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1.
Neurosurg Rev ; 47(1): 72, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38285230

RESUMO

Cranioplasty (CP) after decompressive hemicraniectomy (DHC) is a common neurosurgical procedure with a high complication rate. The best material for the repair of large cranial defects is unclear. The aim of this study was to evaluate different implant materials regarding surgery related complications after CP. Type of materials include the autologous bone flap (ABF), polymethylmethacrylate (PMMA), calcium phosphate reinforced with titanium mesh (CaP-Ti), polyetheretherketone (PEEK) and hydroxyapatite (HA). A retrospective, descriptive, observational bicenter study was performed, medical data of all patients who underwent CP after DHC between January 1st, 2016 and December 31st, 2022 were analyzed. Follow-up was until December 31st, 2023. 139 consecutive patients with a median age of 54 years who received either PMMA (56/139; 40.3%), PEEK (35/139; 25.2%), CaP-Ti (21/139; 15.1%), ABF (25/139; 18.0%) or HA (2/139; 1.4%) cranial implant after DHC were included in the study. Median time from DHC to CP was 117 days and median follow-up period was 43 months. Surgical site infection was the most frequent surgery-related complication (13.7%; 19/139). PEEK implants were mostly affected (28.6%; 10/35), followed by ABF (20%; 5/25), CaP-Ti implants (9.5%; 2/21) and PMMA implants (1.7%, 1/56). Explantation was necessary for 9 PEEK implants (25.7%; 9/35), 6 ABFs (24.0%; 6/25), 3 CaP-Ti implants (14.3%; 3/21) and 4 PMMA implants (7.1%; 4/56). Besides infection, a postoperative hematoma was the most common cause. Median surgical time was 106 min, neither longer surgical time nor use of anticoagulation were significantly related to higher infection rates (p = 0.547; p = 0.152 respectively). Ventriculoperitoneal shunt implantation prior to CP was noted in 33.8% (47/139) and not significantly associated with surgical related complications. Perioperative lumbar drainage, due to bulging brain, inserted in 38 patients (27.3%; 38/139) before surgery was protective when it comes to explantation of the implant (p = 0.035). Based on our results, CP is still related to a relatively high number of infections and further complications. Implant material seems to have a high effect on postoperative infections, since surgical time, anticoagulation therapy and hydrocephalus did not show a statistically significant effect on postoperative complications in this study. PEEK implants and ABFs seem to possess higher risk of postoperative infection. More biocompatible implants such as CaP-Ti might be beneficial. Further, prospective studies are necessary to answer this question.


Assuntos
Benzofenonas , Polímeros , Polimetil Metacrilato , Crânio , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Crânio/cirurgia
2.
Arch Orthop Trauma Surg ; 143(2): 1133-1141, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35974203

RESUMO

INTRODUCTION: The aim of this study was to analyze primary flexor tendon repair results in zones I and II, comparing the rupture rate and clinical outcomes of the controlled active motion (CAM) protocol with the modified Kleinert/Duran (mKD) protocol. MATERIALS AND METHODS: Patients who underwent surgery with traumatic flexor tendon lacerations in zones I and II were divided in three groups according to the type of rehabilitation protocol and period of management: group 1 included patients who underwent CAM rehabilitation protocol with six-strand Lim and Tsai suture after May 2014. Group 2 and 3 included patients treated by six-strand Lim Tsai suture followed by a modified Kleinert/Duran (modK/D) protocol with additional place and hold exercises between 2003 and 2005 (group 2) and between 2011 and 2013 (group 3). RESULTS: Rupture rate was 4.7% at 12 weeks in group 1 (3/63 flexor tendon repairs) compared to 2% (1/51 flexor tendon repairs) in group 2 and 8% in group 3 (7/86 flexor tendon repairs). The grip strength at 12 weeks was significantly better in group 2 compared to the group 1 (35 kg/25 kg, p = 0.006). The TAM in group 1 [113° (30-175°)] was significantly worse (p < 0.001) than the TAM in group 2 [141° (90-195°)] but with similar extension deficits in both groups. The assessment of range of motion by the original Strickland classification system resulted in 20% excellent and 15% good outcomes in the CAM group 1 compared with 42% and 36% in the modK/D group 2. Subanalysis demonstrated improvement of good/excellent results according to Strickland from 45% at 3 months to 63.6% after 6-month follow-up in the CAM group. CONCLUSION: The gut feeling that lead to change in our rehabilitation protocol could be explained by the heterogenous bias. A precise outcome analysis of group 1 could underline that in patients with complex hand trauma, nerve reconstruction, oedema or early extension deficit, an even more intensive and individual rehabilitation has to be performed to achieve better TAM at 6 or 12 weeks. Our study explicitly demonstrated a significant better outcome in the modK/D group compared to CAM group. This monocenter study is limited by its retrospective nature and the low number of patients.


