RESUMEN
Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.
Asunto(s)
Neoplasias de la Mama , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Administración Metronómica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Estudios RetrospectivosRESUMEN
PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Receptor ErbB-2/genética , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HRâ¯=â¯0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HRâ¯=â¯0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.
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Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. MATERIALS AND METHODS: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (pâ¯=â¯0.021) and sexual difficulties (pâ¯=â¯0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (pâ¯=â¯0.039). CONCLUSIONS: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.
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Neoplasias de la Mama/diagnóstico , Toma de Decisiones , Preservación de la Fertilidad/psicología , Preservación de la Fertilidad/estadística & datos numéricos , Calidad de Vida , Adulto , Factores de Edad , Neoplasias de la Mama/psicología , Neoplasias de la Mama/terapia , Estudios de Cohortes , Europa (Continente) , Femenino , Humanos , Italia , Estudios Longitudinales , Estudios Prospectivos , Medición de Riesgo , Encuestas y Cuestionarios , Suiza , Estados UnidosRESUMEN
BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.
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Androstadienos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Everolimus/administración & dosificación , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de NeoplasiasRESUMEN
Triple-negative breast cancer (TNBC) shows a very bad prognosis, even in early stages of disease. Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. In the present article, we review preclinical and clinical data of metronomic administration of chemotherapy agents with or without biological agents in TNBC cell lines and patients, contextually reporting data from the VICTOR-2 study in the subgroup of patients with TNBC, in order to stimulate new ideas for the design of clinical trials in this subset of patients.
RESUMEN
PURPOSE: The VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results. METHODS: Patients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS). RESULTS: Eighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8-63.4) and 51.1 % (95 % CI 35.8-66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2-54.6) and 25.6 % in ≥second-line (95 % CI 13.5-41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients (N = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6-55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %). CONCLUSION: The VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients' dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Administración Metronómica , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Capecitabina/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Retratamiento , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
We conducted a phase III multicenter randomized trial to compare the efficacy of the combination of liposome encapsulated doxorubicin (Myocet(©)) plus either cyclophosphamide (MC) or vinorelbine (MV). Since July 2006, 233 patients affected with metastatic breast cancer were randomized to receive the combination of Myocet (M) 60 mg/m(2) i.v. plus cyclophosphamide (C) 600 mg/m2 on Day 1 of a 21day cycle (Arm A) or Myocet (M) at 50 mg/m2 plus vinorelbine (V) 25 mg/m2 i.v. on Day 1 and V 60 mg/m2 orally on Day 8 on a 21day cycle (Arm B). The primary endpoints of the study was time to progression (TTP); secondary endpoints were RR, toxicity and OS. Response was observed in 53/116 (45.7%) evaluable patients of Arm A vs. 51/112 (45.5%) of Arm B, respectively (P=NS). Median TTP was 41 weeks (95% CI, 3251) and 34 weeks (95% CI, 2639), for M/C and M/V, respectively (P=0.0234). The difference in median OS was not statistically significant (131 vs. 122 weeks; P=0.107). With regard to toxicity, patients treated with MV showed a slight increase of neutropenia and constipation, as compared to those treated with MC. No clinical signs of cardiotoxicity were observed. The MC combination remains as an unbeaten 'standard' in first line treatment of MBC.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Doxorrubicina/análogos & derivados , Vinblastina/análogos & derivados , Adulto , Anciano , Neoplasias de la Mama/patología , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Portadores de Fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Análisis de Supervivencia , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , VinorelbinaRESUMEN
BACKGROUND: In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation. METHODS: We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation. RESULTS: The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 +/- 0.5, 0.5 +/- 0.3, 0.47 +/- 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 +/- 24 vs 73.04 +/- 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 +/- 29 mL/min). CONCLUSION: EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.
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Inmunosupresores/uso terapéutico , Trasplante de Riñón/fisiología , Sirolimus/análogos & derivados , Adulto , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Everolimus , Femenino , Estudios de Seguimiento , Antígenos HLA/inmunología , Humanos , Enfermedades Renales/clasificación , Enfermedades Renales/cirugía , Pruebas de Función Renal , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/sangre , Ácido Micofenólico/uso terapéutico , Proyectos Piloto , Pronóstico , Proteinuria/epidemiología , Tamaño de la Muestra , Sirolimus/uso terapéuticoRESUMEN
The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel-Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P = 0.042), TTP (P = 0.007), and CB (P = 0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P = 0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P = 0.005) and vaginal bleeding (P = 0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.
