RESUMEN
BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Humanos , Linfocitos , Linfocitos Infiltrantes de Tumor , Pronóstico , Receptor ErbB-2/genéticaRESUMEN
PURPOSE: Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. METHODS: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. RESULTS: 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0-15, 63 (24.5%) 16-20, 39 (15.3%) 21-25 and 40 (15.2%) RS 26-100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16-20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of 4 million in treatment costs. Deducting assay costs, savings of 1.9 million were achieved. CONCLUSION: Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over 1,900,000.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Quimioterapia Adyuvante , Estudios Transversales , Femenino , Perfilación de la Expresión Génica , Humanos , Irlanda/epidemiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Receptores de Estrógenos/genética , Estudios RetrospectivosRESUMEN
Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/efectos adversos , Doxorrubicina/efectos adversos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiología , Anciano , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Ecocardiografía , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Disfunción Ventricular Izquierda/inducido químicamenteRESUMEN
INTRODUCTION: Invasive lobular carcinoma (ILC) accounts for 5-15% of invasive breast cancers. Typical ILC is oestrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative. Atypical biomarker profiles (ER- and HER2+, ER+ and HER2+ or triple negative) appear to differ from typical ILCs. This study compared subtypes of ILC in terms of clinical and pathological parameters, and response to neoadjuvant chemotherapy (NACT) according to biomarker profile. METHODS: All patients with ILC treated in a single centre from January 2005 to December 2020 were identified from a prospectively maintained database. Clinicopathologic and outcome data was collected and analysed according to tumour biomarker profile. RESULTS: A total of 582 patients with ILC were treated. Typical ILC was observed in 89.2% (n = 519) and atypical in 10.8% (n = 63). Atypical ILCs were of a higher grade (35% grade 3 vs 9.6% grade 3, p < 0.001). A larger proportion of atypical ILC received NACT (31.7% vs 6.9% p < 0.001). Atypical ILCs showed a greater response to NACT (mean RCB (Residual Cancer Burden Score) 2.46 vs mean RCB 3.41, p = 0.0365), and higher pathological complete response rates (15% vs 0% p = 0.017). Despite this, overall 5-year disease-free survival (DFS) was higher in patients with typical ILC (91% vs 83%, p = 0.001). CONCLUSIONS: Atypical ILCs have distinct characteristics. They are more frequently of a higher grade and demonstrate a superior response to NACT. Despite the latter, atypical ILCs have a worse 5-year DFS which should be taken into consideration in terms of prognostication and may assist patient selection for NACT.
Asunto(s)
Neoplasias de la Mama , Carcinoma Lobular , Terapia Neoadyuvante , Humanos , Femenino , Carcinoma Lobular/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Persona de Mediana Edad , Anciano , Adulto , Quimioterapia Adyuvante , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Biomarcadores de Tumor/análisis , Resultado del Tratamiento , Estudios Retrospectivos , Supervivencia sin Enfermedad , Clasificación del TumorRESUMEN
We have previously reported the cloning of a gene that encodes a copper transporting P-type ATPase (ATP7B) which is defective in Wilson disease. We have now identified in 58 WND patients, 20 new mutations as well as three of five previously published mutations: 11 small insertions and deletions, seven missense, two nonsense and three splice site mutations. Two of the mutations are relatively frequent, representing 38% of the mutations in patients of European origin. Our findings suggest a wider spectrum of age of onset than is considered typical of Wilson disease: mutations that completely disrupt the gene can produce liver disease in early childhood when Wilson disease may not typically considered in the differential diagnosis. The mutations identified provide an explanation for at least part of the wide phenotypic variation observed in Wilson disease.
Asunto(s)
Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión , Degeneración Hepatolenticular/genética , Edad de Inicio , Secuencia de Aminoácidos , Secuencia de Bases , ATPasas Transportadoras de Cobre , Cartilla de ADN/química , Exones , Femenino , Degeneración Hepatolenticular/epidemiología , Degeneración Hepatolenticular/etnología , Heterocigoto , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Fenotipo , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
BACKGROUND: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS: Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. RESULTS: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). CONCLUSIONS: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.
