λ = 1064 nm) and 224.1 ± 2.8 µm (1320-nm laser). Upon faster movement of the laser fibre at the same output, the extent of the coagulation zone decreased in both groups. At a laser power of 60 W, the extent of the coagulation zone was significantly less with the 1064-nm laser (110.3 ± 2.4 µm) than with the 1320-nm laser (324.8 ± 1.9 µm; p < 0.001). When the laser fibre moves more rapidly, the extent of the coagulation zone decreases further. The Nd:YAG laser with a wavelength of 1320 nm still has the optimal ratio of cutting and coagulation capacity on the resection surface. With the 1064-nm Nd:YAG laser, a higher cutting capacity is associated with a decrease of the coagulation capacity.


Assuntos
Terapia a Laser/métodos , Lasers de Estado Sólido/uso terapêutico , Neoplasias Pulmonares/cirurgia , Pulmão/cirurgia , Animais , Suínos
7.
J Surg Res ; 194(2): 388-393, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25439321

RESUMO

BACKGROUND: Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domain-associated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs. METHODS: In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-real-time polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects. RESULTS: A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue. CONCLUSIONS: mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , DNA Helicases/metabolismo , Neoplasias do Íleo/metabolismo , Complexos Multiproteicos/metabolismo , Tumores Neuroendócrinos/metabolismo , Proteínas Nucleares/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Biomarcadores Tumorais/genética , Proteínas Correpressoras , DNA Helicases/genética , Feminino , Humanos , Neoplasias do Íleo/genética , Neoplasias do Íleo/patologia , Íleo/patologia , Imuno-Histoquímica , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Pessoa de Meia-Idade , Chaperonas Moleculares , Terapia de Alvo Molecular , Complexos Multiproteicos/genética , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinases TOR/genética , Proteína Nuclear Ligada ao X
8.
BMC Cancer ; 14: 691, 2014 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-25244967

RESUMO

BACKGROUND: Paraneoplastic neurological syndromes (PNS) have frequently been described in patients with lung or breast cancer. However, some reports also described a correlation to carcinoid tumors, probably triggered via the excessive release of hormones. CASE PRESENTATION: We report the case of a 40-year-old woman that was diagnosed with a neuroendocrine neoplasm (NEN) of the rectum and multiple synchronous liver metastases ten years ago. She initially responded well to transarterial chemoembolization (TACE), resulting in prolonged disease stabilization. However, ten years after initial diagnosis the patient developed unspecific neurological symptoms that could not be classified by standard neurological diagnostic work-up. Special laboratory analysis revealed a high titer of anti-Ri (ANNA-2), a well-characterized antibody that is associated with paraneoplastic neurologic syndromes. The patient's symptoms improved markedly after a 5-day-course of high-dose glucocorticoid therapy. To our knowledge, this is the first report of a Ri-positive PNS in a patient with hormone-negative rectal NEN. CONCLUSION: PNS can complicate the patient's clinical course, response to treatment, impact prognosis and even be interpreted as metastatic spread. However, owing to their rarity, the knowledge of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.


Assuntos
Tronco Encefálico/patologia , Encefalite/complicações , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/patologia , Síndromes Paraneoplásicas do Sistema Nervoso/complicações , Neoplasias Retais/complicações , Neoplasias Retais/patologia , Adulto , Anti-Inflamatórios/uso terapêutico , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Metilprednisolona/uso terapêutico , Tumores Neuroendócrinos/diagnóstico , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , Síndromes Paraneoplásicas do Sistema Nervoso/tratamento farmacológico , Neoplasias Retais/diagnóstico , Resultado do Tratamento
9.
Neuroendocrinology ; 100(4): 300-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25301256

RESUMO

BACKGROUND: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. MATERIAL AND METHODS: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. RESULTS: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. CONCLUSION: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms.