Assuntos
Traumatismos dos Dedos , Traumatismos dos Tendões , Humanos , Estudos Retrospectivos , Traumatismos dos Tendões/cirurgia , Traumatismos dos Tendões/reabilitação , Traumatismos dos Dedos/cirurgia , Tendões/cirurgia , Ruptura/cirurgia , Amplitude de Movimento Articular/fisiologia
3.
Neurochem Res ; 42(5): 1543-1554, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28271323

RESUMO

We have previously reported that combined inhibition of the epidermal growth factor receptor by erlotinib and of RAC1 by NSC23766 yielded a synergistic antiproliferative effect on established and primary cultured glioblastoma cells. The current study aimed at identifying the molecular mechanism. Staining for annexin V/PI or carboxyfluorescein succinimidyl ester was performed in order to determine the induction of apoptosis, necrosis or cytostasis in established and primary cultured glioblastoma cells. Moreover, expression of Ki-67 was determined by immunofluorescence, and the expression of cell cycle proteins was analysed by Western blot. Our data show that combined treatment with erlotinib and NSC23766 resulted in a reduced number of cell divisions, a significantly decreased Ki-67 expression, increased apoptosis and autophagy when compared to single agent treatments. On the molecular level, concomitant treatment with both agents resulted in a pronounced downregulation of cyclin D1, cyclin-dependent kinases 2, 4 and 6, as well as of survivin when compared to treatments with either agent alone. In conclusion, we demonstrate that combined treatment of human glioma cell lines in vitro with erlotinib and NSC23766 markedly inhibits cell division, induces apoptosis independent of caspase-3 activation and induces autophagy concomitant with suppression of survivin.


Assuntos
Citostáticos/administração & dosagem , Receptores ErbB/metabolismo , Glioma/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Transdução de Sinais/fisiologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/administração & dosagem , Aminoquinolinas/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Citostáticos/toxicidade , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/toxicidade , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Survivina , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
4.
HNO ; 65(1): 25-29, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27670420

RESUMO

Intraoperative magnetic resonance imaging is a widely accepted method for resection control of glial tumors. Increasingly, it is also used during the resection of skull base tumors. Several studies have independently demonstrated an increase in the extent of resection in these tumors with improved prognosis for the patients. Technical innovations combined with the easier operation of this imaging modality have led to its widespread implementation. The development of digital image processing has also brought other modalities such as ultrasound and computed tomography to the focus of skull base surgery.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Cirurgia Assistida por Computador/instrumentação , Cirurgia Assistida por Computador/métodos , Neoplasias Encefálicas/patologia , Desenho de Equipamento , Análise de Falha de Equipamento , Medicina Baseada em Evidências , Humanos , Monitorização Intraoperatória/instrumentação , Monitorização Intraoperatória/métodos , Avaliação da Tecnologia Biomédica
5.
HNO ; 64(9): 635-40, 2016 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-27566369

