Martín Gutiérrez

Magnetic nanoparticles for local drug delivery using magnetic implants

Magnetic nanoparticles are good candidates used for the targeted delivery of anti-tumor agents. They can be concentrated on a desired region, reducing collateral effects and improving the efficiency of the chemotherapy. We propose a method in which permanent magnets are implanted by laparoscopic technique directly in the affected organ. This method proposes the use of Fe@C nanoparticles, which are loaded with doxorubicin and injected intravenously. The particles, once attracted to the magnet, release the drug at the tumor region. This method seems to be more promising and effective than that based on the application of external magnetic fields.

Hypercoagulability state in hip and knee surgery: influence of ABO antigenic system and allogenic transfusion

It is well know that people with blood group O have a lower risk for venous thromboembolic disease (VTED) than does the general population. Moreover blood transfusion has been identified as a risk factor for VTED in patients with major trauma. The aim of this work is to investigate the behaviour of several markers of hypercoagulability before and after substitutive surgery of hip and knee in order to evaluate the relationship between the plasmatic levels of these markers, the ABO antigenic system and the allogenic blood transfusion. The plasmatic levels of D dimer (D-D), thrombin-antithrombin complex (TAT), and fragment 1 + 2 of prothrombin (F1 + 2) have been determined by the ELISA method in 79 patients subject to substitutive surgery of hip or knee one day before and one day after surgery. The 41 patients with blood groups different from O had presurgical levels of F1 + 2 higher than those of group O (p = 0.004), while no differences could be found for D-D and TAT. The 28 patients who received allogenic blood presented higher levels of D-D one day after surgery than non-transfused patients (p = 0.043); the practice of transfusion did not modify significantly the levels of TAT and F1 + 2 after surgery. In accordance with these results we suggest that blood group and transfusion are risk factors for hypercoagulability, and therefore we advise for a restrictive policy of transfusion practice. New therapies such as aprotinin should be assayed in order to minimize blood loss.

Quality of life in breast cancer patients assessed using the EORTC questionnaires

The aim of the present study was to evaluate the quality of life in a sample of breast cancer patients during treatment.To that end, one hundred and seventy seven consecutive patients at different stages of the disease and who had previously undergone surgery were recruited. Patients completed the EORTC QLQ-C30 (version 2.0) and the breast cancer module (QLQ-BR23) at three different points of time during treatment and follow-up. Demographic and clinical variables were also recorded. We have compared groups according to stage and surgery. We have studied the changes in their quality of life over time.The quality of life scores reflect moderate limitations in some dimensions at the three assessments. At the second and third assessment, there were also limitations related to treatment side effects. There were differences on most of the quality of life dimensions between patients at different stages of the disease. The differences between surgery modalities were limited to body image. Quality of life seems relatively stable across the first and second assessments and has improved in some areas at the third in the patients who have filled in the three assessments (n=141). Therapies thus cause some deterioration in quality of life at the second assessment, which has improved by time of the third assessment.The quality of life scores and the clinical variables indicate that the situation of these patients is generally satisfactory. A comparison of scores over time of the patients who have filled in the three questionnaires indicates that these women receive treatment that, in general, they can tolerate adequately.ResumenEl objetivo de este trabajo es evaluar la calidad de vida de una muestra de pacientes con cáncer de mama durante el tratamiento.Ciento setenta y siete pacientes con cáncer de mama en diferentes estadios de la enfermedad y que habían recibido cirugía previamente han contestado el cuestionario EORTC QLQ-C30 (versión 2.0) y el módulo de mama QLQ-BR23 en 3 puntos a lo largo del tratamiento y seguimiento. Se han recogido además datos demográficos y clínicos. Se han comparado grupos formados en función del estadio y la cirugía, y se han estudiado los cambios en la calidad de vida a lo largo del tiempo.Las puntuaciones de calidad de vida muestran limitaciones moderadas en algunas dimensiones en las 3 evaluaciones. En la segunda y tercera medición había también limitaciones relacionadas con los efectos secundarios de los tratamientos. Se daban diferencias en la mayoría de las dimensiones de calidad de vida entre los pacientes agrupados según los estadios de la enfermedad. Las diferencias entre las modalidades de cirugía se limitaban a la imagen corporal. La calidad de vida se ha mantenido relativamente estable entre la primera y segunda medición, y ha mejorado en algunas áreas en la tercera en las pacientes que han completado las 3 mediciones (n=141). Los tratamientos, por tanto, causan algún deterioro en la calidad de vida de estos pacientes en la segunda medición que mejora en el momento de la tercera.Las puntuaciones de calidad de vida y las variables clínicas indican que la situación de estos pacientes es generalmente satisfactoria. Una comparación de las puntuaciones a lo largo del tiempo de las pacientes que han completado las 3 mediciones indica que reciben un tratamiento que en general pueden tolerar adecuadamente.

