RESUMO
Importance: A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown. Objective: To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. Design, Setting, and Participants: The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2- BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016. Main Outcomes and Measures: The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors. Results: Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002). Conclusions and Relevance: In ER+/HER2- postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT00004205.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Letrozol/uso terapêutico , Pós-Menopausa , Receptores de Estrogênio/metabolismo , Tamoxifeno/uso terapêutico , Idoso , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Quinolinas/efeitos adversos , Quinolinas/química , Quinolinas/farmacocinética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
PURPOSE: The aim of this study was to investigate the position of the patella relative to the trochlea for a possible correlation with radiologic parameters characterizing the form of the trochlea. METHODS: The computed tomography scans of 36 cases with patellofemoral instability and 30 without (mean age, 24.7 ± 6.8 years) were studied. The height of the patella relative to the trochlea was evaluated as the distance between the axial slice where the patella (P) showed its widest diameter, as the patella at this level has the greatest potential to form the trochlea, and the proximal entrance of the femoral trochlea (TE). The correlations between this parameter and several radiologic parameters used to evaluate trochlear dysplasia, including trochlea height, transverse trochlea shift, trochlea depth, sulcus angle, lateral and medial trochlea slope, trochlea facet asymmetry, and the Dejour trochlea type, were calculated. RESULTS: The P-TE distance correlated significantly with all trochlea parameters evaluated, with a more dysplastic trochlea in cases of higher position of the patella: medial, central, and lateral trochlea height (0.287 Assuntos
Fêmur/diagnóstico por imagem
, Fêmur/patologia
, Instabilidade Articular/diagnóstico por imagem
, Instabilidade Articular/patologia
, Patela/anatomia & histologia
, Patela/diagnóstico por imagem
, Articulação Patelofemoral/diagnóstico por imagem
, Articulação Patelofemoral/patologia
, Adulto
, Estudos Transversais
, Feminino
, Humanos
, Masculino
, Estudos Retrospectivos
, Tomografia Computadorizada por Raios X
, Adulto Jovem
RESUMO
In this work we demonstrate for the first time the micro- and nanostructuring of graphene by means of UV-nanoimprint lithography. Exfoliated graphene on SiO(2) substrates, as well as graphene deposited by chemical vapor deposition (CVD) on polycrystalline nickel and copper, and transferred CVD graphene on dielectric substrates, were used to demonstrate that our technique is suitable for large-area patterning (2 × 2 cm(2)) of graphene on various types of substrates. The demonstrated fabrication procedure of micrometer as well as nanometer-sized graphene structures with feature sizes down to 20 nm by a wafer-scale process opens up an avenue for the low-cost and high-throughput manufacturing of graphene-based optical and electronic applications. The processed graphene films show electron mobilities of up to 4.6 × 10(3) cm(2) V (-1) s(-1), which confirms them to exhibit state-of-the-art electronic quality with respect to the current literature.
RESUMO
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition. MATERIALS AND METHODS: We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual γH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well. RESULTS: Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of γH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor. CONCLUSIONS: The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.
