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The formation of stars and planets is accompanied not only by the build-up of matter, namely accretion, but also by its expulsion in the form of highly supersonic jets that can stretch for several parsecs1,2. As accretion and jet activity are correlated and because young stars acquire most of their mass rapidly early on, the most powerful jets are associated with the youngest protostars3. This period, however, coincides with the time when the protostar and its surroundings are hidden behind many magnitudes of visual extinction. Millimetre interferometers can probe this stage but only for the coolest components3. No information is provided on the hottest (greater than 1,000 K) constituents of the jet, that is, the atomic, ionized and high-temperature molecular gases that are thought to make up the jet's backbone. Detecting such a spine relies on observing in the infrared that can penetrate through the shroud of dust. Here we report near-infrared observations of Herbig-Haro 211 from the James Webb Space Telescope, an outflow from an analogue of our Sun when it was, at most, a few times 104 years old. These observations reveal copious emission from hot molecules, explaining the origin of the 'green fuzzies'4-7 discovered nearly two decades ago by the Spitzer Space Telescope8. This outflow is found to be propagating slowly in comparison to its more evolved counterparts and, surprisingly, almost no trace of atomic or ionized emission is seen, suggesting its spine is almost purely molecular.
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Early results from the James Webb Space Telescope-Mid-InfraRed Instrument (JWST-MIRI) guaranteed time programs on protostars (JOYS) and disks (MINDS) are presented. Thanks to the increased sensitivity, spectral and spatial resolution of the MIRI spectrometer, the chemical inventory of the planet-forming zones in disks can be investigated with unprecedented detail across stellar mass range and age. Here, data are presented for five disks, four around low-mass stars and one around a very young high-mass star. The mid-infrared spectra show some similarities but also significant diversity: some sources are rich in CO2, others in H2O or C2H2. In one disk around a very low-mass star, booming C2H2 emission provides evidence for a "soot" line at which carbon grains are eroded and sublimated, leading to a rich hydrocarbon chemistry in which even di-acetylene (C4H2) and benzene (C6H6) are detected. Together the data point to an active inner disk gas-phase chemistry that is closely linked to the physical structure (temperature, snowlines, presence of cavities and dust traps) of the entire disk and which may result in varying CO2/H2O abundances and high C/O ratios >1 in some cases. Ultimately, this diversity in disk chemistry will also be reflected in the diversity of the chemical composition of exoplanets.
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OBJECTIVE: To study previously identified associations between specific maternal hypertensive disorders and/or prenatal exposure to antihypertensive medication and birth defects. DESIGN: Case-control study. SETTING: Slone Birth Defects Study, 1998-2010. POPULATION: A total of 5568 cases with birth defects and 7253 liveborn infants without malformations as controls. METHODS: Adjusted odds ratios (aORs) for birth defects associated with prenatal exposure to maternal hypertensive disorders and/or antihypertensive medication were calculated using multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Specific birth defects previously linked to maternal hypertension or antihypertensive medication use during pregnancy. RESULTS: Non-pharmacologically managed chronic hypertension was associated with a three-fold risk of oesophageal atresia (95% CI 1.2-8.3), and pre-eclampsia superimposed on non-pharmacologically managed chronic hypertension was associated with ventricular septal defects (aOR 3.9, 95% CI 1.3-11.7) and atrial septal defects (aOR 6.5, 95% CI 1.8-23.7). For chronic hypertension that was pharmacologically treated early in pregnancy, increased risks were observed for first-degree hypospadias (aOR 2.9, 95% CI 1.1-7.4). Non-pharmacologically managed pre-eclampsia was related to second-/third-degree hypospadias and ventricular septal defects. Pharmacological treatment for gestational hypertension was associated with a number of congenital heart defects. CONCLUSIONS: Our results confirm some, but not all, previously identified associations between pharmacologically treated and non-pharmacologically managed hypertensive disorders and specific birth defects. They support the hypothesis that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias.