Hemorheological profile in chronic venous insufficiency after surgery.

In recent years, there have been rheological abnormalities reported in chronic venous insufficiency (CVI), mainly an increase of erythrocyte aggregability (EA), which probably take part in the pathophysiology of the disease. The aim of this study was to analyze the hemorheological profile after stripping in 45 patients suffering from CVI. Follow-up included laboratory tests on the 7th, 60th and 180th day after surgery. EA was assessed with a photometric aggregometer (MA1, Myrenne) in stasis and low shear (3 s–1). The results show an increase of EA on the 7th day after surgery (p < 0.001). Two and 6 months later, EA values returned to those found prior to surgery. The plasma fibrinogen level changes in a way parallel to EA. The association between rheological disturbances and thrombogenesis is well known, so the hyperaggregability found supports the antithrombotic prophylaxis in the early postsurgical period. On the other hand, the hemorheological abnormalities persist after stripping, so postsurgical treatment to inhibit EA may be beneficial.

Etoposide plus cisplatin with concurrent radiotherapy in the treatment of small-cell lung cancer

IntroductionSince the decade of the 80s, the etoposide plus cisplatinum regimen has been the standard treatment in patients with localised small-cell lung cancer (SCLC). Randomised trials have demonstrated the benefit of chemotherapy in combination with hyper-fractionated radiotherapy in this subset of patients.Material and methodsBetween January 1993 and June 1999, a total of 59 patients with localised SCLC were recruited into the study. All patients received 4 cycles of chemotherapy every 21 days. The first cycle was administered concurrently with hyper-fractionated radiotherapy. Prophylactic cranial irradiation (PCI) was administered subsequently when complete response was obtained.ResultsThe proposed treatment schedule was successfully accomplished in 54 patients. The more important toxicities noted were oesophagitis and myelotoxicity, febrile neutropenia in 6 patients (10%), and oesophagitis grade IV in 9 patients (15%). Complete response was achieved in 39 cases (72%) and partial response in 11 (20%). Median survival was 20 months.ConclusionsWe conclude that the schedule combining etoposide + cisplatin with concurrent hyperfractionated radiotherapy is the best therapeutic scheme currently on offer in the management of patients with localised SCLC.ResumenIntroducciónDesde la década de los 80, el etopósido asociado al cisplatino ha sido el tratamiento estándar de los pacientes con carcinoma de pulmón de células pequeñas, enfermedad limitada. Estudios aleatorios han demostrado el beneficio de la asociación de quimioterapia con radioterapia en este grupo de pacientes.Material y métodosEntre enero de 1993 y junio de 1999, un total de 59 pacientes fueron tratados. Todos los pacientes recibieron 4 ciclos de quimioterapia, separados 21 días, siendo el primero de ellos concomitante con la radioterapia hiperfraccionada; posteriormente, se procedió a irradiación profiláctica cerebral a los pacientes que habían alcanzado respuesta completa.ResultadosDe los 59 pacientes, 54 recibieron el tratamiento previsto. Las toxicidades más importantes fueron la esofagitis y la mielotoxicidad, neutropenia febril en 6 pacientes (10%) y esofagitis grado IV en 9 (15%). En 39 pacientes se alcanzó respuesta completa (72%) y respuesta parcial en 11 (20%). La mediana de supervivencia fue de 20 meses, siendo la supervivencia a los 2, 3 y 4 años del 45%, 29% y 22% respectivamente.ConclusionesLa combinación de etopósido y cisplatino con radioterapia hiperfraccionada concomitante es en la actualidad el mejor esquema que podemos ofrecer a los pacientes con carcinoma de pulmón de células pequeñas, enfermedad limitada.