Assuntos
Imidazóis/farmacologia , Quinolinas/farmacologia , Radiossensibilizantes/farmacologia , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
INTRODUCTION: We assessed expression of p85 and p110α PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines. METHODS: Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor, NVP-BEZ235 alone and with an EGFR inhibitor. RESULTS: p85 and p110α tend to be co-expressed (p<0.001); p85 expression was higher in adenocarcinomas than squamous cell carcinomas. High p85 expression was associated with advanced stage and poor survival. p110α expression correlated with mTOR (ρâ=â0.276). In six NSCLC cell lines, addition of rapamycin to LY294002 or NVP-BKM120 was synergistic. Even very low rapamycin concentrations (1 nM) resulted in sensitization to PI3K inhibitors. NVP-BEZ235 was highly active in NSCLC cell lines with IC(50)s in the nanomolar range and resultant down-regulation of pAKT and pP70S6K. Adding Erlotinib to NVP-BEZ235 resulted in synergistic growth inhibition. CONCLUSIONS: The association between PI3K expression, advanced stage and survival in NSCLC suggests that it might be a valuable drug target. Concurrent inhibition of PI3K and mTOR is synergistic in vitro, and a dual PI3K/mTOR inhibitor was highly active. Adding EGFR inhibition resulted in further growth inhibition. Targeting the PI3K/AKT/mTOR pathway at multiple levels should be tested in clinical trials for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Análise Serial de TecidosRESUMO
The aberrant vascular architecture of solid tumors results in hypoxia that limits the efficacy of radiotherapy. Vascular normalization using antiangiogenic agents has been proposed as a means to improve radiation therapy by enhancing tumor oxygenation, but only short-lived effects for this strategy have been reported so far. Here, we show that NVP-BEZ235, a dual inhibitor of phosphoinositide-3-kinase (PI3K) and mTOR, can improve tumor oxygenation and vascular structure over a prolonged period that achieves the aim of effective vascular normalization. Because PI3K inhibition can radiosensitize tumor cells themselves, our experimental design explicitly distinguished effects on the blood vasculature versus tumor cells. Drug administration coincident with radiation enhanced the delay in tumor growth without changing tumor oxygenation, establishing that radiosensitization is a component of the response. However, the enhanced growth delay was substantially greater after induction of vascular normalization, meaning that this treatment enhanced the tumoral radioresponse. Importantly, changes in vascular morphology persisted throughout the entire course of the experiment. Our findings indicated that targeting the PI3K/mTOR pathway can modulate the tumor microenvironment to induce a prolonged normalization of blood vessels. The substantial therapeutic gain observed after combination of NVP-BEZ235 with irradiation has conceptual implications for cancer therapy and could be of broad translational importance.
Assuntos
Neoplasias Experimentais/radioterapia , Neovascularização Patológica , Inibidores de Fosfoinositídeo-3 Quinase , Tolerância a Radiação , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Neoplasias Experimentais/irrigação sanguínea , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive ß-galactosidase staining, G(2)-M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade.
Assuntos
Senescência Celular/genética , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Nus , Complexos Multiproteicos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , RNA Interferente Pequeno/genética , Serina-Treonina Quinases TOR , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110α PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. METHODS: We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR. RESULTS: p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC(50)s in the low ηM range and resultant PARP cleavage. CONCLUSIONS: High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.
Assuntos
Carcinoma de Células Renais/enzimologia , Neoplasias Renais/enzimologia , Terapia de Alvo Molecular , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Automação , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Sinergismo Farmacológico , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Neoplasias Renais/patologia , Morfolinas/farmacologia , Análise Multivariada , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
PURPOSE: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2. RESULTS: PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P = 0.03). CONCLUSION: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy.
Assuntos
Neoplasias da Mama/genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Logísticos , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , PTEN Fosfo-Hidrolase/metabolismoRESUMO
OBJECTIVE: Facial fracture patients who are conscious with a Glasgow Coma Scale (GCS) score of 15 in the absence of clinical neurological abnormalities are commonly not expected to have suffered severe intracranial pathology. However, high velocity impact may result in intracranial haemorrhage in different compartments. METHODS: Over a 7-year period, 1959 facial fracture patients with GCS scores of 15 and the absence of neurological abnormalities were analysed. In 54 patients (2.8%) computed tomography scans revealed the presence of accompanying intracranial haemorrhage (study group). These patients were compared with the 1905 patients without intracranial haemorrhage (control group). RESULTS: Univariate analysis identified accompanying vomiting/nausea and seizures, cervical spine injuries, cranial vault and basal skull fractures to be significantly associated with intracranial bleeding. In multivariate analysis the risk was increased nearly 25-fold if an episode of vomiting/nausea had occurred. Seizures increased the risk of bleeding more than 15-fold. The mean functional outcome of the study group according to the Glasgow Outcome Scale was 4.7+/-0.7. CONCLUSION: Intracranial haemorrhage cannot be excluded in patients with facial fractures despite a GCS score of 15 and normal findings following neurological examination. Predictors, such as vomiting/nausea or seizures, skull fractures and closed head injuries, enhance the likelihood of an intracranial haemorrhage and have to be considered.
