Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Safety and efficacy of autologous hematopoietic stem-cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis.

BACKGROUND AND PURPOSE: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. METHODS: Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow-up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. RESULTS: A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. CONCLUSIONS: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

Local spin dynamics of iron oxide magnetic nanoparticles dispersed in different solvents with variable size and shape: A 1H NMR study.

Colloidal magnetic nanoparticles (MNPs) based on a nearly monodisperse iron oxide core and capped by oleic acid have been used as model systems for investigating the superparamagnetic spin dynamics by means of magnetometry measurements and nuclear magnetic resonance (1H NMR) relaxometry. The key magnetic properties (saturation magnetization, coercive field, and frequency dependent "blocking" temperature) of MNPs with different core size (3.5 nm, 8.5 nm, and 17.5 nm), shape (spherical and cubic), and dispersant (hexane and water-based formulation) have been determined. 1H NMR dispersion profiles obtained by measuring the r1 (longitudinal) and r2 (transverse) nuclear relaxivities in the frequency range 0.01-60 MHz confirmed that in all samples the physical mechanisms that drive the nuclear relaxation are the Néel reversal at low temperature and the Curie relaxation at high frequency. The magnetization reversal time at room temperature extracted from the fitting of NMR data falls in the typical range of superparamagnetic systems (10-9-10-10 s). Furthermore, from the distance of minimum approach we could conclude that water molecules do not arrive in close vicinity of the magnetic core. Our findings contribute to elucidate the local spin dynamics mechanisms in colloidal superparamagnetic nanoparticles which are useful in biomedical application as, e.g., contrast agents for magnetic resonance imaging.

Studying the effect of Zn-substitution on the magnetic and hyperthermic properties of cobalt ferrite nanoparticles.

The possibility to finely control nanostructured cubic ferrites (M(II)Fe2O4) paves the way to design materials with the desired magnetic properties for specific applications. However, the strict and complex interrelation among the chemical composition, size, polydispersity, shape and surface coating renders their correlation with the magnetic properties not trivial to predict. In this context, this work aims to discuss the magnetic properties and the heating abilities of Zn-substituted cobalt ferrite nanoparticles with different zinc contents (ZnxCo1-xFe2O4 with 0 < x < 0.6), specifically prepared with similar particle sizes (∼7 nm) and size distributions having the crystallite size (∼6 nm) and capping agent amount of 15%. All samples have high saturation magnetisation (Ms) values at 5 K (>100 emu g(-1)). The increase in the zinc content up to x = 0.46 in the structure has resulted in an increase of the saturation magnetisation (Ms) at 5 K. High Ms values have also been revealed at room temperature (∼90 emu g(-1)) for both CoFe2O4 and Zn0.30Co0.70Fe2O4 samples and their heating ability has been tested. Despite a similar saturation magnetisation, the specific absorption rate value for the cobalt ferrite is three times higher than the Zn-substituted one. DC magnetometry results were not sufficient to justify these data, the experimental conditions of SAR and static measurements being quite different. The synergic combination of DC with AC magnetometry and (57)Fe Mössbauer spectroscopy represents a powerful tool to get new insights into the design of suitable heat mediators for magnetic fluid hyperthermia.

Characterization of magnetic nanoparticles from Magnetospirillum Gryphiswaldense as potential theranostics tools.

We investigated the theranostic properties of magnetosomes (MNs) extracted from magnetotactic bacteria, promising for nanomedicine applications. Besides a physico-chemical characterization, their potentiality as mediators for magnetic fluid hyperthermia and contrast agents for magnetic resonance imaging, both in vitro and in vivo, are here singled out. The MNs, constituted by magnetite nanocrystals arranged in chains, show a superparamagnetic behaviour and a clear evidence of Verwey transition, as signature of magnetite presence. The phospholipid membrane provides a good protection against oxidation and the MNs oxidation state is stable over months. Using an alternate magnetic field, the specific absorption rate was measured, resulting among the highest reported in literature. The MRI contrast efficiency was evaluated by means of the acquisition of complete NMRD profiles. The transverse relaxivity resulted as high as the one of a former commercial contrast agent. The MNs were inoculated into an animal model of tumour and their presence was detected by magnetic resonance images two weeks after the injection in the tumour mass.

Polydimethylsiloxane films doped with NdFeB powder: magnetic characterization and potential applications in biomedical engineering and microrobotics.