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Anormalidades Induzidas por Medicamentos/etiologia , Anti-Hipertensivos/efeitos adversos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. METHODS: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. RESULTS: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. CONCLUSIONS: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Mutação/genéticaRESUMO
BACKGROUND: Metastatic breast cancer (MBC) is a highly heterogeneous disease with great differences in outcome to both chemo- and endocrine therapy. Better insight into the mechanisms underlying resistance is essential to better predict outcome to therapy and to obtain a more tailored treatment approach. We have previously described that increased mRNA expression levels of Enhancer of Zeste homolog (EZH2) are associated with worse outcome to tamoxifen therapy in MBC. Here, we explored whether this is also the case for EZH2 protein expression. PATIENTS AND METHODS: A tissue microarray (TMA) was created using formalin-fixed, paraffin-embedded estrogen receptor (ER)-positive primary breast tumor tissues of 250 MBC patients treated with first-line tamoxifen. Quantity and intensity of EZH2 expression were determined by immunohistochemistry (IHC) and both were used to generate and group scores according to a previously described method for scoring EZH2. RESULTS: In total, 116 tumors (46%) were considered to be EZH2 positive. The presence of EZH2 protein expression was significantly associated with progression-free survival (PFS) in both univariate [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.17-1.97, P = 0.002] and multivariate analysis including traditional factors associated with tamoxifen outcome (HR 1.41, 95% CI 1.06-1.88, P = 0.017). Considering quantity irrespective of intensity, tumors with >50% EZH2-positive cells had the worst PFS (HR 2.15, 95% CI 1.42-3.27, P < 0.001), whereas intensity alone did not show a significant association with PFS. Application of other methods of scoring EZH2 positivity resulted in a similar significant association between the amount of EZH2 positive cells and PFS. CONCLUSION: In addition to EZH2 mRNA levels, these results suggest that protein expression of EZH2 can be used as a marker to predict outcome to tamoxifen therapy. This provides new rationale to explore EZH2 inhibition in the clinical setting and increases the possibilities for a more personalized treatment approach in MBC patients.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Complexo Repressor Polycomb 2/biossíntese , Tamoxifeno/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Complexo Repressor Polycomb 2/genética , Medicina de Precisão , Prognóstico , RNA Mensageiro/biossíntese , Tamoxifeno/efeitos adversos , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
BACKGROUND: The human parainfluenza virus 3 (HPIV-3) outbreak at the haemato-oncology ward of the Maastricht University Medical Centre in the summer of 2016. AIM: To describe an effective strategy to control the largest reported HPIV-3 outbreak at an adult haematology-oncology ward in the Netherlands by implementing infection control measures and molecular epidemiology investigation. METHODS: Clinical, patient and diagnostic data were both pro- and retrospectively collected. HPIV-3 real-time polymerase chain reaction (HPIV-3 RT-PCR) was validated using oropharyngeal rinse samples. Screening of all new and admitted patients was implemented to identify asymptomatic infection or prolonged shedding of HPIV-3 allowing cohort isolation. FINDINGS: The HPIV-3 outbreak occurred between 9 July and 28 September 2016 and affected 53 patients. HPIV-3 RT-PCR on oropharyngeal rinse samples demonstrated an up to 10-fold higher sensitivity compared with pharyngeal swabs. Monitoring showed that at first positive PCR, 20 patients (38%) were asymptomatic (of which 11 remained asymptomatic) and the average duration of shedding was 14 days (range 1-58). Asymptomatic patients had lower viral load, shorter period of viral shedding (≤14 days) and were mostly immune-competent oncology patients. The outbreak was under control five weeks after implementation of screening of asymptomatic patients. CONCLUSION: Implementation of a sensitive screening method identified both symptomatic and asymptomatic patients which had lower viral loads and allowed early cohort isolation. This is especially important in a ward that combines patients with varying immune status, because both immunocompromised and immune-competent patients are likely to spread the HPIV-3 virus, either through prolonged shedding or through asymptomatic course of disease.
