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1.
Nat Biotechnol ; 38(5): 563-572, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341561

RESUMO

Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. However, the use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dollars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. A consortium of biotech companies, together with the Massachusetts Institute of Technology, has convened to collect data on these events. This industry-wide study provides insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. These results have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise.


Assuntos
Produtos Biológicos/normas , Coleta de Dados/métodos , Contaminação de Medicamentos/prevenção & controle , Vírus/isolamento & purificação , Técnicas de Cultura de Células , Indústria Farmacêutica , Humanos , Disseminação de Informação , Massachusetts
2.
Visc Med ; 33(4): 295-300, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29034258

RESUMO

Due to the current geopolitical situation more refugees from crisis countries were and will be treated in Europe. In 2015 the number of displaced people reached an unprecedented level, with more than one million crossing into Europe. The migration itself can impair both mental and physical health. Therefore, the provision of medical care for refugees and migrants is a novel and major challenge for the health care systems in Europe. In this article we describe our experiences and contribution in providing medical care for refugees who have newly arrived in Stuttgart, Baden-Wuerttemberg, Germany. Furthermore, we report our experiences from a tertiary referral University center in Regensburg, Bavaria, Germany. We focus on challenges in both the outpatient and the inpatient setting, with a special focus on intensive care patients. In addition, we provide an overview about the spectrum of diseases in this specific patient cohort.

3.
Radiother Oncol ; 108(2): 279-86, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23830467

RESUMO

PURPOSE: Linac-based intraoperative radiotherapy with electrons (IOERT) was implemented to prevent local recurrences after breast conserving therapy (BCT) and was delivered as an intraoperative boost to the tumor bed prior to whole breast radiotherapy (WBI). A collaborative analysis has been performed by European ISIORT member institutions for long term evaluation of this strategy. MATERIAL AND METHODS: Until 10/2005, 1109 unselected patients of any risk group have been identified among seven centers using identical methods, sequencing and dosage for intra- and postoperative radiotherapy. A median IOERT dose of 10 Gy was applied (90% reference isodose), preceding WBI with 50-54 Gy (single doses 1.7-2 Gy). RESULTS: At a median follow up of 72.4 months (0.8-239), only 16 in-breast recurrences were observed, yielding a local tumor control rate of 99.2%. Relapses occurred 12.5-151 months after primary treatment. In multivariate analysis only grade 3 reached significance (p=0.031) to be predictive for local recurrence development. Taking into account patient age, annual in-breast recurrence rates amounted 0.64%, 0.34%, 0.21% and 0.16% in patients <40 years; 40-49 years; 50-59 years and ≥ 60 years, respectively. CONCLUSION: In all risk subgroups, a 10 Gy IOERT boost prior to WBI provided outstanding local control rates, comparing favourably to all trials with similar length of follow up.


Assuntos
Braquiterapia/métodos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Cuidados Intraoperatórios/métodos , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Fatores Etários , Idoso , Análise de Variância , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Intervalo Livre de Doença , Elétrons/uso terapêutico , Feminino , Seguimentos , Humanos , Mastectomia Segmentar/métodos , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Cuidados Pós-Operatórios/métodos , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/efeitos da radiação
4.
Lancet Oncol ; 12(7): 631-41, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21641868

RESUMO

BACKGROUND: Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. METHODS: ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. FINDINGS: At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). INTERPRETATION: Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. FUNDING: AstraZeneca; Novartis.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Adulto , Anastrozol , Antineoplásicos Hormonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitrilas/uso terapêutico , Pré-Menopausa , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêutico , Ácido Zoledrônico
6.
Ann Surg Oncol ; 17 Suppl 3: 286-90, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20853048