Hematotoxicity of magnetite nanoparticles coated with polyethylene glycol: in vitro and in vivo studies

Hematotoxicity of magnetite nanoparticles coated with dimercaptosuccinic acid (DMSA) and polyethylene glycol (PEG) has been evaluated by determining their safety in vitro and in vivo in a rat model up to 30 days after administration of a single dose. The in vitro analysis consists of global plasma coagulation (PT, aPTT, and fibrinogen) and platelet aggregation tests while the hematotoxicity studies in vivo include a complete blood count and the possible genotoxic effect analysis in the bone marrow hematopoietic function. Prolonged aPTT values indicate a higher anticoagulant effect for NP-DMSA compared with PEG-coated nanoparticles as a consequence of the higher surface charge of the former. The in vivo tests showed that these bioferrofluids do not cause genotoxic effects, affect erythropoiesis or increase the number of immature erythrocytes in the bone marrow at the analyzed dose. However, nanoparticle administration showed a significant effect on the leukocyte counts in animals treated with DMSA coated nanoparticles 24 h after injection. This response is not observed in animals treated with PEG modified nanoparticles which justifies the use of this polymer in biomasking strategies.

Magnetic Nanoparticle Complexes for Drug Delivery, and Implanted Magnets for Targeting

Bioferrofluids obtained from carbon coated iron nanoparticles are promising candidates for magnetic drug delivery. The magnetic nanoparticles can be concentrated on a desired region, reducing collateral effects and improving the efficiency of the chemotherapy. We propose a method in which permanent magnets are implanted by laparoscopic technique directly in the affected organ. This method proposes the use of Fe@C nanoparticles, which are loaded with doxorubicin and injected intravenously. The particles, once attracted to the magnet, release the drug at the tumor region. This method seems to be more promising and effective than that based on the application of external magnetic fields.

Estudio experimental sobre quimioterapia focalizada en riñón mediante arpón magnético y administración intravenosa de nanopartículas ferrocarbonosas

El empleo de nanoparticulas en el transporte de farmacos es actualmente uno de los temas de interes prioritario dentro del campo de la investigacion biomedica. Nuestro objetivo es mostrar los resultados iniciales de un metodo inedito para focalizar en organos solidos nanoparticulas ferro carbonosas quimioportadoras. Hemos obtenido y caracterizado diversos tipos de nanoparticulas ferromagneticas, y hemos estudiado su comportamiento in vitro e in vivo en animales de experimentacion con dianas magneticas intrarrenales implantadas laparoscopicamente.

Neoadjuvant chemotherapy and preoperative chemoradiotherapy in resectable carcinoma of the rectum

IntroductionThe effectiveness of neoadjuvant chemotherapy (Mayo clinic schedule) and continuous oral chemotherapy (tegafur 400 mg and folinic acid 15 mg every 12 hours) administered during preoperative radiotherapy (4,500 cGy over 5 weeks) were studiedMaterials and methodsA total of 53 patients with surgically-resectable rectal adenocarcinoma were treated.ResultsToxicities of ≤ grade II were lower with neoadjuvant chemotherapy while the chemoradiotherapy had higher toxicity rates including grade III diarrhoea (4%), grade III mucositis (4%), and grade III–IV neutropenia (9%). Symptom improvement ocurred in 38% of patients after neoadjuvant chemotherapy coparative with 55% following the first week of chemoradiotherapy. Surgery was curative in 97% of the patients: abdominoperineal amputation in 24 patients (47%) and conservative surgery in 28 (53%). Down-staging ocurred in 24 patients (46%), and 7 patients (14%) showed pathological complete response. Overvall survival at 5 years, with a median follow-up of 50 months, was 70% (cancer-specific survival was 75%) with significant differences recorded between N+ and N0 patients (56% and 76%, respectively; p<0.001), and between T-0-1-2 and T3 patients (73% and 56%, respectively; p<0.001). Only 2 patients (3%) had local relapse.ConclusionThis treatment scheme was well tolerated and had high rate of local control and longterm times.ResumenIntroducciónEn este estudio analizamos la utilidad de un régimen con quimioterapia neoadyuvante (esquema de la Clínica Mayo) y quimioterapia continua oral (tegafur 400 mg y ácido folínico 15 mg cada 12 horas) asociada a radioterapia preoperatoria (4.500 cGy, en 5 semanas).Materiales y métodosSe trataron 53 pacientes con cáncer de recto resecable.ResultadosLa quimioterapia neoadyuvante presentó baja toxicidad, ≤ grado II, mientras que con la quimiorradioterapia se observaron mayores toxicidades: diarrea grado III (4%), mucositis grado III (4%) y neutropenia grados III–IV (9%). Un 38% de los pacientes presentaron alivio de sus síntomas tras la quimioterapia neoadyuvante (55% tras la primera semana de la quimiorradioterapia). Se realizó cirugía curativa en el 97% de los pacientes: amputación abdominoperineal en 24 (47%) y resección anterior en 28 (53%). Se observó disminución del estadio en 24 pacientes (46%), con 7 pacientes (14%) con respuesta patológica completa. La supervivencia global a 5 años, con una mediana de seguimiento de 50 meses, fue del 70% (cáncer-específica 75%): se encontraron diferencias significativas entre N+y No (56% y 76%, p<0,001), y entre pacientes con To-1-2 y pacientes con T3 (73% y 56%, p<0,001). Sólo dos pacientes (3%) han presentado recaída local.ConclusiónEste esquema de tratamiento fue bien tolerado, consiguiendo unos altosratios de control local y de supervivencia a largo plazo.