Assuntos
Ossos Faciais/lesões , Hemorragia Intracraniana Traumática/epidemiologia , Fraturas Cranianas/epidemiologia , Acidentes de Trânsito/estatística & dados numéricos , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Traumatismos em Atletas/epidemiologia , Áustria/epidemiologia , Estudos de Casos e Controles , Vértebras Cervicais/lesões , Pré-Escolar , Estado de Consciência , Feminino , Escala de Coma de Glasgow , Traumatismos Cranianos Fechados/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Náusea/epidemiologia , Fraturas Orbitárias/epidemiologia , Fatores de Risco , Convulsões/epidemiologia , Vômito/epidemiologia , Adulto Jovem , Fraturas Zigomáticas/epidemiologiaRESUMO
OBJECTIVE: Pain-free movement and stability of the shoulder joint after restoration of muscular balance between the internal and external rotators. Eradication of anterior impingement. INDICATIONS: Irreparable rupture of the subscapularis tendon in active patients. CONTRAINDICATIONS: Less active patients who are older than about 60 years. Concomitant infraspinatus tendon rupture. Frozen shoulder. Rotator cuff arthropathy. SURGICAL TECHNIQUE: General anesthetic and beach-chair position with the arm freely mobile. Deltopectoral approach. Exposure of the lesser tubercle and the conjoined tendon of coracobrachialis and the short head of the biceps. Half to two thirds of the insertion of pectoralis major at the humeral shaft are detached proximally, held in a suture loop, and passed under the conjoined tendon. The tendon is then fixed transosseously to the lesser tubercle, and range of motion is evaluated. External rotation of up to 30 degrees without tension must be confirmed. POSTOPERATIVE MANAGEMENT: A shoulder strap is worn for 6 weeks and passive physiotherapy is commenced on day 2 postoperatively. External rotation can only be practiced after week 7. RESULTS: 23 patients were available to follow-up. There were 13 cases of anterosuperior defect with irreparable supraspinatus tendon. The preoperative Constant Score of 35 points improved to a postoperative score of 68 points. It was not possible to restore powerful internal rotation. Preoperative impingement syndrome was eradicated.
Assuntos
Instabilidade Articular/cirurgia , Músculos Peitorais/transplante , Lesões do Manguito Rotador , Síndrome de Colisão do Ombro/cirurgia , Traumatismos dos Tendões/cirurgia , Adulto , Feminino , Seguimentos , Humanos , Instabilidade Articular/diagnóstico , Masculino , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/etiologia , Manguito Rotador/cirurgia , Síndrome de Colisão do Ombro/diagnóstico , Traumatismos dos Tendões/diagnósticoRESUMO
Appropriate graft tension and secure graft incorporation in bone tunnels are essential for successful anterior cruciate ligament (ACL) reconstruction using hamstring tendon autografts. Permanent viscoplastic elongation in response to cyclic loading in the early postoperative period and the interposition of suture material in the tendon-bone interface might negatively affect graft function and rigid graft incorporation in the bone tunnels. A modified Prusik knot is an alternative option to the commonly used whipstitch technique for soft tissue fixation in ACL reconstruction. This is a controlled laboratory study. Sixteen formalin-fixed human cadaver semitendinosus tendons were armed with a modified Prusik knot or a whipstitch and tested in a load-to-failure test with a constant displacement rate of 1 mm/s, 14 in the cyclic loading test with 100 cycles from 10 to 50 N followed by 100 cycles from 10 to 75 N. The modified Prusik knot showed smaller force-induced displacements and higher stiffness of the entire construct in the load-to-failure test. Smaller preconditioning displacements were the only significant differences in the cyclic loading test. The modified Prusik knot has equal or superior mechanical properties and provides a larger area in the tendon-bone interface without suture material compared with the whipstitch technique.