RESUMO

BACKGROUND: Sentinel lymph node biopsy (SLNB) without axillary lymph node dissection (ALND) in SLN negative patients is a standard of care for most breast cancer patients. SLNB for axillary staging after primary systemic therapy (PST) is still under discussion because of possibly reduced accuracy, while data are lacking. The purpose of this study was to evaluate the accuracy of SLNB after PST. MATERIALS AND METHODS: A total of 185 breast cancer patients were treated with PST; 160 patients received preoperative chemotherapy, and 25 patients received preoperative endocrine therapy. Thus, 143 of 160 patients with preoperative chemotherapy and 22 of 25 patients with preoperative endocrine therapy were eligible for evaluation. The combination of blue dye and radioactive tracer was used for identification of SLNs. All patients received SLNB and axillary lymph node dissection (ALND). Pathologic assessment of SLNs was performed and compared to non-SLN status. RESULTS: Pathologic complete response rates and breast conserving therapy rates were 15.4 and 78.3% in the preoperative chemotherapy group and 0 and 77.3% in the preoperative endocrine therapy group, respectively. Identification rate, sensitivity, overall accuracy, and false-negative rate were 81.1% (116 of 143), 91.7% (55 of 60), 95.7% (111 of 116), and 8.3% (5 of 60) in the preoperative chemotherapy group and 77.3% (17 of 22), 90.0% (9 of 10), 94.1% (16 of 17), and 10.0% (1 of 10) in the preoperative endocrine therapy group, respectively. DISCUSSION: SLNB after primary systemic therapy is accurate, and the results are comparable to those of primary SLNB. SLNB after PST could spare ALND in up to 40% of patients with primary positive axillary lymph nodes and should be considered as a standard for axillary staging in those patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linfonodos/patologia , Biópsia de Linfonodo Sentinela , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/secundário , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/secundário , Carcinoma Lobular/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Mastectomia , Estadiamento de Neoplasias , Prognóstico , Sensibilidade e Especificidade
7.
MAbs ; 2(1): 73-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20081378

RESUMO

Assembly of immunoglobulin G (IgG) molecules from two heavy and two light chains can be facilitated by connecting the light chain to the heavy chain by an oligopeptide linker. Production of the anti-lysozyme D1.3-single chain (sc) IgG1 in HEK293T cells yielded up to 8 mg/L functional scIgG polypeptide. Size exclusion chromatography of material purified by protein-A affinity chromatography revealed that the majority of the D1.3-scIgG1 molecules were 150 kDa monomers, with a K(D) of 1.8 x 10(-10) M measured by surface plasmon resonance; however, significant fractions of scIgG dimers and oligomers with molecular masses of 300 kDa and >600 kDa, respectively, were identified. The oligomerization resulted in an increased avidity. The observed oligomerization capability may allow new approaches for the generation of bispecific/multivalent antibodies.


Assuntos
Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Cadeia Única/metabolismo , Animais , Afinidade de Anticorpos , Linhagem Celular , Cromatografia de Afinidade , Humanos , Camundongos , Muramidase/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Engenharia de Proteínas , Multimerização Proteica , Receptores de IgG/genética , Receptores de IgG/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Ressonância de Plasmônio de Superfície
8.
N Engl J Med ; 360(7): 679-91, 2009 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-19213681

RESUMO

BACKGROUND: Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. METHODS: We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. RESULTS: After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. CONCLUSIONS: The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Gosserrelina/uso terapêutico , Imidazóis/uso terapêutico , Pré-Menopausa , Adulto , Anastrozol , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Difosfonatos/efeitos adversos , Intervalo Livre de Doença , Quimioterapia Combinada , Antagonistas de Estrogênios/efeitos adversos , Antagonistas de Estrogênios/uso terapêutico , Feminino , Seguimentos , Humanos , Imidazóis/efeitos adversos , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Receptores de Estrogênio/análise , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Ácido Zoledrônico
9.
Circulation ; 118(14): 1425-32, 2008 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-18794392