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Hematologia , Infecções por Paramyxoviridae , Adulto , Surtos de Doenças , Humanos , Vírus da Parainfluenza 3 Humana/genética , Infecções por Paramyxoviridae/diagnóstico , Infecções por Paramyxoviridae/epidemiologia , Patologia Molecular , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
The purpose of this study is to investigate EZH2 in a large series of breast cancer patients for its prognostic and predictive value, and to evaluate its functional role in treatment response in vitro. EZH2 levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens and related to clinicopathologic factors and disease outcome. EZH2 expression was downregulated with siRNAs in MCF7, to assess expression alterations of putative EZH2 downstream genes and to determine cell numbers after treatment with the anti-estrogen ICI 164384. In 688 lymph node-negative patients who did not receive adjuvant systemic therapy, EZH2 was not significantly correlated with metastasis-free survival (MFS). In 278 patients with advanced disease treated with first-line tamoxifen monotherapy, the tertile with highest EZH2 levels was associated with the lowest clinical benefit (OR = 0.48; P = 0.02) and with a shorter progression-free survival (PFS) in both univariate (HR = 1.80; P < 0.001) and multivariate analysis, including traditional factors (HR = 1.61; P = 0.004). In vitro, EZH2 silencing in MCF7 caused a 38% decrease in cell numbers (P < 0.001) whereas ICI 164384 treatment resulted in a 25% decrease (P < 0.001) compared to controls. Combining EZH2 silencing with ICI treatment reduced cell numbers with 67% (P < 0.001) compared to control conditions. EZH2 downregulation was associated with an almost two-fold upregulation of the estrogen receptor alpha (ER) (P = 0.001). In conclusion, EZH2 has no prognostic value in breast cancer. High levels of EZH2 are associated with poor outcome to tamoxifen therapy in advanced breast cancer. Downregulated EZH2 leads to upregulation of the ER and better response to anti-estrogens.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Receptor alfa de Estrogênio/genética , Tamoxifeno/uso terapêutico , Fatores de Transcrição/genética , Antineoplásicos Hormonais/farmacologia , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Estradiol/análogos & derivados , Estradiol/farmacologia , Estradiol/uso terapêutico , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Feminino , Imunofluorescência , Inativação Gênica , Humanos , Metástase Neoplásica , Complexo Repressor Polycomb 2 , Reação em Cadeia da Polimerase , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/uso terapêutico , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno , Tamoxifeno/farmacologia , Fatores de Transcrição/metabolismo , Resultado do TratamentoRESUMO
Hemodialysis mainly removes small water-soluble uremic toxins but cannot effectively remove middle molecules and protein-bound uremic toxins. Besides, the therapy is intermittent leading to fluctuating blood values and fluid status which adversely impacts patients' health. Prolonged hemodialysis (with adequate anticoagulation) could improve the removal of toxins and the development of portable and wearable artificial kidneys could offer more flexibility in the dialysis scheme. This would enhance patients' overall health, autonomy, mobility and flexibility, allowing patients to participate in social and economic life. However, the time that patients' blood is exposed to the dialyzer material is longer during prolonged hemodialysis, and blood clots could obstruct the fiber lumen, resulting in a decrease of the effective membrane surface area available for toxin removal. The outside-in filtration (OIF) mode, wherein blood flows through the inter-fiber space instead of through the fiber lumina, has been applied widely in blood oxygenators to prevent fiber clotting, but not in hemodialysis. In this study, we present for the first time the development of a mixed matrix membrane (MMM) for OIF of human blood plasma. This MMM combines diffusion and adsorption and consists of a polymeric membrane matrix with activated carbon (AC) particles on the inside layer, and a polymeric particle-free layer on the outer fiber layer. Our results show that in vitro MMM fibers for OIF demonstrate superior removal of the protein-bound uremic toxins, indoxyl sulfate and hippuric acid, compared to both earlier MMM fibers designed for inside-out filtration mode and commercial high-flux fibers. STATEMENT OF SIGNIFICANCE: Current hemodialysis therapy cannot effectively remove protein-bound toxins. Prolonged hemodialysis could improve toxin removal. However, during prolonged hemodialysis, blood clots could obstruct the fiber lumen, resulting in decreased effective membrane surface area available for toxin removal. We have prepared, for the first time, dual layer mixed matrix hollow fiber membranes (MMM) for outside-in filtration (OIF). The OIF mode wherein blood would flow through the inter-fiber space instead of through the fiber lumina could prevent fiber clotting. Moreover, the MMMs combine diffusion and adsorption to improve (protein-bound) toxin removal. We believe that the new design of our MMM fibers is an important contribution concerning the development of artificial kidney systems and the improvement of the health and well-being of patients with renal failure.
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Membranas Artificiais , Diálise Renal , Adsorção , Filtração , Humanos , PlasmaRESUMO
OBJECTIVE: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment. DESIGN: Historical cohort study. SETTING: Twelve Dutch hospital departments of obstetrics. POPULATION: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension. METHODS: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures. MAIN OUTCOME MEASURES: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age. RESULTS: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups. CONCLUSIONS: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.