Assuntos
Antineoplásicos/administração & dosagem , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Isoxazóis/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Resorcinóis/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/fisiopatologia , RNA Mensageiro/metabolismo
10.
Thorac Cardiovasc Surg ; 62(4): 363-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24297634

RESUMO

BACKGROUND: Heat accumulation might induce thermal damage of the surrounding lung tissue, especially when multiple lesions are resected in one session. The present study aimed to investigate whether heat accumulates in the immediate vicinity of the resection surface and leads to thermal damage of the lung parenchyma, and what is the most effective cooling strategy in this situation. MATERIALS AND METHODS: In normothermic perfused paracardial swine lobes (n = 6), four punctiform laser lesions forming a square were created. Each lesion was lasered at a power of 100 W for 5 seconds. Two test conditions with square sides of either 1.0 or 0.5 cm were compared. Temperatures were recorded immediately after completing the laser procedure in the square center and in the corners using a thermal camera and continued during the cooling process at 10-second intervals until normothermia (37°C). We examined two cooling methods: rinsing with ice-cold (4°C) Ringer solution during the laser procedure (group B, n = 6) or submerging the lung in ice-cold water for 5 seconds immediately after laser application (group C, n = 6). In the control group A (n = 6), there was no cooling. RESULTS: In the 0.5 cm squares, mean temperature in the center immediately after laser application was 103.17 ± 8.56°C, significantly higher than in the corners (76.39 ± 2.87°C, p < 0.05). Normothermia in the quadrant corners was reached after 81 ± 14 and after 108 ± 29 seconds in the centers. Tissue in the square center revealed histological signs of thermic cell damage. In the 1.0 cm squares, mean temperature in the center was 64 ± 5°C, and in the corners was 77 ± 3.1°C (p < 0.05). Normothermia was regained after 93 ± 22 seconds in the center and 120 ± 21 seconds in the corners. Histological examination in the 1.0-quadrant centers revealed no signs of thermic cell damage. Submerging the lobe into ice-cold water lowered the temperature rapidly to under 40°C, and normothermia was regained after 75 ± 1.3 seconds. CONCLUSION: Laser application to the lung parenchyma causes considerable heat accumulation in closely related lesions. To prevent such cell damage, a distance of at least 1.0 cm between laser targets should be maintained. If no topical cooling method applied, sufficient time for spontaneous tissue cooling before additional laser application should be provided. The most effective cooling strategy against heat accumulation is submerging in ice-cold water for at least 5 seconds.


Assuntos
Temperatura Alta , Terapia a Laser/efeitos adversos , Pulmão/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Animais , Desenho de Equipamento , Terapia a Laser/instrumentação , Lasers , Pulmão/patologia , Modelos Animais , Complicações Pós-Operatórias/patologia , Suínos , Fatores de Tempo
11.
BMC Surg ; 13: 11, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23590134

RESUMO

BACKGROUND: Chondral defects of the articular surface are a common condition that can lead to osteoarthritis if not treated. Therapy of this condition is a topic of constant debate and a variety of chondral repair strategies are currently used. One strategy involves implantation of a cell-free matrix of type I collagen (COL1), to provide a scaffold for chondrocyte migration and proliferation and extracellular matrix production. Although several studies have suggested that chondrocytes can move, to the best of our knowledge there is still no proof of chondrocyte occurrence in a former cell-free scaffold for articular cartilage repair in humans. CASE PRESENTATION: An 18-year-old male patient underwent arthroscopic surgery of the knee for patellar instability and a chondral defect of the femoral condyle. Clinical outcome scores were recorded pre-operatively, after 6 weeks and after 6, 12, 24 and 36 months. MRI was recorded after 6 weeks and after 6, 12, 24 and 36 months postoperatively. At 42 months after implantation of a cell-free type I collagen matrix and reconstruction of the medial patellofemoral ligament, the patient was again treated arthroscopically for a tear of the medial meniscus of the same knee. A biopsy of the previous chondral defect was taken during arthroscopy for histological examination. CONCLUSION: In addition to good clinical and radiological results reported for cell-free scaffolds for cartilage repair in several other studies, transformation of the scaffold could be observed during re-arthroscopy for the meniscal tear. Histological examination of the specimen revealed articular cartilage with vital chondrocytes and a strong staining reaction for type II collagen (COL II), but no reaction for type I collagen staining. This might indicate a complete transformation of the scaffold and supports the theory that cell free scaffolds could support cell migration. Although the cell source remains unclear, migrating chondrocytes from the periphery remain a possibility.


Assuntos
Artroscopia/métodos , Doenças das Cartilagens/cirurgia , Condrócitos/transplante , Adolescente , Doenças das Cartilagens/metabolismo , Doenças das Cartilagens/patologia , Movimento Celular/fisiologia , Sistema Livre de Células/metabolismo , Sistema Livre de Células/patologia , Condrócitos/citologia , Condrócitos/metabolismo , Colágeno Tipo I/administração & dosagem , Colágeno Tipo I/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento
13.
Cancers (Basel) ; 14(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36230513

RESUMO

Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.

