RESUMEN
PURPOSE: The standard treatment of T2-T3 rectal adenocarcinoma is radical proctectomy by total mesorectal excision often combined with some neoadjuvant treatment. To reduce morbidity of this surgery, organ preservation strategy using various combination of radiotherapy, chemotherapy and local excision is gaining interest. Some randomized trials have proven the feasibility of such approaches. The OPERA trial demonstrated, for T2 T3<5cm diameter low-middle rectum, that a contact X-ray brachytherapy boost of 90Gy in three fractions over 4 weeks was able to achieve a planned organ preservation in 81% of patients at 3years with 97% success for tumour smaller than 3cm treated with contact X-ray brachytherapy boost first. To try to expand organ preservation to larger tumours we set up a feasibility trial in T2-T3 tumours using total neoadjuvant treatment and a contact X-ray brachytherapy boost. MATERIAL AND METHOD: The trial was approved by the institutional review board of Nice. Inclusion criteria were operable patients, 75years or less, adenocarcinoma of the low-middle rectum staged T2c-T3N0 larger than 3.5cm and less than 6cm in diameter or T2-T3N1 less than 6cm in diameter. Treatment started in all cases with neoadjuvant chemotherapy associating 5-fluoro-uracile, irinotecan and oxaliplatin ('folfirinox' regimen, four to six cycles). In case of good tumour response after four cycles, a contact X-ray brachytherapy boost (delivering 90Gy in three fractions) was given followed by chemoradiotherapy (external beam radiotherapy delivering 50Gy, with concurrent capecitabine). After six cycles if only a partial response (tumour still larger than 3cm) was seen, chemoradiotherapy was given and contact X-ray brachytherapy boost was delivered after that. At the end of this total neoadjuvant treatment a watch and wait strategy was decided in case of clinical complete response or radical proctectomy by total mesorectal excision for partial response. RESULTS: Between July 2019 and October 2022, 14 patients were included; median age was 66years (range: 51-77years), there were nine male and five female, two T2 N1 tumours, seven T3N0, and five T3N1, all were M0. Median tumour diameter was 40mm (range: 11-50mm); three tumours had a circumferential extension greater than 50%. Seven patients received four folfirinox cycles and seven had six cycles. Contact X-ray brachytherapy boost was given during folfirinox chemotherapy before chemoradiotherapy in 11 patients (and after in three). The tolerance was good, with no grade 4-5 toxicity. The main grade 3 early toxicity was in relation with the folfirinox regimen. A clinical complete response was seen in 12 patients at the end of the total neoadjuvant treatment (85%). All these patients are alive and have preserved their rectum with a mean follow-up time of 17.8months (range: 6-48months) and a good bowel function (low anterior rectal resection syndrome score below 30). The main contact X-ray brachytherapy boost toxicity was radiation ulceration in three patients that usually healed within 6 months, sometimes necessitating hyperbaric oxygen. CONCLUSION: The preliminary results of this feasibility study show that early tolerance of these intensive total neoadjuvant treatment is compatible with an acceptable toxicity. The high rate of organ preservation in this intermediate group of T2-T3 tumours is encouraging and is a good argument to start the next randomized TRESOR trial that will aim at achieving a 65% of 3-year survival with organ preservation in this intermediate tumour group.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Braquiterapia , Capecitabina , Quimioradioterapia , Estudios de Factibilidad , Fluorouracilo , Irinotecán , Terapia Neoadyuvante , Oxaliplatino , Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/radioterapia , Neoplasias del Recto/patología , Braquiterapia/métodos , Fluorouracilo/uso terapéutico , Quimioradioterapia/métodos , Adenocarcinoma/terapia , Adenocarcinoma/radioterapia , Adenocarcinoma/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Oxaliplatino/uso terapéutico , Capecitabina/uso terapéutico , Femenino , Masculino , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Tratamientos Conservadores del Órgano/métodos , Estadificación de NeoplasiasRESUMEN
Inflammation and oxidative stress are interrelated processes, during which many pathological processes lead to the reactive oxygen species (ROS) and the cytokines release. The aim of this experimental study was to analyse the effects of chlorogenic acid, in oral daily administration, against the oxidative stress and oedema development in experimental carrageenan-induced rat paw inflammation. The oxidative stress parameters were investigated after a paw inflammation was produced in rats that previoulsy received, for 14 days, either chlorogenic acid (100 mg/day or 150 mg/day) or indomethacin (1 mg/kg/day). The paw oedema was measured through plethysmometry made at 2, 6 and 24 hours after carrageenan injection. The oxidative stress was investigated through spectrophotometry. Blood samples, paw skin and kidneys were collected to investigate malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG). The protein expression of oxidative stress-related pathways was analysed in skin and kidneys through Western blot. The present study showed that indomethacin and both doses of chlorogenic acid, after 14 days of oral administration, exerted antioedematous effects during the inflammation development after carrageenan local injection. Compared to the group that received only carrageenan injection, significant decreases of the inflamed paw volume were shown in the treated groups (P < 0.001), in all inflammation phases. The lipid peroxidation was significantly decreased by both doses of chlorogenic acid in inflamed skin (P < 0.0001) and kidney (P < 0.0001). In serum, it was significantly inhibited by indomethacin (P < 0.01) and by 100 mg/day of chlorogenic acid (P < 0.05). The antioxidant protection, evaluated through the ratio GSH/GSSG, was significantly increased by chlorogenic acid in inflamed skin (P < 0.0001) and kidney (100 mg/day, P < 0.01; 150 mg/day, P < 0.0001). In serum, only indomethacin administration produced significant increases of the antioxidant protection (P < 0.05). Western blot analysis showed significant decreases of COX-2 in inflamed skin and kidney in the groups of rats that received indomethacin or 100 mg/day of chlorogenic acid. The effects of chlorogenic acid on NF-κB and pNF-κB were dose-dependent.
Asunto(s)
Carragenina/toxicidad , Ácido Clorogénico/administración & dosificación , Edema/inducido químicamente , Edema/patología , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Esquema de Medicación , Edema/metabolismo , Masculino , Estrés Oxidativo/fisiología , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Nanotechnology has led to the development of numerous new systems for drug delivery into the target tissue, as well as novel methods that may be useful in the treatment of liver fibrosis. Inorganic and organic nanoparticles (NPs) are currently used in medical investigations and in the treatment of liver diseases, with adverse reactions observed in some cases. A revised treatment procedure involving NPs is necessary to develop future drug delivery systems having minimal noxious effects on the hepatic cells that take up and metabolize these particles in a different manner, in order to find the medication that is capable of blocking and even reversing fibrosis in an inflamed liver. In addition, the administered medication should not induce systemic responses against the NPs used in the treatment.
Asunto(s)
Sistemas de Liberación de Medicamentos , Cirrosis Hepática/tratamiento farmacológico , Nanopartículas , Animales , Desarrollo de Medicamentos , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , NanotecnologíaRESUMEN
It is proposed that at the commercial flight altitude the cosmic radiation affects the human body and induces the oxidative stress. This review presents data to support this idea and also cumulates the information to provide the basis for antioxidant supplementation in persons that travel by plane at high altitudes. The conclusion is that the heterogeneity of cosmic radiation can produce different effects on human body through different mechanisms and the prophylactic treatment with antioxidants can reduce the oxidative stress generated by the radiation exposure.