RESUMO

Intraoperative navigation systems are widely used in ENT, oral and maxillofacial, and neurosurgery. The benefits of such systems have been demonstrated in various applications, including intracranial and skull base surgery. Intraoperative shift, "brain shift" and changes in anatomy caused by the surgical procedure itself impair the accuracy of navigation and represent factors limiting its application, particularly in glioma and metastatic brain surgery. For this reason, intraoperative imaging was incorporated into neurosurgery. A specific application of navigation is thus skull base surgery, where shifts are often negligible due to the bony structures in which pathologies are embedded. Development of new systems with seamless integration into the operative workflow propagated routine use of navigation in neuro- and ENT surgery. Navigation proved especially helpful in interdisciplinary surgery with pathologies located in anatomic regions where competences of different surgical disciplines overlap, as in the skull base. While this increased radicality in tumour resection, there was a high risk of morbidity. The integration of electrophysiological function monitoring served to preserve function and reduce morbidity, and has led to less invasive and radical strategies in skull base surgery. New radiosurgical methods to adjuvantly treat possible tumour remnants have also supported this development. Systems allowing resection borders to be marked in the navigational coordinates would enable direct linking of these data to radiotherapy planning and better interpretation of follow-up imaging. Navigation is thus a valuable tool supporting interdisciplinary cooperation in skull base surgery for the benefit of patients.


Assuntos
Neuronavegação/métodos , Procedimentos Neurocirúrgicos/métodos , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Neoplasias da Base do Crânio/cirurgia , Base do Crânio/cirurgia , Cirurgia Assistida por Computador/métodos , Medicina Baseada em Evidências , Humanos , Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/diagnóstico por imagem , Resultado do Tratamento
7.
Unfallchirurg ; 115(2): 121-4, 2012 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-22331229

RESUMO

Intraoperative magnetic resonance imaging was established 15 years ago due to special requirements for the resection of cerebral gliomas. Several studies have independently shown an increase of the extent of resection of the tumor and also an improved survival of the patients. Technical innovations combined with an easier operation of this imaging modality led to widespread implementation of this method. The introduction of functional and metabolic imaging opened up new prospects of further improving the therapeutic outcome.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Imageamento por Ressonância Magnética/instrumentação , Neuronavegação/instrumentação , Salas Cirúrgicas , Mapeamento Encefálico/instrumentação , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética/instrumentação , Desenho de Equipamento , Glioma/patologia , Humanos , Interpretação de Imagem Assistida por Computador/instrumentação , Imageamento Tridimensional/instrumentação , Microcirurgia/instrumentação , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia
8.
Acta Neurochir Suppl ; 109: 17-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20960315

RESUMO

Intraoperative magnetic resonance imaging (ioMRI) during neurosurgical procedures was first implemented in 1995. In the following decade ioMRI and image guided surgery has evolved from an experimental stage into a safe and routinely clinically applied technique. The development of ioMRI has led to a variety of differently designed systems which can be basically classified in one- or two-room concepts and low- and high-field installations. Nowadays ioMRI allows neurosurgeons not only to increase the extent of tumor resection and to preserve eloquent areas or white matter tracts but it also provides physiological and biological data of the brain and tumor tissue. This article tries to give a comprehensive review of the milestones in the development of ioMRI and neuronavigation over the last 15 years and describes the personal experience in intraoperative low and high-field MRI.


Assuntos
Processamento de Imagem Assistida por Computador/história , Processamento de Imagem Assistida por Computador/instrumentação , Imageamento por Ressonância Magnética/história , Imageamento por Ressonância Magnética/instrumentação , Monitorização Intraoperatória/métodos , Encéfalo/patologia , Encéfalo/cirurgia , História do Século XX , História do Século XXI , Humanos , Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/tendências , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Monitorização Intraoperatória/instrumentação
9.
Acta Neurochir Suppl ; 109: 107-10, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20960329