RESUMO

BACKGROUND: Clinical trials indicate a beneficial effect of intracoronary infusion of progenitor cells on myocardial function in patients with ischemic heart disease. The extent and potential determinants of proangiogenic progenitor cell homing into the damaged myocardium after intracoronary infusion and the underlying mechanisms are still unknown. METHOD AND RESULTS: Circulating proangiogenic progenitor cells isolated from peripheral blood and cultivated for 3 days were labeled with radioactive indium oxine ((111)In-oxine). Radiolabeled proangiogenic progenitor cells (7.6+/-3.0 MBq, mean+/-SD) were administered to patients with previous myocardial infarction and a revascularized infarct vessel at various stages after infarction (5 days to 17 years). Viability of the infarcted myocardium was determined by (18)F-fluorodeoxyglucose-positron emission tomography and microcirculatory function by intracoronary Doppler measurements. One hour after application of progenitor cells, a mean of 6.9+/-4.7% (range, 1% to 19%; n=17) of total radioactivity was detected in the heart, which declined to 2+/-1% after 3 to 4 days. Average activity within the first 24 hours was highest among patients with acute myocardial infarction (14 days to 1 year; 4.5+/-3.2%; n=4) or a chronic stage (infarct age >1 year; 2.5+/-1.6%; n=5). Low viability of the infarcted myocardium and reduced coronary flow reserve were significant (P<0.05) predictors of proangiogenic progenitor cell homing. CONCLUSIONS: In patients after myocardial infarction undergoing intracoronary infusion of (111)In-oxine-labeled proangiogenic progenitor cells, a substantial amount of radioactivity is detected for several days in the heart, indicating homing of progenitor cells to the myocardium. The amount of proangiogenic progenitor cells retained in the heart decreased progressively with time after the acute myocardial infarction. Proangiogenic progenitor cells preferentially home to extensive acute myocardial infarcts characterized by low viability and reduced coronary flow reserve.


Assuntos
Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Miocárdio/citologia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Adolescente , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Projetos Piloto , Células-Tronco/metabolismo
10.
Lancet Oncol ; 9(9): 840-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18718815

RESUMO

BACKGROUND: The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. METHODS: ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. FINDINGS: 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. INTERPRETATION: Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Doenças Ósseas Metabólicas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Osteoporose/prevenção & controle , Adulto , Anastrozol , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Difosfonatos/farmacologia , Feminino , Gosserrelina/administração & dosagem , Humanos , Imidazóis/farmacologia , Modelos Lineares , Nitrilas/administração & dosagem , Osteoporose/induzido quimicamente , Pré-Menopausa , Estudos Prospectivos , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem , Ácido Zoledrônico
11.
Breast J ; 14(4): 324-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18540955

RESUMO

The current study examined predictors of mastectomy in a certified breast center with the main impact on the factor surgeon. A total of 663 patients were analyzed for their mastectomy rates. Included were patients with T1 and T2 tumors, who had their surgery performed by one of three specialized breast surgeons with a workload of at least 50 new breast cancer cases per year. On multivariate analysis central tumor localization, positive lymph node status, nonunifocality, large tumor size, and the surgeon were independent predictors of mastectomy. Surgeon A had a mastectomy rate of 30.5% (50/164), surgeon B 26.9% (43/160) respectively, and surgeon C had a mastectomy rate of 15.8% (27/171), p = 0.005. Patients, who had surgery performed by surgeon A or surgeon B were 2.34 [95% confidence interval (CI): 1.38-3.97, p < 0.005] respectively 1.96 (95% CI: 1.14-3.36, p = 0.01) times as likely to have a mastectomy than patients who had surgery performed by surgeon C. Even in a certified breast center with specialized breast surgeons the surgeon is an independent risk factor of mastectomy, as the tumor criteria are given at the time of diagnosis.


Assuntos
Neoplasias da Mama/cirurgia , Comportamento de Escolha , Mastectomia Segmentar/estatística & dados numéricos , Mastectomia/estatística & dados numéricos , Idoso , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Tomada de Decisões , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
12.
Breast Cancer ; 15(1): 40-6, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18224393

RESUMO

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.


Assuntos
Neoplasias da Mama/radioterapia , Radioterapia/métodos , Neoplasias da Mama/cirurgia , Feminino , Humanos , Cuidados Intraoperatórios , Mastectomia
13.
Blood ; 111(7): 3830-7, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18230757