This work reports the fabrication, magnetic characterization and controlled navigation of film-shaped microrobots consisting of a polydimethylsiloxane-NdFeB powder composite material. The fabrication process relies on spin-coating deposition, powder orientation and permanent magnetization. Films with different powder concentrations (10 %, 30 %, 50 % and 70 % w/w) were fabricated and characterized in terms of magnetic properties and magnetic navigation performances (by exploiting an electromagnet-based platform). Standardized data are provided, thus enabling the exploitation of these composite materials in a wide range of applications, from MEMS/microrobot development to biomedical systems. Finally, the possibility to microfabricate free-standing polymeric structures and the biocompatibility of the proposed composite materials is demonstrated.

Design and optimization of lipid-modified poly(amidoamine) dendrimer coated iron oxide nanoparticles as probes for biomedical applications.

Superparamagnetic iron oxide nanoparticles with a wide size range (2.6-14.1 nm) were synthesized and coated with the amphiphilic poly(amidoamine) PAMAM-C12 dendrimer. The resulting well dispersed and stable water suspensions were fully characterized in order to explore their possible use in biomedical applications. The structural and magnetic properties of the nanoparticles were preserved during the coating and were related to their relaxometric behaviour. The Nuclear Magnetic Resonance Dispersion (NMRD) profiles were found to be in accordance with the Roch model. The biocompatibility was assessed by means of cell viability tests and Transmission Electron Microscopy (TEM) analysis. The nanoparticles' capability of being detected via Magnetic Resonance Imaging (MRI) was investigated by means of clinical MRI scanners both in water and agar gel phantoms, and in a mouse model.

Multifunctional magnetic nanoparticles for enhanced intracellular drug transport.

In this paper we report the synthesis and characterization of biocompatible multi-functional magnetic nanoparticles (MNPs) able to enhance the intracellular transport of N-methylated drugs. The Fe3O4 magnetic core was first functionalized with a mixed monolayer consisting of two different phosphonic acids having terminal acetylenic and amino groups, which provide an active platform for further functionalization with organic molecules. Then, a tetraphosphonate cavitand receptor (Tiiii) bearing an azide moiety and the N-hydroxysuccinimide (NHS) activated forms of poly(ethylene glycol) (PEG), folic acid (FA) and carboxy-X-rhodamine (Rhod) were covalently anchored on alkyne and amine moieties respectively, through 1,3-dipolar cycloaddition and EDC/NHS coupling reactions. The obtained MNPs are biocompatible and possess magnetic, luminescence and recognition properties which make them suitable for multimodal theranostic applications. In particular, combined confocal microscopy and cytotoxicity experiments showed that these multi-functional MNPs are able to recognize a specific drug "in situ" and promote its cellular internalization, thus enhancing its efficiency.

Comparison of the magnetic, radiolabeling, hyperthermic and biodistribution properties of hybrid nanoparticles bearing CoFe2O4 and Fe3O4 metal cores.

Metal oxide nanoparticles, hybridized with various polymeric chemicals, represent a novel and breakthrough application in drug delivery, hyperthermia treatment and imaging techniques. Radiolabeling of these nanoformulations can result in new and attractive dual-imaging agents as well as provide accurate in vivo information on their biodistribution profile. In this paper a comparison study has been made between two of the most promising hybrid core-shell nanosystems, bearing either magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) cores, regarding their magnetic, radiolabeling, hyperthermic and biodistribution properties. While hyperthermic properties were found to be affected by the metal-core type, the radiolabeling ability and the in vivo fate of the nanoformulations seem to depend critically on the size and the shell composition.

Functionalization of PEGylated Fe3O4 magnetic nanoparticles with tetraphosphonate cavitand for biomedical application.

In this contribution, Fe3O4 magnetic nanoparticles (MNPs) have been functionalized with a tetraphosphonate cavitand receptor (Tiiii), capable of complexing N-monomethylated species with high selectivity, and polyethylene glycol (PEG) via click-chemistry. The grafting process is based on MNP pre-functionalization with a bifunctional phosphonic linker, 10-undecynylphosphonic acid, anchored on an iron surface through the phosphonic group. The Tiiii cavitand and the PEG modified with azide moieties have then been bonded to the resulting alkyne-functionalized MNPs through a "click" reaction. Each reaction step has been monitored by using X-ray photoelectron and FTIR spectroscopies. PEG and Tiiii functionalized MNPs have been able to load N-methyl ammonium salts such as the antitumor drug procarbazine hydrochloride and the neurotransmitter epinephrine hydrochloride and release them as free bases. In addition, the introduction of PEG moieties promoted biocompatibility of functionalized MNPs, thus allowing their use in biological environments.

NMR-D study of the local spin dynamics and magnetic anisotropy in different nearly monodispersed ferrite nanoparticles.