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Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Metástasis de la Neoplasia/tratamiento farmacológico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Femenino , Humanos , Posmenopausia , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de SupervivenciaRESUMEN
The aim of the current study was to evaluate the activity and toxicity of a combination of oxaliplatin with bolus fluorouracil and leucovorin in colorectal cancer (CRC) patients pretreated for advanced disease with various schedules including continuous fluorouracil infusion. Thirty consecutive patients with pretreated advanced CRC received oxaliplatin 130 mg/m2 by 2-h infusion dl, leucovorin 100 mg/m2 by 1-h infusion followed by fluorouracil 425 mg/m2 i.v. bolus from day 1 to 3 every 3 weeks for a maximum of 6 cycles. The best overall response rate in an intent-to-treat analysis was 13% (2 complete responses and 2 partial responses) (95% CI, 1.2-25.5%) and 37% of patients obtained stable disease with a tumor growth control rate of 50% (95% CI, 32.1-67.9%). The median progression-free survival was 4.0 months (95% CI, 1.4-6.5 months) and median overall survival was 12.0 months (95% CI, 9.9-14.1 months). The independent prognostic factors for improved overall survival were a good performance status and a response/stabilization of disease to chemotherapy. Severe neutropenia was quite common (43.3% of patients and 14.4% of cycles), although complicated by fever only in one case (3.3% of patients). There was one toxic death. In conclusion, the study combination showed an interesting rate of tumor growth control in a cohort of patients previously treated for advanced disease with various schedules including continuous fluorouracil infusion.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/toxicidad , Leucovorina/toxicidad , Compuestos Organoplatinos/toxicidad , Adulto , Anciano , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Doxorrubicina/uso terapéutico , Receptor ErbB-2/biosíntesis , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study was to characterize the factors associated with chemotherapy-induced amenorrhea (CIA) and to examine whether the phase of the menstrual cycle at chemotherapy start could affect the rate of CIA in premenopausal women with early breast cancer. METHODS: CIA was defined as the cessation of menses for at least 3 months during or after chemotherapy. Menstrual phase was defined as days 1-6, follicular phase as days 7-14, luteal phase as days 15-20 and premenstrual phase as days 21-28. Univariate and multivariate predictors of CIA were examined. RESULTS: Among 111 premenopausal women, univariate analysis showed a higher incidence of CIA in patients treated in the follicular phase rather than in other menstrual cycle phases (67.6% compared with 45.5%; P=0.03). The rate of CIA increased with age: 65.2% and 45.8% in patients aged >42 and =42 years, respectively (P=0.05). Upon multivariate analysis these differences remained statistically significant and duration of chemotherapy of more than six cycles correlated significantly with the incidence of CIA (P=0.03). CONCLUSIONS: The major implication of this analysis is that the timing of treatment within the menstrual cycle may potentially modulate the onset of CIA. This work and its future confirmation using prospective randomized trials would be useful in predicting the likelihood of CIA and in counseling breast cancer patients, especially those with a good prognosis who benefit less from chemical castration.
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Amenorrea/epidemiología , Neoplasias de la Mama/tratamiento farmacológico , Ciclo Menstrual/fisiología , Adulto , Anciano , Amenorrea/inducido químicamente , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Italia/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Factores de TiempoRESUMEN
UNLABELLED: Type 1 diabetes in Sardinia is very common in children, and we hypothesized that Latent Autoimmune Diabetes of Adult (LADA) might constitute a significant proportion of diabetes in adult Sardinian subjects. Since Type 2 diabetes is a familial disorder, we tested this hypothesis by investigating the prevalence of GAD65 and IA-2 autoantibodies (Ab) in Type 2 diabetes multiplex families of Sardinian ancestry enrolled in the Study Group for the Genetics of Diabetes in Sardinia. METHODS: A total of 684 individuals were ascertained from 252 Sardinian Type 2 diabetes multiplex families with 2.4 affected siblings per family comprising 190 families with two affected, 37 with three, 15 with four, 7 with five, and 3 with six, in addition to 80 unaffected siblings. Controls were household contacts representing 204 healthy spouses of affected siblings. Diagnosis was at 35-69 years of age and insulin was not given in the first 4 years after diagnosis. GAD65Ab and IA-2Ab were determined in standard radioligand binding assays. RESULTS: Among affected siblings GAD65Ab were positive in 8.8% of insulin-treated (n = 137; P = 0.0006), in 2.5% of non-insulin-treated (n = 467), and in 1.2% of non-diabetic siblings (n = 80) compared with 0.5% of controls (n = 204). IA-2Ab was positive in 6.6% insulin-treated (P = 0.04), 2.1% non-insulin-treated, and 2.5% non-diabetic siblings compared with 1.5% of controls. CONCLUSION: A high frequency of GAD65Ab and IA-2Ab as markers of Type 1 diabetes was found among Type 2 diabetes siblings from Sardinian multiplex families despite excluding those who had been treated with insulin during the first 4 years of disease. Our data support the hypothesis that LADA may be common in Sardinian Type 2 diabetes and stress the importance of investigating markers of Type 1 diabetes in studies of Type 2 diabetes.