Cisplatin-based chemotherapy and hyperfractionated radiotherapy for stage III non-small cell lung cancer: survival and patterns of failure after long follow-up

The main purpose of this prospective non randomized trial was to analyse whether induction chemotherapy and hyperfractionated radiotherapy combined with cisplatin can improve the long-term survival of patients with locally advanced non small cell lung cancer.From 1992 to 1995, 70 patients received the programmed treatment scheme with: one cycle of induction chemotherapy with mitomycin 10 mg/m2/day 1, cisplatin 100 mg/m2 day 1 and vindesine 3 mg/m2/days 1, 8 and 15, followed after 4 weeks of hyperfractionated radiotherapy (1.2 Gy twice/day, five days per week, until total dose of 69.6 Gy) concomitant with cisplatin 20 mg/m2/day by continuous infusion, for 5 days in the first and fifth weeks of radiotherapy. Patients with stage IIIA, good performance status and radiological partial response were candidated to surgical rescue.Thirty-two patients (45.7%) developed severe toxicity (WHO grade 5–4). Complete radiological response was observed in 9 patients (12.8%). Overall median survival time was 14 months, 2-year survival of 20% and 5-year survival of 12%. The cause of dead was by local progression in 42%, distant metastases in 40%, simultaneous relapse in 10% and intercurrent disease in 8%. Patients with stage IIIA (n=16, 7 with surgical rescue) had a 5-year survival of 52%, and patients with stage IIIB (n=54) of 6%.Long-term results with this treatment scheme are disappointing, only patients with stage IIIA and surgical rescue showed an improvement on survival. In spite of chemotherapy and high radiation dose, local-regional progression and distant metastases remain significant patterns of failure and dead of these patients.ResumenEl objetivo principal de este estudio no aleatorizado fue investigar si la combinación de quimioterapia de inducción con radioterapia hiperfraccionada asociada a cisplatino puede mejorar la supervivencia a largo plazo de los pacientes con carcinoma de pulmón no microcítico en estadio localmente avanzado.Entre 1992 y 1995, 70 pacientes recibieron el esquema de tratamiento programado con un ciclo de quimioterapia de inducción con mitomicina 10 mg/m2/día 1, cisplatino 100 mg/m2 día 1 y vindesina 3 mg/m2 días 1, 8 y 15, administrando 4 senmanas después la radioterapia hiperfraccionada (1,2 Gy sesión/dos veces día, 5 días por semana, hasta dosis total de 69,6 Gy) concomitante con cisplatino 20 mg/m2/día en infusión continua, durante 5 días en la primera y quinta semana de la radioterapia. Los pacientes con estadio IIIA, buen estado general y respuesta parcial radiológica fueron candidatos paracirugía de rescate.Treinta y dos pacientes (45,7%) presentaron toxicidad severa (grados 5–4 de la Organización Mundial de la Salud [OMS]). Se observó respuesta radiológica completa en 9 pacientes (12,8%). La mediana de supervivencia global fue de 14 meses, la supervivencia a dos años del 20% y a 5 años del 12%. La causa de muerte fue progresión local en 42%, metástasis a distancia en 40%, recaída simultánea en 10% y enfermedad intercurrente en 8%. Los pacientes con estadio IIIA (n=16,7 con cirugía de rescate) tuvieron una supervivencia a 5 años del 52% y los pacientes con estadio IIIB (n=54) del 6%.Los resultados a largo plazo con este esquema terapéutico son desalentadores, sólo los pacientes con estadio IIIA y rescate quirúrgico mostraron un incremento en la supervivencia. A pesar de la quimioterapia y altas dosis de radiación, la progresión locorregional y las metástasis a distancia continúan siendo las principales causas de recaída y muerte en estos pacientes.