We present a systematic experimental comparison of the superparamagnetic relaxation time constants obtained by means of dynamic magnetic measurements and (1)H-NMR relaxometry, on ferrite-based nanosystems with different composition, various core sizes and dispersed in different solvents. The application of a heuristic model for the relaxivity allowed a comparison between the reversal time of magnetization as seen by NMR and the results from the AC susceptibility experiments, and an estimation of fundamental microscopic properties. A good agreement between the NMR and AC results was found when fitting the AC data to a Vogel-Fulcher law. Key parameters obtained from the model have been exploited to evaluate the impact of the contribution from magnetic anisotropy to the relaxivity curves and estimate the minimum approach distance of the bulk solvent.

Manejo de enfermedad hepática metastásica colorrectal bilateral: colectomía y hepatectomía multi-etapas: experiencia inicial / Two stage hepatectomy and colectomy among patients with bilateral liver metastases: report of eight cases

Background: Two stage hepatectomy takes advantage of the compensatory regeneration of the liver after a first non curative hepatectomy, to achieve a curative excision in a second intervention. Aim: To report an initial experience with two stage hepatectomy. Material and Methods: Out of sixty four patients who underwent hepatectomy in our institution in the presented period, eight met criteria for colorectal primary and bilateral liver metastatic disease, which we report. Results: Eight patients were subjected to a right portal ligation. In four, a simultaneous metastasis excision in the left lobe was performed. Four to eight weeks later, five were subjected to a right hepatectomy. One patient, that had a relapse of a previous hepatectomy and colectomy, was explored, ligated and afterwards subjected to surgery plus radiofrequency. The six patients that were subjected to excisions were followed for 3 to 39 months. One patient died due to massive pulmonary relapse at 18 months, two were operated again and subjected to radiofrequency, without evidence of residual disease. Two patients have no evidence of relapse and one had a relapse in a rib. Conclusions: In our series, two stage hepatectomy among patients with colorectal cancer and liver metastasis, but its long term results must be evaluated.

Introducción: La hepatectomía en dos etapas utiliza la regeneración compensatoria del hígado tras una primera hepatectomía no curativa para lograr una resección curativa en una segunda intervención. Objetivo: Presentar nuestra experiencia inicial aprovechando esta propiedad, en la estrategia de manejo de pacientes previamente declarados irresecables. Material y Método: Entre Marzo de 2006 y Marzo de 2010, fueron tratados 8 casos. Resultados: De 64 pacientes en los que se realizó hepatectomía, 8 de ellos, con enfermedad metastásica bilateral, confinada al hígado, fueron sometidos a ligadura portal del lado derecho; en la mitad se realizó resección simultánea de enfermedad del futuro remanente hepático izquierdo. Cuatro a 8 semanas más tarde, cinco fueron sometidos a hepatectomía derecha extendida o hepatectomía derecha (con segmento IV previamente resecado), y otro que era recurrente de previa hepatectomía central más colectomía, fue explorado, ligado y luego sometido a cirugía combinada con radiofrecuencia (RFA). Con seguimiento promedio para el grupo resecado RO (n = 6) de 18 meses (3-39), una paciente fallece por recurrencia pulmonar masiva a los 18 meses del diagnóstico, dos se someten a tercera cirugía y RFA con intención curativa, sin evidencia actual de enfermedad, dos no presentan recurrencia y una presenta recurrencia costal, sin evidencia de enfermedad intraabdominal. Otros dos están esperando la hepatectomía post resección del primario y ligadura portal. Conclusión: En nuestro medio, la colectomía y hepatectomía en múltiples etapas en pacientes con enfermedad hepática bilateral metastásica de origen colorrectal es una estrategia factible y razonable para lograr una resección con intención curativa.

Telangiectasia hemorrágica hereditaria: Presentación de un caso clínico y actualización bibliográfica / Hereditary hemorrhagic telangiectasia: Clinical case report and literature update

El propósito de este artículo es presentar un caso clínico de una paciente, con telangiectasia hemorrágica hereditaria. El diagnóstico se basó en los criterios diagnósticos Curaçao. Esta enfermedad es autosómica dominante, edad dependiente y se caracteriza por epistaxis, telangiectasias localizadas en sitios específicos de la piel con compromiso visceral, que incluye malformaciones arteriovenosas en pulmón, sistema nervioso y telangiectasias en el tracto gastrointestinal. Presentamos, asimismo, una revisión de la bibliografía de esta patología.