RESUMO

Targeted RNases (TRs) are immunoenzymes with ribonucleases as cytotoxic effector domains, which are less immunogenic as plant or bacterial toxin components of classical immunotoxins. In this study, we show the generation and production of the first entirely human TR (huTR) directed against CD30+ lymphomas. The scFv-Fc-RNase construct was produced in human embryonic kidney (HEK) 293T cells, yielding up to 4 mg/L soluble protein after purification by protein A affinity chromatography. Size exclusion chromatography revealed a homodimer of the predicted molecular mass. Surface plasmon resonance analysis revealed an affinity to CD30 of KD of less than 1 nM for both the scFv-Fc and the scFv-Fc-RNase proteins. Internalization of the scFv-Fc-RNase protein by CD30+ Karpas-299 cells was demonstrated by confocal microscopy. Proliferation of the CD30+ lymphoma cell line Karpas-299 was strongly inhibited by CD30-specific huTR protein (IC50=3.3 nM). The huTR is a promising candidate for the immunotherapy of CD30+ lymphomas because of its expected low immunogenicity, good production yields, and potent effector function upon target cell binding and internalization. Its modular design is set to target other internalizing tumor antigens using different antibody domains.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias , Proliferação de Células/efeitos dos fármacos , Imunotoxinas/farmacologia , Antígeno Ki-1/antagonistas & inibidores , Linfoma/tratamento farmacológico , Ribonucleases/farmacologia , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Humanos , Regiões Constantes de Imunoglobulina/genética , Regiões Constantes de Imunoglobulina/farmacologia , Regiões Constantes de Imunoglobulina/uso terapêutico , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/farmacologia , Região Variável de Imunoglobulina/uso terapêutico , Imunotoxinas/genética , Imunotoxinas/uso terapêutico , Linfoma/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Ribonucleases/genética , Ribonucleases/uso terapêutico
14.
Breast Cancer Res Treat ; 112(1): 203-13, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18158620

RESUMO

BACKGROUND: A multicenter phase II study was conducted to analyze the clinical activity of the steroidal aromatase inhibitor exemestane in the neoadjuvant treatment of post-menopausal women with strongly ER- and/or PgR- positive operable breast cancer. PATIENTS AND METHODS: From September 2000 to December 2003, 80 women were recruited for treatment with exemestane 25 mg once daily for 4 months. The primary end-point was the clinical response rate according the WHO criteria; the secondary end-points included toxicity and the number of patients who qualified for breast conserving surgery at the end of treatment, comparability of evaluation methods for response, potential alterations of hormone receptor and Her2/neu status during treatment. RESULTS: On an intention to evaluate analysis, according to the prespecified criteria the overall clinical objective response rate was 34%, the pCR rate was 3% and the rate of breast conserving surgery was 76%. When sonographic and mammographic longitudinal measurements were included in patients with missing palpation data, response rates were 38% and 41%, respectively. The tumor response was independent of the Her2/neu status which remained unchanged during treatment. In contrast, while the ER expression remained unaltered, downregulation of the PgR was observed. The treatment was well tolerated with no grade 3 and 4 toxicities except gastrointestinal (one grade 3 case) and hot flushes (two grade 3 cases). CONCLUSION: This study shows that exemestane is effective and safe as a preoperative therapy in post-menopausal patients with strongly hormone receptor-positive breast cancer.


Assuntos
Androstadienos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Prognóstico
15.
J Clin Oncol ; 25(15): 2012-8, 2007 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-17513805

RESUMO

PURPOSE: Preoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate. PATIENTS AND METHODS: Patients with biopsy-proven breast cancer (T1-4a-c, N+/-, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery. RESULTS: A total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment. CONCLUSION: Doubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Axila/patologia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/secundário , Quimioterapia Adjuvante , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Prospectivos , Taxoides/administração & dosagem
16.
BMC Biotechnol ; 7: 14, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17346344

RESUMO

BACKGROUND: The connection of the variable part of the heavy chain (VH) and and the variable part of the light chain (VL) by a peptide linker to form a consecutive polypeptide chain (single chain antibody, scFv) was a breakthrough for the functional production of antibody fragments in Escherichia coli. Being double the size of fragment variable (Fv) fragments and requiring assembly of two independent polypeptide chains, functional Fab fragments are usually produced with significantly lower yields in E. coli. An antibody design combining stability and assay compatibility of the fragment antigen binding (Fab) with high level bacterial expression of single chain Fv fragments would be desirable. The desired antibody fragment should be both suitable for expression as soluble antibody in E. coli and antibody phage display. RESULTS: Here, we demonstrate that the introduction of a polypeptide linker between the fragment difficult (Fd) and the light chain (LC), resulting in the formation of a single chain Fab fragment (scFab), can lead to improved production of functional molecules. We tested the impact of various linker designs and modifications of the constant regions on both phage display efficiency and the yield of soluble antibody fragments. A scFab variant without cysteins (scFabDeltaC) connecting the constant part 1 of the heavy chain (CH1) and the constant part of the light chain (CL) were best suited for phage display and production of soluble antibody fragments. Beside the expression system E. coli, the new antibody format was also expressed in Pichia pastoris. Monovalent and divalent fragments (DiFabodies) as well as multimers were characterised. CONCLUSION: A new antibody design offers the generation of bivalent Fab derivates for antibody phage display and production of soluble antibody fragments. This antibody format is of particular value for high throughput proteome binder generation projects, due to the avidity effect and the possible use of common standard sera for detection.


