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BACKGROUND: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases. METHODS: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. RESULTS: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. CONCLUSIONS: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Melanoma , Viroterapia Oncolítica , Neoplasias de la Mama Triple Negativas , Adulto , Humanos , Melanoma/terapia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/etiología , Estudios de Cohortes , Viroterapia Oncolítica/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Colorrectales/terapiaRESUMEN
A 35-year-old woman who had previously undergone a lung transplantation presented with severe abdominal pain and vomiting. The gastroscopy showed diffuse ulcerative gastric lesions. Tests for varicella zoster virus and Epstein-Barr virus via polymerase chain reactions (PCR) on endoscopically obtained gastric biopsies were found to be positive and confirmed varicella gastritis. Intravenous antiviral therapy with acyclovir was administered resulting in a normalization of all clinical symptoms, especially of abdominal pain and inflammation parameters.
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Varicela/diagnóstico , Gastritis/diagnóstico , Granulomatosis con Poliangitis/cirugía , Trasplante de Pulmón , Aciclovir/uso terapéutico , Adulto , Antivirales/uso terapéutico , Varicela/complicaciones , Varicela/tratamiento farmacológico , Femenino , Gastritis/tratamiento farmacológico , Gastritis/virología , Herpesvirus Humano 3 , Humanos , Huésped InmunocomprometidoRESUMEN
Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.
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Colitis/inmunología , Factores de Transcripción Forkhead/inmunología , Inmunidad Mucosa/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Linaje de la Célula , Colitis/genética , Colitis/patología , Colon/inmunología , Colon/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Epigénesis Genética/inmunología , Femenino , Factores de Transcripción Forkhead/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Inflamación , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Transducción de Señal , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/trasplante , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
Since 2011, telaprevir (TVR)-based triple therapy is the new treatment standard for hepatitis C genotype 1 virus infection. The aim of our retrospective interim analysis encompassing the first 24 weeks on TVR-based triple therapy was to assess 'real-life' antiviral efficacy and side effects in a large single-centre cohort, both in comparison with the data obtained in large prospective clinical trials. In total, we treated 102 patients: 24 treatment-naïve patients, 58 patients pretreated with PEG-IFN/RBV (thereof: 28 with nonresponse, 25 with relapse, five unknown) and 20 patients who previously had received nonpegylated interferon. 74 of 102 patients were assigned with HCV genotype 1b; 34 of 102 patients were treated in the context of liver cirrhosis. 72 of 102 patients have reached treatment week 24 (mean treatment duration 31 weeks). In the ITT analysis, overall response rates were at: week 4: 66%; week 12: 85%; and week 24: 78%. So far, 24 patients discontinued treatment prematurely, of those, 10 patients were due to virological failure. Haematological side effects were frequent (40% anaemia), as were 'flu-like' symptoms (94%), rash (65%) and pruritus (79%). According to our interim ITT analysis encompassing up to 24 weeks of TVR-based triple therapy, our 'real-life' antiviral effects are comparable to the results of large multicentric clinical trials. However, TVR-based triple therapy exhibited a high frequency of side effects requiring multiple therapeutic interventions. Notably, in our 'real-life' cohort, no lethal case was observed so far.
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Antivirales/efectos adversos , Antivirales/uso terapéutico , Hepacivirus/aislamiento & purificación , Oligopéptidos/efectos adversos , Oligopéptidos/uso terapéutico , Carga Viral , Adulto , Anciano , Estudios de Cohortes , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Humanos , Interferones/efectos adversos , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ribavirina/efectos adversos , Ribavirina/uso terapéutico , Resultado del Tratamiento , Adulto JovenAsunto(s)
Amiloide/análisis , Amiloidosis/diagnóstico , Ictericia/etiología , Hepatopatías/diagnóstico , Amiloidosis/patología , Electroforesis de las Proteínas Sanguíneas , Médula Ósea/patología , Diagnóstico Diferencial , Diagnóstico por Imagen , Resultado Fatal , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Ictericia/patología , Hígado/patología , Hepatopatías/patología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Miocardio/patología , Bazo/patologíaRESUMEN
Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.