Assuntos
Ligamento Cruzado Anterior/cirurgia , Técnicas de Sutura , Transferência Tendinosa/métodos , Fenômenos Biomecânicos , Cadáver , Humanos , Estatísticas não Paramétricas , Estresse Mecânico , Transplante AutólogoRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor. METHODS: Pretreatment serum EGFR levels were quantified by using an enzyme-linked immunoadsorbent assay in a Phase III first-line trial of letrozole and tamoxifen and were correlated with patient outcomes. RESULTS: Serum EGFR levels in a control group of 117 healthy, postmenopausal women measured 64.1 +/- 13.3 ng/mL (mean +/- standard deviation). Using a cutoff EGFR level of 44.1 ng/mL from the control group (5% nonparametric method), 53 of 535 patients (10%) had decreased serum levels of EGFR. Patients with decreased serum EGFR had no significant difference in objective response rate (ORR), clinical benefit rate (CBR), time to progression (TTP), or time to treatment failure (TTF); however, they did have significantly reduced survival compared with patients who had normal serum EGFR levels (median survival, 23.3 months vs. 30.9 months; P = .007). A combined analysis of pretreatment serum EGFR and HER-2 yielded no additional predictive information for ORR, CBR, TTP, or TTF compared to serum HER-2 alone. However, in the current analysis, a subgroup of patients who had decreased serum EGFR and normal serum HER-2 was identified (n = 39 of 535 patients; 7.3%) that had significantly reduced survival compared with patients who had normal serum levels of both EGFR and HER-2 (median survival, 23.5 months vs. 37.1 months; P = .005). In multivariate analysis, a decreased serum EGFR level remained a significant independent prognostic factor for decreased survival (hazards ratio, 1.58; P = .007). CONCLUSIONS: In patients who had metastatic breast cancer, decreased serum EGFR/normal serum HER-2 predicted shorter survival compared with patients who had normal levels of serum EGFR/HER-2. This patient subgroup deserves further study to assess their response to and selection for anti-EGFR-directed therapies.
Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Carcinoma/sangue , Carcinoma/mortalidade , Receptor ErbB-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Método Duplo-Cego , Receptores ErbB/uso terapêutico , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/tratamento farmacológico , Nitrilas/uso terapêutico , Prognóstico , Análise de Sobrevida , Tamoxifeno/uso terapêutico , Triazóis/uso terapêuticoRESUMO
BACKGROUND: Prolonged exposure of breast carcinoma cells in vitro to tamoxifen results in tamoxifen resistance. Tamoxifen-resistant cells express increased HER-2/neu mRNA and protein. The objective of this study was to determine whether patients with metastatic or locally advanced breast carcinoma who have negative serum HER-2/neu status at the initiation of first-line hormone therapy with letrozole or tamoxifen convert to positive serum HER-2/neu status at the time of disease progression and to determine whether serum HER-2/neu conversion to positive status is associated with response to therapy and overall survival. METHODS: Serum samples were obtained at baseline and at the time of disease progression from 240 patients who initially had negative serum HER-2/neu status (< 15 ng/mL). A manual microtiter, enzyme-linked immunosorbent assay that was specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to quantitate serum levels. RESULTS: Among 240 patients, 61 patients (26%) converted from serum HER-2/neu negative to positive (> 15 ng/mL) at the time of disease progression. Thirty-two of 129 patients (25%) who were treated with tamoxifen and 29 of 111 patients (26%) who were treated with letrozole became converted to positive serum HER-2/neu status at the time of disease progression. The response rate and the time to disease progression on first-line hormone therapy were not affected by serum HER-2/neu conversion. The survival of patients who converted to positive serum HER-2/neu status was significantly shorter compared with the survival of patients who remained negative for serum HER-2/neu. A multivariate analysis revealed that conversion to positive serum HER-2/neu status was an independent prognostic variable for survival. CONCLUSIONS: Conversion to positive serum HER-2/neu status occurred in approximately 25% of patients who received first-line hormone therapy. Conversion to serum HER-2/neu-positive status occurred with equal frequency in antiestrogen and aromatase-inhibitor therapy. The current results showed that serum conversion to HER-2/neu-positive status was an independent risk factor for decreased survival in patients with breast carcinoma.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/sangue , Carcinoma/sangue , Nitrilas/uso terapêutico , Receptor ErbB-2/sangue , Tamoxifeno/uso terapêutico , Triazóis/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Progressão da Doença , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Letrozol , Prognóstico , Análise de SobrevidaRESUMO
Exemestane, a non-steroidal aromatase inhibitor that shuts down estrogen synthesis, and paclitaxel, an antineoplastic drug, inhibiting microtubule formation and interfering with the cells potential to proliferate, are well established treatments for metastatic breast cancer. Given that exemestane is a treatment for hormone-sensitive tumors in postmenopausal women with more favorable prognosis, while paclitaxel is normally used for women suffering from hormone-insensitive breast cancers with less favorable prognoses, there is currently no experience with the combination of the two drugs. In order to find out to what extent exemestane and paclitaxel add to each other's effects when given concomitantly, the effect of the two drugs alone and in combination on the growth of various gynecological tumor cell lines was assessed. Tumor cell growth was measured according to the cell titer cell proliferation technique, also referred to as the MTS assay, by measurement of relative cell numbers. In gynecological cancer cells expressing aromatase, the effect of a treatment with paclitaxel (10 nM) on cell growth was enhanced by co-treatment with exemestane. This additive effect was independent of ERalpha expression, but dependent on the presence of androstenedione. It was observed in HEC-1A and Ishikawa endometrial adenocarcinoma cells as well as in SK-OV-3 ovarian cancer and in MDA-MB-231 breast cancer cells. Our findings suggest that a combination of paclitaxel with exemestane might be beneficial for the treatment of aromatase-positive gynecological cancer, because it may allow us to reduce the paclitaxel dosage and therefore the toxicity of the treatment.