The purpose of this article is to describe a female patient with hereditary hemorrhagic telangiectasia. The diagnosis was based on Curaçao criteria. This illness is an autosomal dominant and age-dependent vascular disorder, caracterized by epistaxis, telangiectasias located in specific sites on the skin, and visceral involvement, including arteriovenous malformations in lung, brain and liver or telangiectasias in the gastrointestinal tract. We also present a review of the literature, including etiopathogenia and treatment aspects.

Synthesis and characterization of polyethylenimine-based iron oxide composites as novel contrast agents for MRI.

OBJECT: Use of polyethylenimines (PEIs) of different molecular weight and selected carboxylated-PEI derivatives (PEI-COOH) in the synthesis and stabilization of iron oxide nanoparticles, to obtain possible multifunctional contrast agents. MATERIALS AND METHODS: Oxidation of Fe(II) at slightly elevated pH and temperature resulted in the formation of highly soluble and stable nanocomposites of iron oxides and polymer. Composites were characterized and studied by atomic force microscopy (AFM), transmission electron microscopy (TEM), X-ray diffractometry, AC and DC magnetometry, NMR relaxometry and magnetic resonance imaging (MRI). RESULTS: From AFM the dimensions of the aggregates were found to be in the ~150-250 nm size region; the mean diameter of the magnetic core of the compounds named PEI-25, PEI-500 and PEI-COOH60 resulted d approximately 20 +/- 5 nm for PEI-25, d approximately 9.5 +/- 1.0 nm for PEI-500 and d approximately 6.8 +/- 1.0 nm for PEI-COOH60. In PEI-COOH60 TEM and X-ray diffractometry revealed small assemblies of mineral magnetic cores with clear indications that the main constituents are maghemite and/or magnetite as confirmed by AC and DC SQUID magnetometry. For PEI-COOH60, the study of NMR-dispersion profiles revealed r (1) and r (2) relaxivities comparable to superparamagnetic iron-oxide commercial compounds in the whole investigated frequency range 7 < or = nu < or = 212 MHz. CONCLUSION: PEI-25 was studied as possible MRI contrast agent (CA) to map the cerebral blood volume (CBV) and cerebral blood flow (CBF) in an animal model obtaining promising results. The reported compounds may be further functionalized to afford novel multifunctional systems for biomedical applications.

Angiolipoma renal con extensión tumoral a vena cava inferior y aurícula derecha / Left kidney angiomyolipoma, spreading to the renal vein, inferior vena cava and involving the heart: report of one case

El angiomiolipoma renal es un tumor benigno mesenquimático. Constituyen sólo del 2 al 6 por ciento de los tumores renales. Existen alrededor de 12 casos reportados con invasión a las venas renales y la cava inferior. En menos de 5, hay extensión de trombo tumoral hasta aurícula derecha. Objetivo: Presentar el caso clínico, manejo y evolución de una paciente con un angiomiolipoma renal con extensión tumoral a vena renal y cava inferior y que compromete la cavidad auricular derecha casi en su totalidad. Paciente y método: 50 años, sexo femenino con hallazgo del tumor por un ultrasonografía abdominal motivada por el estudio de síntomas digestivos de origen probablemente funcional. Se confirma el diagnóstico con TAC y ecocardiograma doppler. Se realiza una cirugía combinada, abdominal y esternotómica, con la ayuda de un by pass aortopulmonar. Resultados: Nefrectomia izquierda, liberación intravascular del tumor que se empuja por cava inferior y se extrae en block por la aurícula derecha. Evoluciona inicialmente en forma satisfactoria, pero desarrolla distress respiratorio con angio TAC de tórax negativo para TEP a las 48 h de la cirugía. Se inicia anticoagulación empírica con HBPM y encontrándose extubada y en buenas condiciones hace un hemoperitoneo el día 14, encontrándose hemorragia en napa en los sitios de disección previa. De alta a los 21 días. El seguimiento alejado a los 2 años revela una hernia incisional, reparada sin incidentes, y sin otras complicaciones ni signos de recidiva de patología original. Conclusión: El manejo de equipo multidisciplinario nos permitió ayudar exitosamente a esta paciente con patología rara y compleja.