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Hepatitis C/etiología , Hepatitis C/prevención & control , Trasplante de Hígado/efectos adversos , Oligopéptidos/administración & dosificación , Anciano , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Hepatitis C/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Prevención Secundaria , Resultado del TratamientoRESUMEN
Due to late diagnosis and a pronounced chemoresistance, most patients with hepatocellular carcinoma (HCC) have an overall poor prognosis. Measles vaccine viruses (MeV) have been shown to possess anti-tumor properties and their efficacy has been enhanced by arming with suicide genes. To test armed MeV for the treatment of HCC, we equipped it with the suicide gene Super-cytosine deaminase (SCD) and tested the efficacy in cell culture and in a mouse xenograft model of human HCC. Prodrug conversion was investigated in cell culture and quantified by high-performance liquid chromatography. We observed a strong oncolytic activity of MeV-SCD against human HCC in vitro and in vivo. The prodrug was efficiently converted in infected cells leading to a significant enhancement of the cytotoxic effect. Treatment of HCC xenografts with MeV caused long-term virus replication in tumor tissue. We show that the suicide gene therapy induces an apoptosis-like cell death but is not dependent on intact apoptosis pathways. These results demonstrate that MeV-based suicide gene therapy is a promising novel therapy regimen for HCC overcoming resistance towards conventional therapy. The independence from apoptosis raises hopes for the treatment of patients whose tumor cells exert defects in this cell death mechanism.
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Apoptosis , Carcinoma Hepatocelular/terapia , Citosina Desaminasa/genética , Virus del Sarampión , Viroterapia Oncolítica , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Chlorocebus aethiops , Cromatografía Liquida , Terapia Combinada , Citosina Desaminasa/metabolismo , Resistencia a Antineoplásicos , Genes Transgénicos Suicidas , Terapia Genética , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/terapia , Vacuna Antisarampión , Virus del Sarampión/genética , Ratones , Ratones Desnudos , Virus Oncolíticos/genética , Células Tumorales Cultivadas , Células Vero , Replicación Viral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To preclinical assess the feasibility of combining oncolytic measles vaccine virus (MeV) with suicide gene therapy for ovarian cancer treatment. METHODS: We genetically engineered a recombinant MeV armed with a yeast-derived bifunctional suicide gene that encodes for cytosine deaminase and uracil phosphoribosyltransferase (MeV-SCD). From this suicide gene, a chimeric protein is produced that converts the non-toxic prodrug 5-fluorocytosine (5-FC) into highly cytotoxic 5-fluorouracil (5-FU) and directly into 5-fluorouridine monophosphate (5-FUMP) thereby bypassing an important mechanism of chemoresistance to 5-FU. RESULTS: MeV-SCD was demonstrated to infect, replicate in and effectively lyse not only human ovarian cancer cell lines, but also primary tumor cells (albeit at lower efficiencies) that were derived from malignant ascites of ovarian cancer patients. Addition of the prodrug 5-FC significantly enhanced cell killing. Importantly, precision-cut tumor slices of human ovarian cancer patient specimens were efficiently infected with MeV-SCD. The prodrug-converting enzyme SCD was expressed by all infected tumor slices, thereby ensuring provision of the suicide gene arming function in patient-derived materials. CONCLUSIONS: With respect to safety and therapeutic impact, arming of oncolytic measles vaccine virus warrants further clinical investigation for ovarian cancer treatment.
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Citosina Desaminasa/genética , Terapia Genética , Virus del Sarampión/genética , Viroterapia Oncolítica/métodos , Neoplasias Ováricas/terapia , Pentosiltransferasa/genética , Línea Celular Tumoral , Femenino , Flucitosina/farmacología , Humanos , Vacuna Antisarampión , Saccharomyces cerevisiae/enzimologíaRESUMEN
Oncolytic viruses are replication competent "live" viruses. They infect tumor cells, replicate highly selective inside and thereby destroy them. Because of the enormous advances in the field of genetic engineering and biotechnology during the last decade, virotherapy is increasingly used within clinical trials and proved to be safe and effective. In particular, treatment of ovarian cancer patients is one main focus of research. On the one hand, this is due to the poor prognosis of this dismal entity, resulting in the urgent need for novel therapeutics. On the other hand, as ovarian cancer typically spreads within the peritoneal cavity, intraperitoneal administration of oncolytic viruses is feasible. This paper provides an overview of promising results from clinical trials to treat ovarian cancer patients with oncolytic viruses.