Asunto(s)
Neoplasias de la Mama , Anciano , Femenino , Humanos , Antraciclinas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Volumen Sistólico , Trastuzumab , Función Ventricular IzquierdaRESUMEN
Wilson disease (WND), an autosomal recessive disorder of copper transport, shows wide genotypic and phenotypic variability, with hepatic and/or neurological symptoms. The WND gene, ATP7B, encodes a copper transporting ATPase that is involved in the transport of copper into the plasma protein ceruloplasmin, and in the excretion of copper from the liver. ATP7B mutations result in copper storage in liver and brain. From 247 WND patients worldwide whose DNA has been sequenced in our laboratory, we have identified 24 new mutations. The origins of the patients were European white (one deletion, one nonsense, one splice site, and 18 missense), Chinese (one deletion, one missense) and Bangladeshi (one missense). Most of these had strong support as disease causing mutations, based on conservation between species, structural changes, and absence in controls. One missense mutation in a Chinese patient was considered uncertain because of its conservative nature and position in the protein. We also identified 15 nucleotide substitutions (11 of them new) causing silent or intronic changes, none of which produce an additional splice site that could lead to disease. Characterization of mutations, both disease-causing and normal variants, is essential for accurate molecular diagnosis of this condition.
Asunto(s)
Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión/genética , Degeneración Hepatolenticular/genética , Mutación , Secuencia de Bases , ATPasas Transportadoras de Cobre , Cartilla de ADN/química , Europa (Continente) , Genotipo , Degeneración Hepatolenticular/etnología , Humanos , Hígado/metabolismo , Datos de Secuencia Molecular , Fenotipo , Mutación PuntualAsunto(s)
Degeneración Hepatolenticular/historia , Neurología/historia , Quelantes/historia , Quelantes/uso terapéutico , Dimercaprol/historia , Dimercaprol/uso terapéutico , Descubrimiento de Drogas/historia , Descubrimiento de Drogas/métodos , Degeneración Hepatolenticular/tratamiento farmacológico , Historia del Siglo XXRESUMEN
During the period 1957-1987, 189 patients with neurological signs and symptoms were referred to the Wilson's disease clinic at Addenbrooke's Hospital, Cambridge. The diagnosis was not confirmed in 52 patients. Thirty-three of these 52 patients were sent with a definite diagnosis of Wilson's disease, and 12 had received chelation treatment. Ten patients were labelled as probable Wilson's disease; in nine cases no diagnosis had been made but Wilson's disease was considered a possibility requiring exclusion. One patient only was mistakenly reported to have Kayser-Fleischer rings. The presenting symptoms were tremor (n = 17), involuntary movements (n = 16), difficulty in walking (n = 12), personality changes (n = 4) and epilepsy (n = 3). The mean delay in referral was 8 years (range 6 months to 20 years). Compared with the number of patients with confirmed neurological Wilson's disease seen in this period (137 patients) the referral diagnosis was correct in only 72% of cases. The reasons for error, both clinical and biochemical, are discussed.
Asunto(s)
Degeneración Hepatolenticular/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Cobre/análisis , Errores Diagnósticos , Femenino , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/complicaciones , Departamentos de Hospitales , Humanos , Hígado/química , Masculino , Persona de Mediana Edad , Neurología , Derivación y ConsultaRESUMEN
BACKGROUND: Wilson's disease is associated with heavy copper overload, primarily in the liver. Copper is a toxic metal, and might be expected to be associated with cancer induction, as iron is in haemochromatosis. However, liver cancer is currently believed to be extremely rare in this disease, and other intra-abdominal malignancies have not been reported. AIM: To assess the frequency of abdominal malignant disease in patients with Wilson's disease on long-term follow-up. DESIGN: Retrospective study in two specialist Wilson's disease clinics: Cambridge/London and Uppsala. METHODS: We reviewed the case records of 363 patients seen at three centres: Addenbrooke's Hospital, Cambridge, 1955-1987; the Middlesex Hospital, London, 1987-2000; and the University Hospital, Uppsala, Sweden, 1966-2002. Patients were grouped by length of follow-up: 10-19 years; 20-29 years; 30-39 years; and 40 years or more. RESULTS: No cancers were seen in patients followed for <10 years. For patients in the 10-19 years group, the frequency was 4.2%; at 20-29 years, it was 5.3%; and at 30-39 years, 15%. No cancers were seen in the 40+ years follow-up group. The cancers consisted of hepatomas, cholangiocarcinomas, and poorly differentiated adenocarcinomas of undetermined primary site. DISCUSSION: Patients with Wilson's disease appear to be vulnerable to the formation of aggressive malignant intra-abdominal tumours during long-term follow-up, irrespective of treatment. Ultrasound scanning of the abdomen seems to be a useful screening procedure.