RESUMO

OBJECTIVE: Current literature only gives sparse account of aneurysm surgery in an intraoperative MRI environment. After installation of a BrainSuite(®) ioMRI Miyabi 1.5 T at our institution the aim of the present preliminary study was to evaluate feasibility, pros and cons of aneurysm surgery in this special setting. MATERIAL AND METHODS: Since February 2009, during a 3 months period we performed elective image guided aneurysm surgery in 4 ACM and 1 ACOM aneurysm (four patients) in this ioMRI setting. The patients' heads were rigidly fixed in the Noras 8-Channel OR Head Coil. Our imaging protocol included MP-RAGE, T2-TSE axial, TOF-MRA and diffusion-/perfusion-imaging immediately before surgery and after clip application. Presurgical 3D-planning was performed using the iPlan®-Software. RESULTS: All five aneurysms were operated without temporary clipping. There were no intra- or postoperative complications. Patient positioning and head fixation with the integrated Noras Head Clamp was feasible, but there were significant limitations particularly with regard to more complex approaches and patient physiognomy. Image quality especially TOF-MRA was good in 4, insufficient in 1 aneurysm. Presurgical planning especially vessel extraction from TOF-MRA was possible but certainly needs significant future improvement. Diffusion- and perfusion weighted examinations yielded good image quality. CONCLUSION: Our limited experience is encouraging so far. Further improvement particularly concerning flexibility of patient positioning and presurgical 3D-planning for vascular procedures is most necessary. As a future perspective image guided aneurysm surgery in an ioMRI-environment may be helpful especially in complex aneurysms and provide neurosurgeons and neuroanaesthesiologists with additional information about cerebral haemodynamics and perfusion pattern in the vascular territory distal to the target vessel.


Assuntos
Aneurisma/patologia , Angiografia por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/instrumentação , Neuronavegação , Aneurisma/cirurgia , Humanos , Angiografia por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Procedimentos Neurocirúrgicos/instrumentação , Procedimentos Neurocirúrgicos/métodos , Estudos Retrospectivos , Resultado do Tratamento
11.
Oper Orthop Traumatol ; 32(4): 340-358, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32719994

RESUMO

OBJECTIVE: Use of distal femur replacement implants in advanced bone defects after multiple bone-damaging revision surgery on the knee joint. INDICATIONS: Advanced femoral bone defects (AORI IIb and III defects) in revision arthroplasty of the knee joint. CONTRAINDICATIONS: Persistent or current joint infection, general infection, defect and/or nonreconstructable insufficient extensor apparatus. SURGICAL TECHNIQUE: Standard access including existing skin scars, arthrotomy, removal of cement spacer if necessary and removal of multiple tissue samples; preparation of tibia first to define the joint line, then preparation of the femur. Determining the resection height of the remaining femur corresponding to the preoperative planning. Gradual drilling using flexible medullary drills and then preparation by femoral rasps. Two stem systems are available for coupling to the distal femur (MUTARS). First there is the standard MUTARS stem (available lengths of 90, 120 and 160 mm); if longer shafts are required, so-called revision shaft (RS) stems are necessary (stems available in 150, 200 and 250 mm). In case of extensive femoral defects extension sleeves in different lengths can be used to reconstruct the femur. After preparation the implant position and the joint line height is checked. POSTOPERATIVE MANAGEMENT: Full weight bearing, in case of existing bony defects possibly partial load of a maximum of 10 kg für 6 weeks; regular wound control; limitation of the degree of flexion only with weakened or reconstructed extensor apparatus. RESULTS: Between February 2015 and August 2018, a total of 34 distal femurs were implanted. In 19 patients, the implantation was performed after septic and aseptic loosening of a knee prosthesis. All patients had an intraoperative AORI III defect of the femur. Of the 19 patients who underwent a distal femur implantation, 7 had to be revised due to a persistent infection; 4 of these 7 patients had to be revised several times and, finally, had a conversion to a knee arthrodesis. One patient had to undergo a revision with a stem change due to a secondary aseptic loosening of the cemented stem. The mean follow-up period was 11.2 months (range 4-29 months). The follow-up included clinical examination, KSS (Knee Society Score) and X­ray analysis. A significant improvement in range of motion from 65 ± 16° to 83 ± 14° (p < 0.01) was noted. The KSS improved significantly from 69 ± 9 points preoperatively to 115 ± 15 points postoperatively. Four patients complained of persistent symptoms during exercise after 9 months; femoral shaft pain was denied by all patients. After about 11 months, an implant survival rate of 73.7% was observed in the patient collective.