RESUMEN
HISTORY AND CLINICAL FINDINGS: Case 1: A 46-year old female patient presented with a recently occurred icterus of unknown origin as well as dark urine and decolored stool. No diseases were found in the patient's medical history. Clinical examination showed no other findings exept from the icterus. Case 2: A 48-year old female patient was admitted to hospital with epigastric pain and icterus. Similar symptoms reoccurred regularly since several years. The patient already underwent cholecystectomy and an ERCP (endoscopic retrograde cholangiopancreaticography) that showed no pathological findings. She reported chronic pain in her finger joints and appearance of haematomas without adequate trauma. CLINICAL INVESTIGATIONS: Case 1: We found highly elevated liver enzymes and bilirubin. Ultrasound examination was unremarkable.The laboratory examination showed a negative serology for hepatitis A, B and C, marked immunoglobulin G (IgG) elevation and hypergammaglobulinaemia. Liver biopsy and analysis of autoimmune antibodies were performed showing high titers of antinuclear antibodies (ANA) and smooth muscle antibodies (SMA). Case 2: We found a considerably reduced liver function with low albumin and prothrombin time, as well as a moderate elevation of liver enzymes and a high bilirubin. Ultrasound examination revealed hepatic parenchymal changes, splenomegaly, and ascites. Oesophagogastroduodenoscopy showed oesophageal varices I°. Serology for hepatitis A, B, and C was negative. Also in this case, a marked IgG elevation and hypergammaglobulinaemia were found. Liver biopsy was performed. Autoimmune antibodies (ANA and SMA) were detectable with high titers. DIAGNOSIS, TREATMENT AND COURSE: In both cases, we diagnosed an autoimmune hepatitis by means of laboratory values, histological findings and detection of typical autoantibodies. Immediate therapy with high-dose prednisolone therapy was initiated (case 1: 60 mg/day; case 2: 100 mg/day), resulting in improvement of patients' condition, clinical findings and laboratory values in both cases. Case 1: The patient showed fast recovery under prednisolone and the further course was without any complications. Continuous therapy with 15 mg /day and clinical monitoring through day hospital was recommended. Case 2: We saw a slower recovery and prolonged reduced liver function with the necessity to substitute coagulation factors. Furthermore, the therapy of subsequent complications, such as surgical drainage of a haematoma, oedema, wound healing disorder and infections under prednisolone was necessary. Liver transplantation is planned if the disease progresses further. CONCLUSION: Elevated liver enzymes should always be further investigated. Autoimmune hepatitis is a rare disease. Rapid response to immunosuppressive therapy, such as prednisolone, is characteristic. Early diagnosis and therapy are essential for the patients prognosis. Liver transplantation is indicated in advanced disease.
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Hepatitis Autoinmune/diagnóstico , Antiinflamatorios/uso terapéutico , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Bilirrubina/sangre , Biopsia , Terapia Combinada , Progresión de la Enfermedad , Femenino , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/patología , Humanos , Inmunoglobulina G/sangre , Ictericia/etiología , Hígado/patología , Pruebas de Función Hepática , Trasplante de Hígado , Persona de Mediana Edad , Músculo Liso/inmunología , Prednisolona/uso terapéutico , PronósticoRESUMEN
The misuse of somatic gene therapy for the purpose of enhancing athletic performance is perceived as a coming threat to the world of sports and categorized as 'gene doping'. This article describes a direct detection approach for gene doping that gives a clear yes-or-no answer based on the presence or absence of transgenic DNA in peripheral blood samples. By exploiting a priming strategy to specifically amplify intronless DNA sequences, we developed PCR protocols allowing the detection of very small amounts of transgenic DNA in genomic DNA samples to screen for six prime candidate genes. Our detection strategy was verified in a mouse model, giving positive signals from minute amounts (20 µl) of blood samples for up to 56 days following intramuscular adeno-associated virus-mediated gene transfer, one of the most likely candidate vector systems to be misused for gene doping. To make our detection strategy amenable for routine testing, we implemented a robust sample preparation and processing protocol that allows cost-efficient analysis of small human blood volumes (200 µl) with high specificity and reproducibility. The practicability and reliability of our detection strategy was validated by a screening approach including 327 blood samples taken from professional and recreational athletes under field conditions.