Asunto(s)
Neoplasias Abdominales/complicaciones , Degeneración Hepatolenticular/complicaciones , Neoplasias Abdominales/epidemiología , Neoplasias Abdominales/genética , Adenocarcinoma/complicaciones , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Adolescente , Adulto , Edad de Inicio , Neoplasias del Sistema Biliar/complicaciones , Neoplasias del Sistema Biliar/epidemiología , Neoplasias del Sistema Biliar/genética , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/genética , Niño , Colangiocarcinoma/complicaciones , Colangiocarcinoma/epidemiología , Colangiocarcinoma/genética , Femenino , Degeneración Hepatolenticular/epidemiología , Degeneración Hepatolenticular/genética , Humanos , Incidencia , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/genética , Cuidados a Largo Plazo , Masculino , Mutación , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Estudios Retrospectivos , Suecia/epidemiología , Factores de TiempoRESUMEN
Wilson's disease should be considered as a possible diagnosis in any child, adolescent or young adult with liver damage without other explanation, especially when haemolysis is present. However, it may also present in adolescents or young adults with neurological signs confined to the motor system. The first diagnostic screening test is the estimation of the serum caeruloplasmin and total serum copper concentrations, with calculation of the serum non-caeruloplasmin-bound ('free') copper. Serum caeruloplasmin, which contains copper, is best determined by measurement of its oxidase activity, as the immunonephelometric method measures both caeruloplasmin and the biologically inactive apo-form. Diagnosis may be confirmed by an elevated urinary copper excretion. All close relatives of an identified patient must be screened and, where doubt persists, investigation of the Wilson's gene at chromosome 13q14.3 can be employed. Lifelong follow-up studies are best conducted in a specialist centre. Compliance with chelating therapy (penicillamine or trientine) or administration of the metal antagonist tetrathiomolybdate or zinc is monitored by determination of the serum 'free' copper, which should be maintained at or near 1.6 micromol/L (10 microg/100 mL). Side-effects of therapy are detected by the estimation of urinary total protein, full blood count and erythrocyte sedimentation rate, clotting factors and liver function tests.
Asunto(s)
Ceruloplasmina/biosíntesis , Química Clínica/métodos , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/diagnóstico , Cobre/sangre , Femenino , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/terapia , Humanos , Masculino , Repeticiones de Microsatélite , Oxidorreductasas/metabolismo , LinajeRESUMEN
An account is given of the identification of penicillamine in human urine by chromatographic and analytical techniques. At that time this observation appeared to be of esoteric interest only. Some years later, working at the Thorndike Memorial Laboratory at the Boston City Hospital, it occurred to me that the formula of this compound was ideally suited for use as a copper chelating agent for the treatment of Wilson's disease. The subsequent work leading to the acceptance of penicillamine as an important new therapy and also as to its mode of action is given with illustrations of some key experiments and with reference to the first patient ever treated with this drug.
Asunto(s)
Degeneración Hepatolenticular/tratamiento farmacológico , Penicilamina/uso terapéutico , Adolescente , Quelantes/metabolismo , Cobre/metabolismo , Cobre/orina , Femenino , Historia del Siglo XX , Humanos , Ninhidrina/orina , Penicilamina/historia , Penicilamina/aislamiento & purificación , Penicilamina/metabolismo , Compuestos de Sulfhidrilo/uso terapéuticoRESUMEN
Penicillamine-induced systemic lupus erythematosus (SLE) and penicillamine-immune complex nephritis are histologically and serologically distinct. One hundred and twenty patients with Wilson's disease treated with penicillamine have been analyzed. Eight developed the serologic changes of SLE; in 4, it was necessary to discontinue treatment. In addition, 6 patients developed immune complex nephritis, which necessitated discontinuing treatment. All but 1 have since been managed on triethylene tetramine 2HCl (Trien).