14.
BMC Cancer ; 10: 264, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20529315

RESUMO

BACKGROUND: Malignant degeneration in association with orthopaedic implants is a known but rare complication. To our knowledge, no case of osseous malignant fibrous histiocytoma after anterior cruciate ligament reconstruction is reported in the literature. CASE PRESENTATION: We report a 29-year-old male Turkish patient who presented with severe pain in the operated knee joint 40 months after arthroscopic anterior cruciate ligament reconstruction. X-ray and MR imaging showed a large destructive tumor in the medial femoral condyle. Biopsy determined a malignant fibrous histiocytoma. After neoadjuvant chemotherapy, wide tumor resection and distal femur reconstruction with a silver-coated non-cemented tumor knee joint prosthesis was performed. Adjuvant chemotherapy was continued according to the EURAMOS 1 protocol. CONCLUSIONS: Though secondary malignant degeneration after orthopaedic implants or prostheses is not very likely, the attending physician should take this into consideration, especially if symptoms worsen severely over a short period of time.


Assuntos
Ligamento Cruzado Anterior/cirurgia , Artroscopia/efeitos adversos , Neoplasias Femorais/etiologia , Histiocitoma Fibroso Maligno/etiologia , Transferência Tendinosa/efeitos adversos , Adulto , Lesões do Ligamento Cruzado Anterior , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Artroplastia do Joelho , Biópsia , Quimioterapia Adjuvante , Neoplasias Femorais/diagnóstico , Neoplasias Femorais/terapia , Histiocitoma Fibroso Maligno/diagnóstico , Histiocitoma Fibroso Maligno/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Terapia Neoadjuvante , Dor/etiologia , Reoperação , Ruptura , Transferência Tendinosa/instrumentação , Resultado do Tratamento
15.
Urol Oncol ; 38(1): 3.e7-3.e15, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30241953

RESUMO

Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue. In parallel, we measured several members of the neuropilin/plexin/semaphorin family (NRP, PLXN, and SEMA) as possible targets mediating innervation. The TE-gene-fusion status was determined at the mRNA level in CaP tissues by nested RT-PCR. Transcript levels were analyzed by quantitative RT-PCR in CaP tissue or cell line homogenate. ERG was analyzed by immunostaining, and the nerve density was evaluated by immunostaining for PGP9.5 and axonal neurofilament. Data were analyzed by correlation (Spearman), linear regression, Mann-Whitney U test, and contingency table analyses. TE-positive (TE-1) vs. TE-negative (TE-0) CaP tissues displayed significantly enhanced ERG-mRNA levels (TE-0: -4.183; TE-1: -2.994, P < 0.001) and ERG immunostaining (Erg-IH score; TE-0: 0.4211; TE-1: 1.391; P < 0.0001). Notably, the nerve density was significantly increased in CaP tissue samples with positive TE status compared to negative TE status (TE-0, ND score = 1.5; TE-1, ND score = 2.0; P <0.01). NRP1, NRP2, PLXNA2, PLXNB1, SEMA3A, and SEMA4B mRNAs were detectable in CaP tissues and CaP cell lines at quite heterogeneous levels. In CaP tissues, we observed significant positive correlations of ERG with NRP2, PLXNA2, PLXNB1, and SEMA4B. TE-positive CaP tissues displayed enhanced nerve density. ERG correlated with some NRP/PLXN/SEMA components suggesting possible regulatory relevance of ERG for CaP innervation.


Assuntos
Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade
16.
Mol Oncol ; 14(9): 2142-2162, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32533757

RESUMO

A hallmark of ovarian high-grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites-derived spheroids. The adhesion-induced transcriptional alterations in metastases and adherent cells resembled epithelial-mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA-mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal-mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.