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Anti-Hipertensivos/efeitos adversos , Desenvolvimento Infantil/efeitos dos fármacos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Labetalol/efeitos adversos , Metildopa/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Atenção/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Repouso em Cama , Criança , Pré-Escolar , Feminino , Humanos , Inteligência/efeitos dos fármacos , Países Baixos , Gravidez , Desempenho Psicomotor/efeitos dos fármacos , Instituições AcadêmicasRESUMO
BACKGROUND: Endocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance. METHODS: Gene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT-PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer. RESULTS: mRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease. CONCLUSIONS: Most retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expression profile, suggesting that their causative role in cell growth may be accomplished by post-transcriptional processes. The associations of NCOR2 and CITED2 with outcome in oestrogen receptor-positive breast cancer patients underscore the clinical relevance of functional genetic screens to better understand disease progression, which may ultimately lead to the development of improved treatment options.
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Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/farmacologia , Correpressor 2 de Receptor Nuclear/metabolismo , Proteínas Repressoras/metabolismo , Tamoxifeno/farmacologia , Transativadores/metabolismo , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Correpressor 2 de Receptor Nuclear/biossíntese , Correpressor 2 de Receptor Nuclear/genética , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Transativadores/biossíntese , Transativadores/genéticaRESUMO
Home haemodialysis (HHD) has gained popularity in recent years, due to improved clinical outcomes associated with frequent or prolonged haemodialysis sessions, best achievable at home. However, several barriers to HHD are perceived by the physician and patient, among which lack of experience and education, logistic difficulties and reimbursement issues seem to be the most important ones. HHD, in particular when performed with intensified frequency or duration, is associated with improved quality of life, blood pressure control and survival. Serious adverse events are rare; however, more vascular access complications arise due to frequent needling. This emphasises the importance of comprehensive education and training. This review aims to provide the physician with a detailed state of the art overview on HHD in the Netherlands, discussing potential barriers and benefits, and offering practical advice.
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Falência Renal Crônica/terapia , Diálise Renal/métodos , Autocuidado , Derivação Arteriovenosa Cirúrgica , Cateteres de Demora , Medo , Humanos , Falência Renal Crônica/complicações , Países Baixos , Aceitação pelo Paciente de Cuidados de Saúde , Educação de Pacientes como Assunto , Seleção de Pacientes , Diálise Renal/efeitos adversos , Diálise Renal/psicologia , Diálise Renal/tendências , Engenharia Sanitária , Autoeficácia , Taxa de Sobrevida , Dispositivos de Acesso VascularRESUMO
--London was one of the most rapidly expanding cities in the world in the nineteenth century, but the water supply and sanitary conditions were extremely poor. --In the nineteenth century, there were many theories regarding the causes and spread of epidemic diseases. The miasma theory, which postulated that disease was the result of bad air and odours, was the most popular. --In 1858, as a result of the foul smells from the Thames, the decision was made to improve the sewage system. The new system was first used in 1865, but its actual effect on public health is not clear. --The life expectancy of Londoners did not change in the period 1826-1871, but increased substantially thereafter. In view of this time window, this may have been a result of improvements in the sewage system. --However, it is likely that several other factors, such as improvements in the food and water supply, vaccination programmes, and natural circumstances, were responsible for a large part of this increase.
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Doenças Transmissíveis/história , Surtos de Doenças/história , Controle de Infecções/história , Saúde Pública/história , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/transmissão , Surtos de Doenças/prevenção & controle , História do Século XVII , História do Século XIX , Humanos , Expectativa de Vida , Londres/epidemiologia , Esgotos , Abastecimento de Água/história , Abastecimento de Água/normasRESUMO
For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for alloHCT.