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Rendimiento Atlético , Doping en los Deportes/métodos , Doping en los Deportes/prevención & control , Terapia Genética/métodos , Transgenes/genética , Animales , Dependovirus/genética , Componentes del Gen , Humanos , Ratones , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la Polimerasa/métodos , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
A 67-year-old male patient with a pancreatic carcinoma and hepatic metastases was admitted with progressive dyspnea and anuria. Previously he had received five cycles of a palliative chemotherapy with gemcitabine and responded well with a reduction of the tumor mass. The laboratory results showed a distinct anemia, thrombocytopenia, an increase in creatinine and lactate dehydrogenase levels. With an additional finding of 21 per mille fragmentocytes in the periphery blood smear, we diagnosed a thrombotic microangiopathy (TMA). Until now the literature lacks well-defined therapy standards for this known but rare condition of gemcitabine. In a few case reports addressing the related microangiopathy of thrombotic thrombocytopenic purpura (TTP), which is characterised by a significant reduction of the von Willebrand factor (vWF) cleaving serum protease ADAMTS-13, encouraging results have been achieved by an immediate plasma exchange. Though ADAMTS-13 activity was not relevantly reduced in our patient, we still observed a rapid improvement of the clinical features as well as of LDH, thrombocytes and fragmentocytes under plasma exchange. The patient was discharged after one month in good clinical condition. Interestingly, during follow-up for further 21 months we found a continued stable status of the pancreatic carcinoma without any cytostatic therapy. In summary, this case provides evidence that the use of plasma exchange therapy in gemcitabine-associated TMA is justified.
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Antimetabolitos Antineoplásicos/efectos adversos , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/secundario , Desoxicitidina/análogos & derivados , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/inducido químicamente , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Eritrocitos/patología , Síndrome Hemolítico-Urémico/inducido químicamente , Síndrome Hemolítico-Urémico/patología , Humanos , Masculino , Cuidados Paliativos , Plasmaféresis , Púrpura Trombocitopénica Trombótica/patología , Púrpura Trombocitopénica Trombótica/terapia , Resultado del Tratamiento , GemcitabinaAsunto(s)
Aire , Pólipos del Colon/cirugía , Colonoscopía/efectos adversos , Neumoperitoneo/etiología , Complicaciones Posoperatorias/etiología , Escroto , Enfisema Subcutáneo/etiología , Anciano , Enfermedades del Colon/etiología , Enfermedades del Colon/cirugía , Humanos , Perforación Intestinal/etiología , Perforación Intestinal/cirugía , Masculino , Neumoperitoneo/cirugía , Complicaciones Posoperatorias/cirugía , Reoperación , Enfisema Subcutáneo/cirugía , Instrumentos Quirúrgicos , Procedimientos InnecesariosAsunto(s)
Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Intrahepáticos , Colangiocarcinoma/diagnóstico , Hepatopatías/diagnóstico , Sarcoidosis/diagnóstico , Anciano , Colangiopancreatografia Retrógrada Endoscópica , Diagnóstico Diferencial , Humanos , Ictericia Obstructiva/etiología , Imagen por Resonancia Magnética , MasculinoRESUMEN
New therapeutic strategies that notably lack cross resistance with established treatment regimens are much needed in gastroenterological oncology. One such approach is therapeutic anti-angiogenesis which aims at the inhibition of vasculature growth in solid tumours. Since numerous gastrointestinal tumours show strong tumour neoangiogenesis and consequently are highly vascularised, anti-angiogenic therapies will play a pivotal role in tomorrow's gastroenterological oncology. Hence, this review covers (i) basic mechanisms of tumour angiogenesis, (ii) recent anti-angiogenic strategies in the field of gastroenterological oncology as well as (iii) a discussion of their current limitations and perspectives.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular , Adulto , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Celecoxib , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Modelos Animales de Enfermedad , Neoplasias Esofágicas/tratamiento farmacológico , Femenino , Predicción , Neoplasias Gastrointestinales/irrigación sanguínea , Neoplasias Gastrointestinales/prevención & control , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Neoplasias Pancreáticas/tratamiento farmacológico , Lesiones Precancerosas/prevención & control , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Factores de Crecimiento Endotelial Vascular , Sulfonamidas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Magnetic resonance (MR)-guided liver biopsy was performed in three patients with hepatocellular carcinoma. The tumor was considered (n = 2) or proven (n = 1) inaccessible with ultrasound or computed tomographic guidance. Because all lesions were poorly delineated on nonenhanced MR imaging, contrast agents (Gd-BOPTA, n = 1; ferucarbotran, n = 2) were applied to facilitate biopsy in an open low-field scanner. Postcontrast tumor conspicuity was fair in the patient receiving Gd-BOPTA and excellent in both patients receiving ferucarbotran, and biopsy was successful in all cases.
