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Modulation of global mRNA translation, which is essential for intestinal stem cell function, is controlled by Wnt signaling. Loss of tumor supressor APC in stem cells drives adenoma formation through hyperactivion of Wnt signaling and dysregulated translational control. It is unclear whether factors that coordinate global translation in the intestinal epithelium are needed for APC-driven malignant transformation. Here we identified nucleotide exchange factor eIF2Bε as a translation initiation factor involved in Wnt-mediated intestinal epithelial stemness. Using eIF2BεArg191His mice with a homozygous point mutation that leads to dysfunction in the enzymatic activity, we demonstrate that eIF2Bε is involved in small intestinal crypt formation, stemness marker expression, and secreted Paneth cell-derived granule formation. Wnt hyperactivation in ex vivo eIF2BεArg191His organoids, using a GSK3ß inhibitor to mimic Apc driven transformation, shows that eIF2Bε is essential for Wnt-mediated clonogenicity and associated increase of the global translational capacity. Finally, we observe high eIF2Bε expression in human colonic adenoma tissues, exposing eIF2Bε as a potential target of CRC stem cells with aberrant Wnt signaling.
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Adenoma , Células Epiteliales , Animales , Mucosa Intestinal , Intestinos , Ratones , Factores de Iniciación de Péptidos , Vía de Señalización WntRESUMEN
A new species, Emoleptalea nwanedi n. sp. is described from the intestine of Schilbe intermedius, the silver catfish or butter barbel, from the Nwanedi-Luphephe Dam in the Limpopo Province of South Africa. Fish were collected using gill nets where after they were euthanised and dissected. The parasites were sampled, fixed in 70 % EtOH and stained with Van Cleave's haematoxylin. This species represents an addition to the African cluster of Emoleptalea species previously described and differs from the known species due to its unique size, equal size of oral and ventral suckers, position of ovary and seminal receptacle, number of vitelline follicles and their size, as well as the unique ciliated receptors on the wall of the acetabulum. This is the first record of this parasite from the silver catfish and from southern Africa.
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Temperature-dependent sum-frequency scattering spectroscopy is used to study the properties of hexadecane and dodecane oil droplets in water. The sum-frequency scattering spectra contain vibrational bands that correspond to the symmetric and antisymmetric CH stretching vibrations of the methylene (CH2) and methyl (CH3) groups of the alkane molecules. The relative amplitudes of the vibrational bands provide information on the surface structure and the shape of the oil droplets. We study the sum-frequency scattering spectra over a temperature range of -48 to 24 °C, including the freezing transitions of the water matrix and the oil droplets. Hexadecane oil droplets freeze at a higher temperature than the surrounding water, whereas dodecane oil droplets freeze at a lower temperature than the surrounding water. This allows us to independently study the freezing effect of oil and water on the surface structure of the oil droplets. In both cases, freezing leads to a change in the polarization dependencies that are valid in the case of the spherical-symmetric shapes that the oil droplets assume when both water and oil are liquid. We find that the freezing of water leads to a strong distortion of the liquid dodecane surface but has little effect on the surface of already solidified hexadecane. For completely frozen emulsions a further decrease in temperature is observed to lead to a further distortion of the surface of the solid oil particles, which might be caused by increasing hardness of the ice matrix encapsulating the particles.
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BACKGROUND: Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. METHODS: Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. RESULTS: In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response. CONCLUSION: Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Quinazolinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Estudios de Cohortes , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Fatiga/inducido químicamente , Femenino , Humanos , Lapatinib , Persona de Mediana Edad , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , GemcitabinaRESUMEN
STUDY QUESTION: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors? SUMMARY ANSWER: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood. WHAT IS KNOWN ALREADY: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before. STUDY DESIGN, SIZE, DURATION: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36). MAIN RESULTS AND THE ROLE OF CHANCE: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen. LIMITATIONS, REASONS FOR CAUTION: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed. STUDY FUNDING/COMPETING INTERESTS: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.
