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  1. Article ; Online: Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated.

    Cabrera-López, Cristina / Bullich, Gemma / Martí, Teresa / Català, Violeta / Ballarín, Jose / Bissler, John J / Harris, Peter C / Ars, Elisabet / Torra, Roser

    BMC medical genetics

    2015  Volume 16, Page(s) 39

    Abstract: Background: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the ... ...

    Abstract Background: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the PKD1/TSC2 contiguous gene syndrome (CGS), are characterized by severe ADPKD, plus TSC. mTOR inhibitors have proven effective in reducing angiomyolipoma (AML) in TSC and total kidney volume in ADPKD but without a positive effect on renal function.
    Methods and results: We describe a patient with independent truncating PKD1 and TSC2 mutations who has the expected phenotype for both diseases independently instead of the severe one described in PKD1/TSC2-CGS. Treatment with mTOR inhibitors reduced the AML and kidney volume for 2 years but thereafter they resumed growth; no positive effect on renal function was seen throughout. This is the first case addressing the response to mTOR treatment when independent truncating mutations in PKD1 and TSC2 are present.
    Conclusions: This case reveals that although PKD1 and TSC2 are adjacent genes and there is likely cross-talk between the PKD1 and TSC2 signalling pathways regulating mTOR, having independent TSC2 and PKD1 mutations can give rise to a milder kidney phenotype than is typical in PKD1/TSC2-CGS cases. A short-term beneficial effect of mTOR inhibition on AML and total kidney volume was not reflected in improved renal function.
    MeSH term(s) Adult ; Aged ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TRPP Cation Channels/genetics ; Treatment Outcome ; Tuberous Sclerosis/diagnosis ; Tuberous Sclerosis/drug therapy ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/metabolism ; Tumor Suppressor Proteins/genetics
    Chemical Substances Protein Kinase Inhibitors ; TRPP Cation Channels ; Tumor Suppressor Proteins ; polycystic kidney disease 1 protein ; tuberous sclerosis complex 2 protein (4JG2LF96VF) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2015-06-17
    Publishing country England
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-2350
    ISSN (online) 1471-2350
    DOI 10.1186/s12881-015-0185-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Renal angiomyolipoma bleeding in a patient with TSC2/PKD1 contiguous gene syndrome after 17 years of renal replacement therapy.

    Furlano, Mónica / Barreiro, Yaima / Martí, Teresa / Facundo, Carme / Ruiz-García, César / DaSilva, Iara / Ayasreh, Nadia / Cabrera-López, Cristina / Ballarín, José / Ars, Elisabet / Torra, Roser

    Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia

    2017  Volume 37, Issue 1, Page(s) 87–92

    Abstract: We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a ... ...

    Title translation Sangrado de angiomiolipoma renal en paciente con síndrome de genes contiguos (TSC2/PKD1) tras 17 años de tratamiento renal sustitutivo.
    Abstract We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a kidney transplant at the age of 12. The native kidneys presented angiomyolipomas (AML), which are common benign tumours in patients with TS. Seventeen years after transplantation, he presented with abdominal pain, anaemia and a retroperitoneal haematoma, the latter caused by renal AML bleeding. Selective embolisation was performed. Our patient could have benefited from the administration of mTOR inhibitors at transplant. This therapy is immunosuppressive and reduces the size of benign tumours in TS as well as the risk of rupture and bleeding. This patient did not receive mTOR inhibitors at the time of the transplant because the relationship between mTOR inhibitors and TS was unknown at that time. This case confirms the persistent risk of renal AML bleeding for both transplanted patients and patients on dialysis. As a result, we would recommend routine check-ups of native kidneys and nephrectomy assessment.
    Language Spanish
    Publishing date 2017-01
    Publishing country Spain
    Document type Journal Article
    ZDB-ID 632512-9
    ISSN 1989-2284 ; 0211-6995
    ISSN (online) 1989-2284
    ISSN 0211-6995
    DOI 10.1016/j.nefro.2016.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis

    Cabrera-López Cristina / Martí Teresa / Catalá Violeta / Torres Ferran / Mateu Silvia / Ballarín Jose / Torra Roser

    Orphanet Journal of Rare Diseases, Vol 7, Iss 1, p

    a two years trial

    2012  Volume 87

    Abstract: Abstract Background Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test ...

    Abstract Abstract Background Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the effect of rapamycin in reducing the volume of AML in TS. Methods Twenty four-month prospective open-label, single arm, unicentre Phases II andIII study. The primary endpoint was to evaluate the effect of treatment on the reduction of at least 50% AML volume from baseline at 24 months. The secondary endpoints were: average tumour reduction, surgical complications, skin lesions and drug safety. The study population comprised 17 patients, aged >10 years who were diagnosed with TS and had ≥1 renal AML >2 cm of diameter and had a serum creatinine < 2mg/dl and urine protein/creatinine ratio < 22.6 mg/mmol. The trial was conducted at Fundació Puigvert. Rapamycin was given to achieve stable plasma levels between 4 and 8 ng/ml. AML volume was estimated using orthogonal measurements by MRI at baseline, 6, 12 and 24 months. Results Ten out of 17 patients were success responders for the main outcome −58.8%, 95%CI: 32.9% to 81.6%-. After 6 months of therapy, the mean volume decrease was 55.18% (5.01 standard error (SE); p<0.001) and 66.38% (4.41 SE; p<0.001) at year 1. There was no significant decrease between year 1 and 2. According to RECIST criteria, all patients achieved a partial response at year 1 and all but two had already achieved this partial response after 6 months. The main analysis was performed according to the intention-to-treat principle analysis. Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis. We used the baseline tumour volume as a covariate for the absolute change and percentage change from baseline data. The analysis was performed using SAS version 9.2 software, and the level of significance was established at 0.05 (two-sided). Conclusions This study show that mTOR inhibitors are a ...
    Keywords Angiomyolipoma ; mTOR ; Rapamycin ; Treatment ; Tuberous sclerosis ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2012-11-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial.