Assuntos
Fêmur , Artroplastia de Quadril , Artroplastia do Joelho , Humanos , Articulação do Joelho , Prótese do Joelho , Reoperação , Resultado do Tratamento
12.
Oper Orthop Traumatol ; 32(4): 309-328, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32728790

RESUMO

OBJECTIVE: Reconstruction of stable knee joint kinematics using modular axis-guided revision implants after failed knee arthroplasty surgery. INDICATIONS: Revision implant for bone defects (type Anderson Orthopaedic Research Institute [AORI] III) in case of revision arthroplasty. Primary implant in case of mediolateral instability (>grade I) or multidirectional instability. CONTRAINDICATIONS: Persistent or current joint infection, general infection (e.g. pneumonia), missing metaphysis femoral and/or tibial, insufficient extensor apparatus. SURGICAL TECHNIQUE: Standard approach extending the previously used skin incision. Arthrotomy, synovectomy and collection of multiple samples for microbiological and histopathological analyses. Preparation of the femur with reamers of increasing diameter. Subsequently, a reference stem is anchored and after referencing the correct rotation and joint line height; the femoral osteotomy is performed after fixation of the 5­in­1 cutting block. Following the femoral osteotomy, the box of the femoral prosthesis is prepared. In addition, the tibia is prepared using an intramedullary reference system. Level of constraint and additional tibial augmentation is chosen according to the amount of defect bone and according to ligament stability. POSTOPERATIVE MANAGEMENT: Full load bearing; standard wound control and sterile dressings; limitation of active/passive range of motion only in case of weakened extensor apparatus. RESULTS: Between 03/2011 and 05/2018, a total of 48 patients underwent revision arthroplasty using the described system. The mean follow-up was 24 months (range 21-35 months). In 30 of the 48 cases, a rotating hinge variant was implanted, while in 18 cases a semiconstrained variant was implanted. Indications to revision arthroplasty: infection (n = 22), aseptic loosening (n = 11), instability (n = 11), periprosthetic fracture (n = 3) and PMMA allergy (n = 1). In 11 cases, revision had to be performed due to persistent infection (n = 6) and aseptic loosening (n = 5): 9 cases could be successful treated by a two-step revision procedure, while in 2 cases it was necessary to perform an arthrodesis. The 2­year implant survival rate was 77%.


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Humanos , Desenho de Prótese , Procedimentos de Cirurgia Plástica , Reoperação , Resultado do Tratamento
13.
Oncotarget ; 8(21): 35124-35137, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28410232

RESUMO

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 µM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.


Assuntos
Trifosfato de Adenosina/farmacologia , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Piperidinas/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinolinas/farmacologia , Canais de Cátion TRPM/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Caspase 3/metabolismo , Caspase 7/metabolismo , Morte Celular , Linhagem Celular Tumoral , Cimenos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Monoterpenos/farmacologia
14.
J Hematol Oncol ; 9(1): 77, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27585656

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. METHODS: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. RESULTS: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. CONCLUSIONS: Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.


Assuntos
Glioblastoma/mortalidade , Adulto , Idoso , Antígenos CD/sangue , Apirase/sangue , Biomarcadores/sangue , Feminino , Glioblastoma/diagnóstico , Humanos , Imunofenotipagem/métodos , Interleucina-10/sangue , Células Matadoras Naturais , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Adulto Jovem
15.
Cell Death Dis ; 7: e2209, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-27124583

RESUMO

Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy.


Assuntos
Neoplasias Encefálicas/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Recidiva Local de Neoplasia/genética , Receptor fas/genética , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Glioblastoma/classificação , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Imunoglobulina G/farmacologia , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Análise de Sobrevida , Temozolomida , Receptor fas/metabolismo , Receptor fas/farmacologia
16.
Am J Cardiol ; 65(2): 74A-81A; discussion 82A-83A, 1990 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-2403737