Asunto(s)
Lupus Eritematoso Sistémico/inducido químicamente , Penicilamina/efectos adversos , Adolescente , Adulto , Quelantes/uso terapéutico , Femenino , Degeneración Hepatolenticular/tratamiento farmacológico , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Manganeso/sangre , Manganeso/metabolismoAsunto(s)
Quelantes/administración & dosificación , Degeneración Hepatolenticular/tratamiento farmacológico , Penicilamina/administración & dosificación , Trientina/administración & dosificación , Quelantes/efectos adversos , Esquema de Medicación , Interacciones Farmacológicas , Quimioterapia Combinada , Degeneración Hepatolenticular/diagnóstico , Humanos , Penicilamina/efectos adversos , Trientina/efectos adversos , Zinc/administración & dosificaciónRESUMEN
An analysis of 321 case notes of patients with Wilson's disease seen between 1955 and 2000 and one case seen in 1949 has revealed that 22 patients presented with a haemolytic crisis. This study was not a specific research project but a retrospective analysis of 321 patients with Wilson's disease seen between 1949 and 2000. All investigations were carried out in the best interests of diagnosis and management of patients referred to my clinic. The delay in diagnosis in 18 cases resulted in progression to severe hepatic disease in 14 cases and to neurological disease in 4 cases. One patient had no symptoms at the time her sister's illness was diagnosed as Wilson's disease. In a second patient, with liver disease, the diagnosis was also made when a sister was found to have Wilson's disease. There was a female to male ratio of 15:7. The average age of onset was 12.6 years and the incidence 6.9%. Delay in diagnosis resulted in nine deaths. Three patients, late in the series, were admitted in the acute phase, two female and one male; of these two responded to chelation therapy, the third required liver transplantation. Haemolysis appeared to be extravascular, and possible mechanisms of the haemolysis are discussed.
Asunto(s)
Anemia Hemolítica/etiología , Degeneración Hepatolenticular/complicaciones , Degeneración Hepatolenticular/diagnóstico , Enfermedad Aguda , Adolescente , Quelantes/uso terapéutico , Niño , Diagnóstico Tardío/efectos adversos , Progresión de la Enfermedad , Femenino , Degeneración Hepatolenticular/mortalidad , Humanos , Masculino , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
BACKGROUND: The relationship between serum 'free' copper and urine copper in patients with Wilson disease has not been explored. AIM: The object of this study is to ascertain if there is a direct relationship between these two parameters. METHOD: The case notes of 320 patients with Wilson disease, seen between 1960 and 1987, have been reviewed. Eighty of these patients had received no treatment before referral and the results of serum 'free' copper and urine copper on admission and at one year of treatment have been analysed. RESULTS: Except for patients with acute haemolysis, the ratio between 'free' serum copper and urine copper before treatment, on average, is around 7:1, after treatment this falls to around 5:1. But results show a wide scatter and there is no direct linear relationship. CONCLUSION: The term 'free' copper is misleading and should be replaced by the more cumbersome but accurate term 'noncaeruloplasmin bound copper'. Most 'free' copper is complexed to albumin and is only available for excretion if there is significant protein loss by the kidneys.
Asunto(s)
Cobre/sangre , Cobre/orina , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/orina , Adolescente , Adulto , Ceruloplasmina/análisis , Quelantes/uso terapéutico , Niño , Preescolar , Degeneración Hepatolenticular/tratamiento farmacológico , Humanos , Penicilamina/uso terapéutico , Trientina/uso terapéutico , Adulto JovenRESUMEN
Penicillamine, dimethyl cysteine, thiovaline, remains the drug of choice for the treatment of patience with Wilson disease. It is also of value in the treatment of cysteinuria and rheumatoid arthritis, it has also been suggested that it has value in the management of other rare diseases. It also has multiple toxicities. The majority of these can be explained as chemical toxicity, for instance its weak antipyridoxine action and its ability to interfere with lysyloxidea resulting in skin lesions. More important are its ability to induce immune reactions such as SLE, immune complex nephritis, the Ehlers Danlos syndrome and Goodpasture's syndrome. However the sudden increase in neurological signs which may occur in a small number of patients remains unexplained. The theory is proposed that this is due to lethal synthesis. In susceptible patients the-SH radical is liberated from penicillamine and will inhibit-SH dependent enzymes in the Krebs cycle leading to death in neurones. Other toxic metabolites may also be produced such as methyl mercaptan and ethyl mercaptan either of which could produce a similar metabolic block.