Assuntos
Androstadienos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Paclitaxel/farmacologia , Androstadienos/uso terapêutico , Antineoplásicos/uso terapêutico , Aromatase/genética , Inibidores da Aromatase , Neoplasias da Mama , Ensaios de Seleção de Medicamentos Antitumorais , Quimioterapia Combinada , Neoplasias do Endométrio , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Neoplasias Ovarianas , Paclitaxel/uso terapêutico , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: Patients sustaining facial fractures are at risk for accompanying traumatic intracranial hematomas, which are a major cause of morbidity and mortality. Prompt recognition is crucial in improving patient survival and recovery. This study examined which simple clinical signs identify facial fracture patients at risk for intracranial hemorrhage before the performance of computed tomography. DESIGN AND METHODS: Retrospective study of 2,195 patients with facial fractures during a period of 7 years. By means of univariate and multivariate analysis clinical features potentially predictive for (a) intracranial hemorrhage and (b) surgery for intracranial hemorrhage were identified. SETTING: Critical care units of anesthesiology and neurology, general traumatology, and oral and maxillofacial surgery in a level I trauma university hospital. RESULTS: Seizures (OR 22.1) and vomiting/nausea (OR 20.2) were the strongest independent predictors of intracranial bleeding in facial fracture patients. For intracranial hemorrhages requiring surgical intervention closed head injuries (OR 9.75) and cranial vault fractures (OR 5.0) were the most significant risk factors. However, among those patients without vomiting/nausea and without seizures and without closed head injury ( n=1,628), 20 patients (1.2%) suffered intracranial hemorrhage, and six (0.37%) of them required surgical intervention. CONCLUSIONS: Simple clinical symptoms, such as seizures, vomiting/nausea, history of a closed head injury or cranial vault fractures are strong predictors for intracranial hemorrhage in facial fracture patients. The early consideration of such important indicators allows us to detect patients at elevated risk of an intracranial hematoma requiring surgical intervention.
Assuntos
Ossos Faciais/lesões , Fraturas Ósseas/complicações , Hemorragia Intracraniana Traumática/etiologia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour-suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1-associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1-unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms. PATIENTS AND MEASUREMENTS: We screened MEN1 coding regions and flanking intronic sequences of 136 sporadic pituitary adenomas by temporal temperature gradient gel electrophoresis (TTGE) and studied menin expression by immunoblotting in 11 of these tumours. RESULTS: Sequencing of DNAs showing aberrant migration on TTGE revealed five somatic MEN1 mutations, including two missense mutations (F134L, E530K), a 2-bp deletion in exon 10 (c.1567-1568del) leading to a premature stop codon, and two 3-bp deletions in intron 5 (g.5236-5238del, g.5237-5239del). These mutations have not been reported previously in studies analysing the MEN1 gene. Immunoblotting showed menin upregulation in all adenomas examined (including one case with a missense mutation) from 1.7-fold to 10.4-fold (mean, 4.2-fold) compared to non-neoplastic adenohypophysis. CONCLUSIONS: Our data suggest that neither MEN1 mutations nor menin downregulation play a significant role in the development of sporadic pituitary adenomas.