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Carcinoma Hepatocelular/patología , Medios de Contraste , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Meglumina/análogos & derivados , Anciano , Biopsia , Gadolinio , Humanos , Hígado/patología , Masculino , Compuestos OrganometálicosRESUMEN
Current concerns over insertional mutagenesis by retroviral vectors mitigate investigations into alternative, potentially persistent gene therapy vector systems not dependent on genomic integration, such as Sendai virus vectors (SeVV). Prenatal gene therapy requires efficient gene delivery to several tissues, which may not be achievable by somatic gene transfer to the adult. Initially, to test the potential and tropism of the SeVV for gene delivery to fetal tissues, first-generation (replication- and propagation-competent) recombinant SeVV, expressing beta-galactosidase was introduced into late gestation immunocompetent mice via the amniotic and peritoneal cavities and the yolk sac vessels. At 2 days, this resulted in very high levels of expression particularly in the airway epithelium, mesothelium and vascular endothelium, respectively. However, as expected, substantial vector toxicity was observed. The efficiency of gene transfer and the level of gene expression were then examined using a second-generation SeVV. The second generation was developed to be still capable of cytoplasmic RNA replication and therefore high-level gene expression, but incapable of vector spread due to lack of the gene for viral F-protein. Vector was introduced into the fetal amniotic and peritoneal cavities, intravascularly, intramuscularly and intraspinally; at 2 days, expression was observed in the airway epithelia, peritoneal mesothelia, unidentified cells in the gut wall, locally at the site of muscle injection and in the dorsal root ganglia, respectively. Mortality was dramatically diminished compared with the first-generation vector.
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Enfermedades Fetales/terapia , Feto/metabolismo , Terapia Genética/métodos , Vectores Genéticos/toxicidad , Enfermedades Pulmonares/terapia , Proteínas Virales de Fusión/genética , Adenoviridae/genética , Animales , Animales Recién Nacidos , Virus Defectuosos , Inyecciones Intravenosas , Pulmón/enzimología , Enfermedades Pulmonares/embriología , Ratones , Ratones Endogámicos , Modelos Animales , Virus Sendai/genética , beta-Galactosidasa/genéticaRESUMEN
PURPOSE: Imaging artifacts in magnetic resonance tomography (MRT) caused by metallic vascular implants (stents) were characterized systematically in dependence on the material and the construction of the implants as well as with respect to different measurement protocols and for different static field strength B (0). METHODS: Twelve stents, different in material (stainless steel, nitinol, Co-alloy) and/or construction, were examined at B (0) = 0.2 T and 1.0 T with two 2D gradient echo (GE) sequences (TE = 4 and 10 ms), one 3D GE sequence and one spin echo (SE) sequence. The stents were put into water with Gd-DTPA contrast agent. The dependence on the orientation was analyzed for the 9 possibilities of an orthogonal alignment of the stent axis, the direction of B (0), the slice, the read out, and the phase encoding direction. Special interest was given to the visibility of the stent lumen at forced rf excitation, as well as to the influence of broken struts on the signal obtained. RESULTS: For the examined stents GE technique showed, due to spin dephasing regions a total signal loss ranging up to 8 mm away from the stent mashes. The value depends on the stent material, the stent orientation in the scanner and grows with voxel size, echo time and B (0). In SE technique dephasing artifacts vanish and wrong spatial encoding gets visible, rf shielding is more pronounced. The visibility of the stent lumen ranges from nearly unperturbed down to a complete signal loss. An improvement is possible using enlarged flip angles. Broken struts can not be imaged significantly. DISCUSSION: The MR representation of metallic stents commercially available at the time, especially of nitionol stents, can be optimized with a suitable adaptation of the imaging parameters. However, a profound improvement can only be expected from new stent material and design.
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Artefactos , Imagen por Resonancia Magnética , Stents , Aleaciones , Medios de Contraste , Gadolinio DTPA , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Metales , Acero Inoxidable , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
Gastroenterological oncology requires new strategies with new mechanisms of action and without cross-resistance to currently available treatment regimes. Virotherapy which is based on the employment of replication-competent viral vectors exhibiting strong oncolytic properties is such an approach currently under preclinical/clinical investigation. Techniques of molecular virology are required for further improvement of current vectors, particularly with respect to oncolytic activity, tumour selectivity, tumour spread capacity, and safety.