Assuntos
Fragmentos Fab das Imunoglobulinas/biossíntese , Fragmentos Fab das Imunoglobulinas/química , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Antígenos/imunologia , Sequência de Bases , Sítios de Ligação de Anticorpos/imunologia , Cromatografia em Gel , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Escherichia coli/genética , Expressão Gênica , Vetores Genéticos/genética , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/imunologia , Camundongos , Dados de Sequência Molecular , Biblioteca de Peptídeos , Pichia/genética , Solubilidade
18.
J Immunol Methods ; 318(1-2): 113-24, 2007 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-17161420

RESUMO

Monoclonal antibodies (Mab) are the fastest growing group of biopharmaceuticals in development. For production in mammalian cells, the four polypeptide chains of the immunoglobulin diheterotetramer must be assembled prior to exit from the endoplasmic reticulum. Various recombinant Mab expression vectors have been developed utilizing mono-and bicistronic expression cassettes encoded on one or two plasmids. However, there are only few studies providing information on the type of vector design optimal for stable or transient production of recombinant IgG. Consequently, in this study, we have constructed a series of mammalian expression vectors for the production of recombinant human or chimeric IgG antibodies with different expression cassette designs. Versions for monocistronic and bicistronic expression with different promoters and cistron arrangements were generated. Antibody production levels were evaluated in transiently transfected 293T and CHO-K1 cells. Furthermore, stable CHO cell lines were generated and analyzed for antibody production levels and stability. Our results indicate that compared to monocistronic expression, EMCV IRES-mediated bicistronic expression constructs yield similar antibody expression levels and show long-term stability in CHO cell lines. Addition of a third cistron encoding YFP was shown to facilitate screening and isolation of clones using a FACS sorter.


Assuntos
Anticorpos Monoclonais/biossíntese , Vetores Genéticos/genética , Imunoglobulina G/biossíntese , Proteínas Recombinantes/biossíntese , Regiões 5' não Traduzidas/genética , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Citomegalovirus/genética , Eletroforese em Gel de Poliacrilamida , Vírus da Encefalomiocardite/genética , Citometria de Fluxo , Expressão Gênica , Genes Reporter/genética , Humanos , Imunoglobulina G/química , Imunoglobulina G/genética , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/biossíntese , Cadeias Leves de Imunoglobulina/química , Cadeias Leves de Imunoglobulina/genética , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Camundongos , Peso Molecular , Fator 1 de Elongação de Peptídeos/genética , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Transfecção
19.
J Clin Oncol ; 25(7): 820-8, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17159195

RESUMO

PURPOSE: Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients. PATIENTS AND METHODS: This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) +/- zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin +/- zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months. RESULTS: Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, -14.4% after 36 months; mean T score reduction, -1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, -17.3%; mean T score reduction, -2.6) compared with patients receiving tamoxifen/goserelin (BMD, -11.6%; mean T score reduction, -1.1). In contrast, BMD remained stable in zoledronic acid-treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted. CONCLUSION: Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.


Assuntos
Antineoplásicos/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Gosserrelina/efeitos adversos , Imidazóis/uso terapêutico , Nitrilas/efeitos adversos , Osteoporose Pós-Menopausa/prevenção & controle , Tamoxifeno/efeitos adversos , Triazóis/efeitos adversos , Adulto , Anastrozol , Densidade Óssea/efeitos dos fármacos , Difosfonatos/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Pessoa de Meia-Idade , Ácido Zoledrônico
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