Renal angiomyolipoma is an uncommon benign tumor of mesenchymal origin. In less than five of 12 cases reported with renal vein and inferior vena cava involvement the thrombus extends to the right atrium. We report a 50 years old female with a left kidney angiomyolipoma, spreading to the renal vein, inferior vena cava and involving the heart, invading the right atrium almost completely. The tumor was found during a study for abdominal pain. She underwent combined abdominal and cardiac surgery with pulmonary bypass. A left nephrectomy, cavotomy and intravascular dissection of the tumor were performed. The intravascular mass was pushed from abdomen and pulled out through the right atrium. Forty eight hours after surgery, she developed respiratory distress. A chest angio CT scan negative for pulmonary thromboembolism. However, anticoagulation with low molecular weight heparin was started due to the high risk for thromboembolism. She recovered, but 14 days after the original surgery, presented a massive hemoperitoneum. She was operated again, finding a diffuse oozing from the sites of previous dissection. The dose of anticoagulation was lowered, with a good postoperative evolution, being discharged 21 days later. After two years of follow up, she developed an incisional hernia that is repaired.

Falla hepática fulminante por parvovirus B 19 y trasplante hepático, caso clínico / Acute liver failure by Parvovirus B19 and liver transplant: case report

Introducción: La infección por parvovirus humano B19 (PHB 19) produce un amplio rango de enfermedades que van desde eritema infeccioso en niños hasta artritis aguda en adultos. Algunos estudios sugieren un rol patogénico del PHB 19 en el desarrollo de la hepatitis aguda (HA) y falla hepática fulminante (FHF) en niños y adultos. La Anemia aplástica (AA) es una complicación reconocida de la HA y FHF por PHB 19. Objetivo: Reportar un caso de FHF por infección por PHB 19 y revisar la literatura. Caso clínico: Niña de 7 años de edad con HA que en una semana desarrolló FHF con serología IgM anti-PHB 19 positiva. Otras causas virales, autoinmunes, metabólicas o toxicas fueron descartadas. Fue sometida a trasplante hepático ortotópico (THO) y un año después no ha presentado complicaciones. Conclusiones: El PHB 19 puede causar HA y FHF, su oportuno diagnóstico y tratamiento, que en el caso de la FHF incluye el THO puede resultar en un pronóstico favorable.

Polipo anexial de la piel neonatal / Adnexal polyp of neonatal skin

El pólipo anexial de la piel neonatal (PAPN) es un tumor pequeño, localizado principalmente en la areola de los recién nacidos. Usualmente solitario, se desprende espontáneamente durante la primera semana de vida. Según nuestra casuística, se observa en el 3,6 porciento de los neonatos. Histológicamente se caracteriza por la presencia de elementos anexiales (folículos pilosos, glándulas ecrínas y vestigios de glándulas sebáceas)inmersos en un tejido colágeno laxo

Polipo anexial de la piel neonatal / Adnexal polyp of neonatal skin

El pólipo anexial de la piel neonatal (PAPN) es un tumor pequeño, localizado principalmente en la areola de los recién nacidos. Usualmente solitario, se desprende espontáneamente durante la primera semana de vida. Según nuestra casuística, se observa en el 3,6 porciento de los neonatos. Histológicamente se caracteriza por la presencia de elementos anexiales (folículos pilosos, glándulas ecrínas y vestigios de glándulas sebáceas)inmersos en un tejido colágeno laxo(AU)

Piggyback con anastomosis cavo suprahepáticas término-terminal: una técnica segura en implantación de aloinjerto en trasplante hepático ortotópico / Piggyback with termino-terminal suprahepatic caval anastomosis: a safe technique in allograft implantation in orthotopic liver transplantation

Con el progreso del manejo perioperatorio y la experiencia acumulada por los equipos, el trasplante hepático se ha convertido en una terapia consolidada y exitosa en muchos centros en el mundo. Además de franquear en el tiempo numerosas barreras de tipo técnico, su progreso ha sido potenciado por los avances en inmunosupresión. Se presenta nuestra técnica de elección con preservación de vena cava del receptor (Técnica "piggyback"). Objetivo: Evaluar los resultados con esta técnica y un manejo perioperatorio basado en protocolos clínicos en un centro de trasplante. Métodos: Se incluyen los pacientes cuyo injerto hepático fue implantado por el autor entre los años 2001 y 2003 ambos inclusive. Los datos son recolectados en forma prospectiva. La selección de pacientes, la cirugía del donante y receptor, manejo postoperatorio y seguimiento se realizan según protocolos previamente diseñados. Resultados: Se realizaron 31 trasplantes hepáticos en 30 pacientes cuya edad estaba en el rango 10 meses y 65 años. 16 por ciento de ellos son urgencias. La estadía postoperatoria es de 12 días y disminuye a 9 días si se excluyen las urgencias y los pacientes pediátricos. La sobrevida actuarial de los pacientes e injertos es de 97 y 90 por ciento a 3 años respectivamente. Los resultados son comparables con los mejores reportados en la literatura médica.