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Criopreservación , Fertilidad , Enfermedad de Hodgkin/terapia , Preservación de Semen , Semen , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Estudios de Cohortes , Enfermedad de Hodgkin/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , SobrevivientesRESUMEN
The temperature dependence of the vibrational T1 lifetime of the OD stretch vibration of HDO in H2O ice was measured with femtosecond mid-IR pump-probe spectroscopy. We found an increase of T1 from 480 ± 40 fs at 25 K to 860 ± 60 fs at 265 K. These lifetimes are remarkably shorter than the vibrational lifetime of the OD stretch vibration of HDO in H2O in the liquid phase, which has a value of 1.7 ± 0.1 ps at 274 K and increases to 2.24 ± 0.09 at 343 K. The observed temperature dependence of T1 can be well explained from a relaxation mechanism in which the OD vibration relaxes via energy transfer to the bend-libration combination tones of H2O and HDO.
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In this study, we tested the hypothesis whether breast conserving therapy (BCT) compared with mastectomy is associated with a negative outcome in terms of distant metastases or death (DMD) and investigated the relation between locoregional recurrence (LRR) and DMD in young breast cancer (BC) patients. This study included a consecutive series of 536 patients ≤40 years of age at diagnosis with pathological T1N0-3M0 BC, treated between 1989 and 2005. A multistate survival model was used to evaluate the influences of local treatment and LRR on DMD, adjusted for potential prognostic factors. Patients were treated with mastectomy (N = 213) or BCT (N = 323). Median age at diagnosis was 36.3 years, with a median follow-up of 9.0 years. The 10-year actuarial cumulative incidence of DMD was 30.6 % after mastectomy and 26.3 % after BCT (P = 0.04). In total, 81 (15 %) LRRs were observed. After BCT, patients had a threefold higher risk of LRR than after mastectomy (HR 2.9; 95 % CI 1.6-5.3). Patients with LRR had a higher risk of DMD compared with patients without LRR (HR 5.5; 95 % CI 2.1-14.5). However, BCT was not negatively associated with DMD-after-LRR (HR 0.47; 95 % CI 0.2-1.1, BCT vs mastectomy). In conclusion, although LRR significantly affected DMD, the increased risk of LRR after BCT compared with mastectomy did not lead to a worse DMD outcome in BC patients ≤40 years of age.
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Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Recurrencia Local de Neoplasia/mortalidad , Adulto , Neoplasias de la Mama/radioterapia , Femenino , Estudios de Seguimiento , Humanos , Mastectomía , Mastectomía Segmentaria , Análisis Multivariante , Recurrencia Local de Neoplasia/patologíaRESUMEN
BACKGROUND: In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer. PATIENTS AND METHODS: In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). RESULTS: 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. CONCLUSION: Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Taxoides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Carcinoma Epitelial de Ovario , Celecoxib , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel , Neoplasias de las Trompas Uterinas/mortalidad , Neoplasias de las Trompas Uterinas/cirugía , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/cirugía , Pirazoles/efectos adversos , Sulfonamidas/efectos adversos , Taxoides/efectos adversosRESUMEN
BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor 2 (HER2), has shown activity in combination with capecitabine in patients with HER2-positive advanced breast cancer progressive on standard treatment regimens. We present results on preapproval drug access for this combination in such patients occurring in the general oncology practice in the Netherlands. METHODS: Patients with HER2-positive advanced breast cancer progressive on schedules containing anthracyclines, taxanes, and trastuzumab were eligible. Brain metastases were allowed if stable. Lapatinib 1250 mg÷day was given continuously in combination with capecitabine 1000 mg÷m2 twice daily for two weeks in a three-week cycle. Efficacy was assessed by use of response evaluation criteria in solid tumours version 1.0. Progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Eighty-three patients were enrolled from January 2007 until July 2008. The combination was generally well tolerated and the most common drug-related serious adverse events were nausea and÷or vomiting (5%) and diarrhoea (2%). Seventy-eight patients were evaluable for response. Clinical benefit (response or stable disease for at least 12 weeks) was observed in 50 patients (64%) of whom 15 had a partial response and 35 stable disease. The median PFS and OS were 17 weeks (95% CI: 13 to 21) and 39 weeks (95% CI: 24 to 54), respectively. For OS, higher Eastern Cooperative Oncology Group (ECOG) status (p=0.016), brain metastases at study entry (p=0.010) and higher number of metastatic sites (p=0.012) were significantly negative predictive factors. CONCLUSION: In a patient population with heavily pretreated HER2-positive advanced breast cancer lapatinib plus capecitabine was well tolerated and offered clinical benefit.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Capecitabina , Intervalos de Confianza , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Indicadores de Salud , Humanos , Estimación de Kaplan-Meier , Lapatinib , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Tirosina Quinasas/antagonistas & inhibidoresRESUMEN
Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cateterismo/efectos adversos , Catéteres de Permanencia/efectos adversos , Terapia Combinada/efectos adversos , Infecciones/etiología , Nutrición Parenteral Total/efectos adversos , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/cirugía , Femenino , Humanos , Infecciones/epidemiología , Países Bajos , Neutropenia/etiología , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de TiempoRESUMEN
A prospective randomized phase III study was performed to evaluate whether intensified cytarabine would induce a higher response rate and longer event-free interval as compared to low-dose cytarabine in chronic myeloid leukemia (CML). One hundred and eighteen patients with CML in early chronic phase entered the study. Twenty-eight out of 32 patients assigned to group A received two cycles of a combination of intensified cytarabine and idarubicin followed by interferon alfa (IFN-alpha) maintenance, 28 patients in group B received standard treatment by a combination of low-dose cytarabine and IFN-alpha. Forty-nine patients with a human leukocyte antigen-identical sibling donor proceeded to allogeneic stem cell transplantation (allo-SCT) and nine patients were excluded from the analysis. Hematological response was observed in 97% of the patients in group A vs 86% of the patients in group B during the first year of treatment. In group A, 16 patients (50%) achieved a major cytogenetic response, which compared to seven patients (25%) with a major cytogenetic response in group B. With a median follow-up of 58 months (range 34-76), event-free survival was not significantly different between arms A and B. The estimated 5-year survival rate was 56% in the intensified arm and 77% in the low-dose arm (P = 0.05). Recipients of allo-SCT showed a 5-year estimated survival rate of 55%. Although intensified cytarabine induced a higher initial percentage of major and complete cytogenetic responses, responses were not sustained by IFN-alpha maintenance therapy.
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Citarabina/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/patología , Adolescente , Adulto , Anciano , Citarabina/administración & dosificación , Citogenética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Interferón-alfa/efectos adversos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/cirugía , Masculino , Persona de Mediana Edad , Trasplante de Células Madre , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.
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Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/terapia , Adulto , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/enzimología , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Países Bajos , Trasplante de Células Madre de Sangre Periférica , Proteínas de Unión a Poli-ADP-Ribosa , Pronóstico , Receptor ErbB-2/genética , Tiotepa/administración & dosificación , Resultado del TratamientoRESUMEN
Ultrafiltration failure (UFF) is a serious complication of peritoneal dialysis (PD). The aim of the study was to analyze changes in water transport and their determinants in UFF patients over the time on PD. Standard peritoneal permeability analyses of 50 stable PD patients with UFF were analyzed. Fluid transport through small pores (SPT), free water transport (FWT) at 60 min, their contributions on total ultrafiltration (SPTC and FWTC), and their determinants were assessed. Patients were divided in Group I (UFF) treated for less than 24 months, Group II treated 24-60 months, and Group III treated for more than 60 months. Group I (UFF) was compared with Group I (non-UFF) matched for the duration of PD treatment and age. Transcapillary ultrafiltration (TCUF), SPT, FWT, and FWTC were significantly lower in Group III when compared to the other UFF groups. In this group also, negative relationship was present between FWT, the ultrafiltration coefficient LpA, and osmotic conductance to glucose on one hand and PD duration on the other. FWT was positively related to osmotic conductance to glucose in all groups. Group I (UFF) showed significantly higher solute transport, effective lymphatic absorption rate, lower TCUF, and lower FWT than Group I (non-UFF). The patterns of UFF in PD patients are dependent on the duration of treatment.
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Agua Corporal/metabolismo , Diálisis Peritoneal/efectos adversos , Adulto , Anciano , Estudios Transversales , Femenino , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Ósmosis/fisiología , Factores de Tiempo , Ultrafiltración , Equilibrio HidroelectrolíticoRESUMEN
In an attempt to decrease mortality in dialysis patients, the care for end-stage renal disease patients has been a focus of nephrologists for many years. Good pre-dialysis care has been found to improve mortality numbers in several studies. However, it is still not exactly clear, when the best moment has arrived to start renal replacement therapy. By illustrating two totally different patient cases the effect of outcome and quality of life are discussed-demonstrating on the one hand the role of clinical parameters, and on the other hand the influence of biochemical parameters.