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Autoanticuerpos/sangre , Diabetes Mellitus Tipo 2/inmunología , Glutamato Descarboxilasa/inmunología , Isoenzimas/inmunología , Adulto , Anciano , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Núcleo Familiar , Ensayo de Unión RadioliganteRESUMEN
BACKGROUND: Alport syndrome (AS) is a hereditary disease of the glomerular basement membrane in the kidney characterized by progressive renal failure, sensorineural deafness, and/or ocular abnormalities. In contrast to the well-known X-linked phenotype, very little is known about the autosomal dominant form. Rare autosomal forms of AS have been described with mutations in COL4A3 and COL4A4 at chromosome region 2q35-q37, but there have been no descriptions of dominant forms due to a mutation in COL4A4. METHODS: We describe a Sardinian family with a classical AS-phenotype plus hypercholesterolaemia, a clinical feature also present in Fechtner syndrome (FS), a disease that segregates as an autosomal dominant trait. RESULTS: A suggestive linkage (LOD=2.7) between AS and the COL4A3/A4 locus at 2q35-q37 was identified. Other candidate collagen genes encoding basement membrane collagen (COL4A1/A2 and COL4A5/A6) were excluded by linkage analysis (13q33-q34 and Xq22), or by sequence (COL4A3). DNA sequence analysis of the COL4A4 gene revealed that the Lys325Asn mutation was present in all affected family members, but was absent in all unaffected members and in a random sample of the Sardinian population. A clear indication of a gene-dosage effect was seen in the most severely affected family member, since she carried the mutation in the homozygous form. CONCLUSIONS: These data confirm the importance of collagen 4A4 as a component in the structural integrity of the glomerular basement membrane and confirm the phenotypic and genetic heterogeneity of collagen disorders.
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Colágeno Tipo IV/genética , Hiperlipoproteinemia Tipo II/genética , Mutación , Nefritis Hereditaria/genética , Adulto , Anciano , Secuencia de Bases , Cromosomas Humanos Par 2/genética , ADN/genética , Femenino , Dosificación de Gen , Genes Dominantes , Ligamiento Genético , Pérdida Auditiva Sensorineural/genética , Homocigoto , Humanos , Italia , Masculino , Persona de Mediana Edad , Nefritis Hereditaria/patología , Linaje , FenotipoRESUMEN
BACKGROUND: Experimental evidence indicates that statins might have direct vascular effects independently from low-density lipoprotein (LDL) cholesterol reduction and we reported that the reduction in urinary albumin excretion rate during Simvastatin treatment in type 2 diabetic patients was not correlated with LDL-cholesterol decrease. However in humans there are no data regarding possible additional effects of Simvastatin on blood pressure and urinary albumin excretion beyond its capacity to lower serum cholesterol. PATIENTS AND METHODS: Twenty-six microalbuminuric hypertensive type 2 diabetic patients (diastolic blood pressure - after four months wash-out from the previous antihypertensive therapy - consistently > 90 and < 100 mmHg; plasma LDL-cholesterol > 3.9 and < 6.5 mmol L-1) were enrolled in the study. In random order, these patients received Simvastatin (20 mg day-1) or Cholestyramine (6 g three times a day) for a period of 10 months and after three months of wash-out (cross-over) the sequence was reversed for an additional 10 months. Blood pressure, lipid parameters, glycated haemoglobin and urinary albumin excretion were measured during the study. Additionally, in eight patients, urinary glycosaminoglycan excretion (GAG) was also measured during the study. RESULTS: Simvastatin and Cholestyramine were equally effective in reducing total and LDL cholesterol. Only during Simvastatin treatment a significant reduction in diastolic blood pressure and both 24 h urinary albumin and GAG excretion rates were observed, while no significant changes were seen with Cholestyramine treatment. CONCLUSIONS: Our results clearly show for the first time that the reduction of blood pressure, together with 24 h urinary albumin excretion rate - two established cardiovascular risk factors, obtained during Simvastatin therapy in hypertensive type 2 diabetic patients - is in large part independent from the reduction of LDL Cholesterol.