RESUMO

Key safety parameters of sotalol were examined in 1,288 patients entered into recent controlled trials of ventricular (85% of patients) or supraventricular arrhythmias (15%). Most patients were middle-aged male Caucasians with significant heart disease. The most serious adverse event was proarrhythmia, occurring in 56 patients (4.3%). Of these, 27 had hemodynamic compromise due to malignant ventricular arrhythmias. Most had a history of sustained ventricular tachycardia, myocardial infarction, congestive heart failure (CHF) or cardiomyopathy, or a combination of these. The other 29 had nonsevere events; 38% continued taking sotalol. Proarrhythmia was manifested by torsades de pointes in 24 of the 56 patients. No universal causal relation was found with commonly associated factors such as bradycardia, hypokalemia and long QT interval. The mean QT and QTc at baseline within 1 week of a severe proarrhythmic event were greater than those of patients not having proarrhythmia. Nineteen patients (1%) discontinued therapy with sotalol because of drug-related CHF. Predisposing conditions included low initial baseline ejection fraction, history of CHF, cardiomyopathy or cardiomegaly, or both, male gender and age greater than 65 years. Heart failure usually occurred within 7 to 30 days of initiating therapy. The most common reason for premature discontinuation of the drug in patients treated for sustained ventricular tachycardia was ineffectiveness (39%), whereas adverse effects were the most common reasons among patients treated for complex ventricular ectopy (21%). Dyspnea and bradycardia were the most common cardiovascular effects, and fatigue, dizziness and asthenia the most common noncardiac, adverse effects. Although frequently reported, these adverse effects resulted in discontinuation of only 1 to 4% of the patients at risk.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Sotalol/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Sotalol/uso terapêutico
17.
Am J Clin Pathol ; 114(6): 890-5, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11338478

RESUMO

Samples of Barrett metaplastic specialized epithelium (SE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive adenocarcinoma (CA) derived from 36 esophagectomy specimens were studied for loss of heterozygosity (LOH) in APC and MCC and for expression of APC protein. Of 18 cases that were heterozygous (informative) for APC, LOH was found in none of 14 SE samples, 2 of 8 LGD samples, 3 of 11 HGD samples, and 5 of 17 CA samples. Immunohistochemically, markedly reduced expression of APC protein (< 50% positive cells) was found in 3 of 19 HGD samples and 4 of 35 CA samples but not in SE or LGD samples. Of 17 cases informative for the MCC gene, LOH was detectable in 1 of 14 SE samples, none of 7 LGD samples, none of 9 HGD samples, and 4 of 16 CA samples. Allelic loss of APC and/or loss of APC protein expression occurs earlier in the metaplasia-dysplasia-carcinoma sequence in Barrett esophagus than LOH in the MCC gene. The determination of alterations at APC or MCC would be of limited importance for the surveillance of patients with Barrett esophagus.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Genes APC , Genes MCC , Perda de Heterozigosidade , Lesões Pré-Cancerosas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteína da Polipose Adenomatosa do Colo , Adulto , Idoso , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Proteínas do Citoesqueleto/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaplasia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia
18.
AJNR Am J Neuroradiol ; 20(8): 1547-53, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10512244

RESUMO

BACKGROUND AND PURPOSE: Intraoperative MR imaging is being used increasingly during neurosurgical interventions. The aim of this study was to describe and classify different forms of surgically induced intracranial contrast enhancement observed during intraoperative MR examinations. METHODS: A total of 51 intraoperative MR examinations were performed to assess the extent of brain tumor removal. The intraoperative MR results (T1-weighted images, unenhanced and obtained serially after the IV administration of paramagnetic contrast material) were compared with preoperative and early postoperative MR findings. Animal experiments were conducted to obtain further evidence of the mechanism of surgically induced contrast enhancement. RESULTS: Four different types of surgically induced contrast enhancement were found: meningeal enhancement, increased enhancement of the choroid plexus, delayed enhancement at the resection margins, and immediate intraparenchymal contrast enhancement. The types of surgically induced contrast enhancement differ regarding their location, configuration, and time course. Their potential to be confused with contrast-enhancing, residual tumor also varies. Three of the four types of surgically induced contrast enhancement were reproducible in an animal model. CONCLUSION: Surgically induced contrast enhancement is a potential source of error in intraoperative MR imaging. Careful analysis of the location, configuration, and time course of intraoperatively observed intracranial enhancement is critical to avoid confusing surgically induced contrast enhancement with contrast-enhancing, residual tumor.