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Fallo Renal Crónico/terapia , Diálisis Peritoneal , Anciano , Creatinina/sangre , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Hipertensión/complicaciones , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Terapia de Reemplazo Renal , Factores de Tiempo , Resultado del TratamientoRESUMEN
The well-being and survival of dialysis patients not only depend on the removal of waste products and excess fluid, but also on the prevention of cardiovascular complications by maintaining normovolaemia and adequate blood pressure and avoidance of ectopic calcification. Also, the maintenance of nutritional status and adequate removal of middle molecules are amongst the most important issues in long-term renal replacement therapy. In this review, attention is given to optimal peritoneal small solute clearance and Kt/V and to the evidence concerning the role of residual renal function. In addition, factors that can influence this residual function are also discussed.
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Enfermedades Renales/terapia , Riñón/fisiopatología , Diálisis Peritoneal , Creatinina/metabolismo , Humanos , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , Tasa de Depuración Metabólica , Estado Nutricional , Garantía de la Calidad de Atención de SaludRESUMEN
BACKGROUND: Inoperable or metastatic oesophagogastric adenocarcinoma has a poor prognosis. From the many different chemotherapeutic regimens used in the past, a combination of epirubicin, cisplatin and continuous 5-fluorouracil infusion (ECF) showed a consistent response rate of +/- 50% with acceptable toxicity. Continuous 5-FU infusion may be replaced by oral fluoropyrimidines. Here we evaluate treatment with epirubicin and cisplatin combined with oral capecitabine (ECC), replacing intravenous 5-FU infusion. METHODS: Retrospectively, we analysed 23 consecutive patients who were treated with epirubicin, cisplatin and oral capecitabine for inoperable or metastatic oesophagogastric adenocarcinoma during 2002 and 2003. RESULTS: The overall response rate was 57%; another 26% achieved stable disease and only 17% had progressive disease. The median duration of response was 6.4 months; the median survival was 9.0 months. Previously treated patients (n=10) had a significantly worse overall response rate (20%) compared with previously untreated patients (85%). A nonsignificant difference in median survival was found between these groups (3.9 vs 9.8 months in previously treated vs untreated patients). An acceptable incidence of grade 3 and 4 toxicity was found. CONCLUSION: Capecitabine in combination with epirubicin and cisplatin is an effective and safe alternative to ECF, without the risks of a continuous venous access.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Capecitabina , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Epirrubicina/administración & dosificación , Neoplasias Esofágicas/mortalidad , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Análisis de SupervivenciaRESUMEN
BACKGROUND: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. PATIENTS AND METHODS: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. RESULTS: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02). CONCLUSIONS: The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Genes erbB-2 , Antineoplásicos Alquilantes/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunohistoquímica , Neoplasias Primarias Secundarias/inducido químicamente , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.
Asunto(s)
Materiales Biocompatibles/efectos adversos , Naltrexona/efectos adversos , Antagonistas de Narcóticos/efectos adversos , Poliésteres/efectos adversos , Piel/patología , Grasa Subcutánea/patología , Materiales Biocompatibles/administración & dosificación , Implantes de Medicamentos , Femenino , Fibrosis , Reacción a Cuerpo Extraño/inducido químicamente , Reacción a Cuerpo Extraño/patología , Dependencia de Heroína/rehabilitación , Humanos , Masculino , Microesferas , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Necrosis/inducido químicamente , Necrosis/patología , Poliésteres/administración & dosificación , Piel/efectos de los fármacos , Grasa Subcutánea/efectos de los fármacos , Factores de TiempoRESUMEN
Ultrafiltration failure (UFF) is the insufficient ability to remove excess fluid from the body by dialysis. In peritoneal dialysis (PD) this is a common complication, the frequency increases with duration of treatment. In this review a summary of peritoneal transport mechanisms and the conditions associated with UFF are discussed. The 2 most common circumstances in which ultrafiltration failure occurs, peritonitis and long-term PD treatment, are outlined more extensively. In addition a diagnostic approach and therapeutic options for the different causes of UFF are given.