    Cabrera-López, Cristina / Martí, Teresa / Catalá, Violeta / Torres, Ferran / Mateu, Silvia / Ballarín, Jose / Torra, Roser

    Orphanet journal of rare diseases

    2012  Volume 7, Page(s) 87

    Abstract: Background: Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the ... ...

    Abstract Background: Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the effect of rapamycin in reducing the volume of AML in TS.
    Methods: Twenty four-month prospective open-label, single arm, unicentre Phases II andIII study. The primary endpoint was to evaluate the effect of treatment on the reduction of at least 50% AML volume from baseline at 24 months. The secondary endpoints were: average tumour reduction, surgical complications, skin lesions and drug safety.The study population comprised 17 patients, aged >10 years who were diagnosed with TS and had ≥1 renal AML >2 cm of diameter and had a serum creatinine < 2mg/dl and urine protein/creatinine ratio < 22.6 mg/mmol. The trial was conducted at Fundació Puigvert. Rapamycin was given to achieve stable plasma levels between 4 and 8 ng/ml. AML volume was estimated using orthogonal measurements by MRI at baseline, 6, 12 and 24 months.
    Results: Ten out of 17 patients were success responders for the main outcome -58.8%, 95%CI: 32.9% to 81.6%-. After 6 months of therapy, the mean volume decrease was 55.18% (5.01 standard error (SE); p<0.001) and 66.38% (4.41 SE; p<0.001) at year 1. There was no significant decrease between year 1 and 2. According to RECIST criteria, all patients achieved a partial response at year 1 and all but two had already achieved this partial response after 6 months.The main analysis was performed according to the intention-to-treat principle analysis. Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis. We used the baseline tumour volume as a covariate for the absolute change and percentage change from baseline data. The analysis was performed using SAS version 9.2 software, and the level of significance was established at 0.05 (two-sided).
    Conclusions: This study show that mTOR inhibitors are a relatively safe, efficacious and less aggressive alternative than currently available options in the management of AML in TS.
    Trial registration: EudraCT number: 2007-005978-30, ClinicalTrials.gov number: NCT0121712.
    MeSH term(s) Adult ; Angiomyolipoma/complications ; Angiomyolipoma/drug therapy ; Antibiotics, Antineoplastic/adverse effects ; Antibiotics, Antineoplastic/therapeutic use ; Female ; Humans ; Male ; Prospective Studies ; Sirolimus/adverse effects ; Sirolimus/therapeutic use ; Treatment Outcome ; Tuberous Sclerosis/complications
    Chemical Substances Antibiotics, Antineoplastic ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2012-11-11
    Publishing country England
    Document type Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1750-1172
    ISSN (online) 1750-1172
    DOI 10.1186/1750-1172-7-87
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis.

    Cabrera López, Cristina / Martí, Teresa / Catalá, Violeta / Torres, Ferrán / Mateu, Silvia / Ballarín Castán, Jose / Torra Balcells, Roser

    Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia

    2011  Volume 31, Issue 3, Page(s) 292–298

    Abstract: Background: Tuberous sclerosis (TS) is a systemic disease, with an autosomal dominant pattern of inheritance caused by mutations in two genes (TSC1 and TSC2) that cause tumours (angiomyolipomas [AML], angiofibromas, astrocytomas). Constant and ... ...

    Abstract Background: Tuberous sclerosis (TS) is a systemic disease, with an autosomal dominant pattern of inheritance caused by mutations in two genes (TSC1 and TSC2) that cause tumours (angiomyolipomas [AML], angiofibromas, astrocytomas). Constant and inadequate proliferation occurring in TS may be blocked by mTOR inhibitors (mammalian target of rapamycin), such as rapamycin.
    Material and methods: At present, our study includes 17 patients with TS. All had at least one AML greater than 2cm in diameter diagnosed by MRI. They received rapamycin during 12 months. Plasma levels remained stable between 4-8ng/dl. The AML size was monitored every six months by abdominal MRI.
    Results: At 12 months of inclusion, MRI indicated a decrease in the size of AML in all patients showing at least a 50% reduction in 82.4% (14/17, 95% CI [56.57%, 96.20%]). The mean percent reduction was 66.3% (95% CI [56.9%, 75.6%], P<.0001). The major side effects observed were: oral aphthous ulcers (5/17); hypertriglyceridemia (3/17); microcytosis and hypochromia (3/17); diarrhea (2/17); acne (1/17); acute pyelonephritis (1/17); and proteinuria (1/17).
    Conclusions: These preliminary clinical data suggest that rapamycin can play a beneficial role in the treatment of TS. Our experience in 17 patients treated for 12 months demonstrates safety and efficacy in reducing AML volume.
    MeSH term(s) Adolescent ; Angiomyolipoma/drug therapy ; Angiomyolipoma/etiology ; Antibiotics, Antineoplastic/therapeutic use ; Child ; Female ; Humans ; Male ; Sirolimus/therapeutic use ; Tuberous Sclerosis/complications ; Tuberous Sclerosis/drug therapy ; Young Adult
    Chemical Substances Antibiotics, Antineoplastic ; Sirolimus (W36ZG6FT64)
    Language Spanish
    Publishing date 2011
    Publishing country Spain
    Document type Clinical Trial, Phase IV ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632512-9
    ISSN 1989-2284 ; 0211-6995
    ISSN (online) 1989-2284
    ISSN 0211-6995
    DOI 10.3265/Nefrologia.pre2011.Apr.10812
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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