Assuntos
Neoplasias Encefálicas/cirurgia , Meios de Contraste , Complicações Intraoperatórias/diagnóstico , Imageamento por Ressonância Magnética , Monitorização Intraoperatória , Animais , Artefatos , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico , Erros de Diagnóstico , Humanos , Masculino , Complicações Pós-Operatórias/diagnóstico , Ratos , Ratos Wistar
19.
AJNR Am J Neuroradiol ; 22(1): 99-102, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11158894

RESUMO

BACKGROUND AND PURPOSE: Intraoperative MR imaging is increasingly being used to control the extent of surgical resection; however, surgical manipulation itself causes intracranial contrast enhancement, which is a source of error. Our purpose was to investigate the potential of monocrystalline iron oxide nanoparticles (MIONs) to solve this problem in an animal model. METHODS: In male Wistar rats, surgical lesions of the brain were produced. The animals underwent MR examination immediately afterward. In the first group, a paramagnetic contrast agent was administered, whereas the second group of animals received MIONs 1 day before surgery. In a third group of animals, malignant glioma cells were stereotactically implanted in the caudoputamen. Two weeks later, MIONs were IV injected and the tumor was (partially) resected. Immediately after resection, MR examination was performed to determine the extent of residual tumor. RESULTS: Surgically induced intracranial contrast enhancement was seen in all animals in which a paramagnetic contrast agent was used. Conversely, when MIONs had been injected, no signal changes that could be confused with residual tumor were detected. In the animals that had undergone (partial) resection of experimental gliomas, MR assessment of residual tumor was possible without any interfering surgically induced phenomena. CONCLUSION: Because MIONs are stored in malignant brain tumor cells longer than they circulate in the blood, their use offers a promising strategy to avoid surgically induced intracranial contrast enhancement, which is known to be a potential source of error in intraoperative MR imaging.


Assuntos
Encefalopatias/cirurgia , Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Ferro , Imageamento por Ressonância Magnética , Monitorização Intraoperatória , Óxidos , Animais , Meios de Contraste/efeitos adversos , Óxido Ferroso-Férrico , Gadolínio DTPA/efeitos adversos , Aumento da Imagem , Masculino , Transplante de Neoplasias , Ratos , Ratos Wistar
20.
AJNR Am J Neuroradiol ; 20(9): 1642-6, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10543634

RESUMO

BACKGROUND AND PURPOSE: MR is being used increasingly as an intraoperative imaging technique. The purpose of this study was to test the hypothesis that intraoperative MR imaging increases the extent of tumor resection, thus improving surgical results in patients with high-grade gliomas. METHODS: Thirty-eight patients with intracranial high-grade gliomas underwent 41 operations. Using a neuronavigation system, tumors were resected in all patients to the point at which the neurosurgeon would have terminated the operation because he thought that all enhancing tumor had been removed. Intraoperative MR imaging (0.2 T) was performed, and surgery, if necessary and feasible, was continued. All patients underwent early postoperative MR imaging (1.5 T). By comparing the proportions of patients in whom complete resection of all enhancing tumor was shown by intraoperative and early postoperative MR imaging, respectively, the impact of intraoperative MR imaging on surgery was determined. RESULTS: Intraoperative MR imaging showed residual enhancing tumor in 22 cases (53.7%). In 15 patients (36.6%), no residual tumor was seen, whereas the results of the remaining four intraoperative MR examinations (9.7%) were inconclusive. In 17 of the 22 cases in which residual tumor was seen, surgery was continued. Early postoperative MR imaging showed residual tumor in eight patients (19.5%) and no residual tumor in 31 cases (75.6%); findings were uncertain in two patients (4.9%). The difference in the proportion of "complete removals" was statistically highly significant (P = .0004). CONCLUSION: Intraoperative MR imaging significantly increases the rate of complete tumor removal. The rate of complete removal of all enhancing tumor parts was only 36.6% when neuronavigation alone was used, which suggests the benefits of intraoperative imaging.


Assuntos
Astrocitoma/cirurgia , Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Imageamento por Ressonância Magnética , Monitorização Intraoperatória , Oligodendroglioma/cirurgia , Adulto , Astrocitoma/diagnóstico , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Neoplasia Residual/cirurgia , Oligodendroglioma/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Reoperação , Sensibilidade e Especificidade
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