Assuntos
Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Regulação para Cima/genética , Apoptose/genética , Ascite/genética , Ascite/patologia , Biomarcadores Tumorais/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Intervalo Livre de Doença , Feminino , Humanos , Gradação de Tumores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Peritoneais/secundário , Polimorfismo de Nucleotídeo Único/genética , Esferoides Celulares/patologia , Resultado do Tratamento
17.
Oncol Rep ; 19(1): 151-6, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18097589

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor characterized by excessive angiogenesis. The dismal prognosis of patients with GBM warrants the development of new targeting therapies based on novel molecular markers. The EphA2 receptor tyrosine kinase plays a pivotal role in tumor angiogenesis and an increased expression in glioma patients has recently been reported. In this study, we investigated the expression of EphA2 in human normal brain, primary and recurrent GBM and correlated it with clinical pathological parameters and patient's outcome. In addition, intratumor microvascular density was quantified by immunostaining for the endothelial cell marker, von Willebrand factor. A different intensity of the membranous and cytoplastic expression of EphA2 was observed in the 40 primary and recurrent samples of GBM analyzed but not in the normal brain. A high level expression of EphA2 was demonstrated in 24 (60%) of the primary and recurrent GBM analyzed. The increased expression of the EphA2 protein was significantly associated with the adverse outcome of GBM patients (p<0.01 for overall survival). The data presented in this study define the expression pattern of EphA2 in both primary and recurrent glioblastoma and suggest an important role of EphA2 in the pathogenesis of GBM. The EphA2 may be used as a surrogate marker to screen patients for tyrosine kinase inhibitor therapy.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptor EphA2/biossíntese , Adulto , Idoso , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/mortalidade , Feminino , Glioblastoma/irrigação sanguínea , Glioblastoma/mortalidade , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Prognóstico
18.
Anticancer Res ; 38(5): 2749-2754, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29715095

RESUMO

BACKGROUND: We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC). MATERIALS AND METHODS: CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis. RESULTS: CD200 was detectable at mRNA and protein levels in TCC homogenate and TCC cell lines (T24, UMUC3). TCC tissues showed significantly higher CD200 expression (p<0.005) than normal bladder tissues. CD200 signals were also higher in metastasized compared to localized TCC (p<0.05). CD200 was significantly correlated to tumor grading (p<0.001) and was strongest in the subgroup with high-grade G2 TCC (vs. low-grade G2 p<0.05). CONCLUSION: This is the first report of CD200 expression in patients with TCC. The significant correlation between CD200 expression and tumor grading may suggest CD200 as a potential target and marker for immunotherapeutic approaches.


Assuntos
Antígenos CD/biossíntese , Carcinoma de Células de Transição/patologia , Proteínas de Neoplasias/biossíntese , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos CD/genética , Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/metabolismo , Diferenciação Celular , Feminino , Humanos , Masculino , Gradação de Tumores , Metástase Neoplásica , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Evasão Tumoral , Neoplasias da Bexiga Urinária/metabolismo
19.
Anticancer Res ; 37(5): 2491-2500, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476818

RESUMO

BACKGROUND/AIM: Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. PATIENTS AND METHODS: We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. RESULTS: There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. CONCLUSION: Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Estreptozocina/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
BMC Res Notes ; 9: 326, 2016 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-27349224

RESUMO

BACKGROUND: Pulmonary neuroendocrine tumors (NET) form a heterogeneous group of rare diseases. In these tumors, paraneoplastic syndromes have been described to drive the course of the disease, among them acromegaly induced by paraneoplastic secretion of growth hormone-releasing hormone (GHRH). CASE PRESENTATION: We report the case of a 43 years old patient initially diagnosed with acromegaly accompanied by weight gain and acral enlargement. Subsequently, further diagnostic work-up identified a solitary pulmonary neuroendocrine tumor (NET). Laboratory tests revealed markedly increased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) without GHRH elevation in the absence of pituitary pathologies confirming the paraneoplastic origin of clinical presentation with acromegaly. Curative surgery was performed leading to normalization of the elevated hormone levels and improvement of the clinical symptoms. Immunohistochemically, a typical carcinoid (TC) was seen with low proliferation index and abundant IGF-1 expression. CONCLUSIONS: The association of acromegaly and pulmonary NET has only rarely been reported. We present an individual case of paraneoplastic GH- and IGF-1 secretion in a patient with pulmonary NET. Based on their rarity, the knowledge of paraneoplastic syndromes occurring in patients with pulmonary NET such as acromegaly due to paraneoplastic GH- and IGF-1 secretion is mandatory to adequately diagnose and treat these patients.


Assuntos
Acromegalia/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Acromegalia/complicações , Acromegalia/metabolismo , Adulto , Hormônio do Crescimento Humano/metabolismo , Humanos , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Antígeno Ki-67/análise , Neoplasias Pulmonares/complicações , Masculino , Tumores Neuroendócrinos/complicações , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
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