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Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Adulto , Fatores Etários , Idoso , Doadores de Sangue , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais , Análise de Sobrevida , Transplante Homólogo , Falha de Tratamento , Adulto JovemRESUMO
Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Aloenxertos , Criança , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Sociedades Médicas , Taxa de Sobrevida , Fatores de TempoRESUMO
Despite a slight decrease in mortality over the last decade, breast cancer still remains a leading cause of cancer-related death in women. Although anti-tumor effects have been observed after allogeneic stem cell transplantation (SCT), this treatment is not standard care owing to graft-versus-host disease (GVHD) and scarcity of suitable donors. With the aim of reducing treatment-related mortality and increasing donor availability in clinical situations, we developed a preclinical mouse model that combines nonmyeloablative conditioning with the use of haploidentical donor-recipient pairs. To mimic active disease, CB6F1 mice were inoculated with 5 x 10(4) 4T1 mammary carcinoma cells 10 days before transplantation. Keratinocyte growth factor (KGF) was used as GVHD prophylaxis. Syngeneic (CB6F1) SCT did not cure any of the mice and KGF treatment did not influence tumor development. After transplantation with haploidentical (B6CBAF1) bone marrow and splenocytes, however, tumor outgrowth was reduced and long-term disease-free survival (>3 months) was observed in 9/18 (50%) (P=0.0011) of the animals. We conclude that in a model of murine breast cancer, a graft-versus-tumor effect can be induced by a nonmyeloablative haploidentical SCT procedure.
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Efeito Enxerto vs Tumor , Neoplasias Mamárias Experimentais/terapia , Transplante de Células-Tronco , Animais , Feminino , Fator 7 de Crescimento de Fibroblastos/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Haplótipos , Humanos , Masculino , Camundongos , Proteínas Recombinantes/farmacologia , Condicionamento Pré-Transplante , Transplante Homólogo , Transplante IsogênicoRESUMO
BACKGROUND: The product of the Bcar1/p130Cas (breast cancer resistance/p130Crk-associated substrate) gene causes resistance to antiestrogen drugs in human breast cancer cells in vitro. To investigate its role in clinical breast cancer, we determined the levels of Bcar1/p130Cas protein in a large series of primary breast carcinomas. METHODS: We measured Bcar1/p130Cas protein in cytosol extracts from 937 primary breast carcinomas by western blot analysis. The levels of Bcar1/p130Cas protein were tested for associations and trends against clinicopathologic and patient characteristics, the lengths of relapse-free survival and overall survival (n = 775), and the efficacy of first-line treatment with tamoxifen for recurrent or metastatic disease (n = 268). RESULTS: Bcar1/p130Cas levels in primary tumors were associated with age/menopausal status and the levels of estrogen receptor and progesterone receptor. In univariate survival analysis, higher Bcar1/p130Cas levels were associated with poor relapse-free survival and overall survival (both two-sided P =.04; log-rank test for trend). In multivariate analysis, a high level of Bcar1/p130Cas was independently associated with poor relapse-free survival and overall survival. The response to tamoxifen therapy in patients with recurrent disease was reduced in patients with primary tumors that expressed high levels of Bcar1/p130Cas. In multivariate analysis for response, Bcar1/p130Cas was independent of classical predictive factors, such as estrogen receptor status, age/menopausal status, disease-free interval, and dominant site of relapse. CONCLUSION: Patients with primary breast tumors expressing a high level of Bcar1/p130Cas protein appear to experience more rapid disease recurrence and have a greater risk of (intrinsic) resistance to tamoxifen therapy. Thus, measurement of Bcar1/p130Cas may provide useful prognostic information for patients with primary or metastatic breast cancer.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Moduladores de Receptor Estrogênico/uso terapêutico , Genes BRCA1/efeitos dos fármacos , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/metabolismo , Fosfoproteínas/genética , Proteínas , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/farmacologia , Western Blotting , Proteína Substrato Associada a Crk , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Fosfoproteínas/efeitos dos fármacos , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Progesterona/efeitos dos fármacos , Proteína p130 Retinoblastoma-Like , Análise de Sobrevida , Tamoxifeno/farmacologia , Resultado do TratamentoRESUMO
A 26-year-old woman who later turned out to have the rarely seen histiocytic necrotising lymphadenitis of Kikuchi was twice diagnosed incorrectly with malignant T-cell lymphoma. She was treated with standard chemotherapy, whereas Kikuchi's disease has a self-limiting course. Fear for recurrent lymphoma greatly affected the patient's life until the proper diagnosis was ultimately made. This occurred after the patient herself had seen in her dossier that the diagnosis 'Kikuchi's histiocytic lymphadenitis' had been proposed by two pathologists of the consulted regional lymphoma board in the past, but had been rejected by the board after external consultation.