Meta-analysis of long-term efficacy and safety of hypofractionated radiotherapy in the treatment of early breast cancer.

PURPOSE: To evaluate the efficacy and safety of hypofractionated radiotherapy in women with early stage breast cancer after breast conservative surgery. METHODS: We performed a search for randomized controlled trials (RCTs) that compare conventional fractioning and hypofractioned radiotherapy. The studied outcomes were local and loco-regional recurrence, disease-free survival, mortality, cardiac ischemia, rib fracture and pulmonary fibrosis up to 5 years and 5 years after treatment. Shrinkage of the breast, breast tightening, telangiectasia, breast edema, shoulder stiffness and arm edema were evaluated within 10 years. Cosmesis and acute skin radiation toxicity were evaluated. RESULTS: Ten publications of six RCTs were included. No statistical difference in local and loco-regional recurrence, disease-free survival, mortality, cardiac ischemia, ribs fracture and pulmonary fibrosis, shrinkage of the breast, breast tightening, shoulder stiffness, arm edema and cosmesis was found. However, there was a significant difference in favor of hypofractionated for breast edema (RR 0.68, 95% CI 0.53 to 0.88, p = 0.003, 4675 patients), telangiectasia (RR 0.41, 95% CI 0.19 a 0.87, p = 0.02, 5167 patients), and acute skin radiation toxicity (RR 0.34, 95% CI 0.19 to 0.61, p = 0.0003, 347 patients). CONCLUSION: There is no difference between conventional fractionation and hypofractionated in terms of efficacy when we evaluate local recurrence, loco-regional recurrence, distance recurrence, disease-free survival and mortality. There is also no difference concerning safety when we assess the occurrence of fibrosis, ischemia and ribs fractures. Hypofractionated showed better results in relation to breast edema, telangiectasia, and acute skin radiation toxicity.

Outcome of cerebral arteriovenous malformations after linear accelerator reirradiation.

BACKGROUND: The aim of this study was to evaluate the clinical outcome of patients undergoing single-dose reirradiation using the Linear Accelerator (LINAC) for brain arteriovenous malformations (AVM). METHODS: A retrospective study of 37 patients with brain AVM undergoing LINAC reirradiation between April 2003 and November 2011 was carried out. Patient characteristics, for example, gender, age, use of medications, and comorbidities; disease characteristics, for example, Spetzler-Martin grading system, location, volume, modified Pollock-Flickinger score; and treatment characteristics, for example, embolization, prescription dose, radiation dose-volume curves, and conformity index were analyzed. During the follow-up period, imaging studies were performed to evaluate changes after treatment and AVM cure. Complications, such as edema, rupture of the blood-brain barrier, and radionecrosis were classified as symptomatic and asymptomatic. RESULTS: Twenty-seven patients underwent angiogram after reirradiation and the percentage of angiographic occlusion was 55.5%. In three patients without obliteration, AVM shrinkage made it possible to perform surgical resection with a 2/3 cure rate. A reduction in AVM nidus volume greater than 50% after the first procedure was shown to be the most important predictor of obliteration. Another factor associated with AVM cure was a prescription dose higher than 15.5 Gy in the first radiosurgery. Two patients had permanent neurologic deficits. Factors correlated with complications were the prescription dose and maximum dose in the first procedure. CONCLUSION: This study suggests that single-dose reirradiation is safe and feasible in partially occluded AVM. Reirradiation may not benefit candidates whose prescribed dose was lower than 15.5 Gy in the first procedure and initial AVM nidus volume did not decrease by more than 50% before reirradiation.

Amifostine Increases FAS and Caspase-3 Expression in Colonic Tissue of Irradiated Mice.

BACKGROUND/AIM: The aim of this study was to evaluate the expression of FASL, FAS and FADD and caspase-3 in oesophagus, stomach and colonic tissues of mice irradiated in vivo by immunohistochemistry. MATERIALS AND METHODS: A total of 48 adult male C57BL mice were distributed into four groups: Ami(-)/Rad(-): Mice received 0.5 ml of 0.9% physiological saline solution (PPS) intraperitioneally (i.p.); Ami(+)/Rad(-): mice received amifostine (400mg/kg i.p.) freshly dissolved in double-distilled water; Ami(-)/Rad(+): mice received 0.5 ml of PSS i.p. 30 min before a single whole-body radiation dose of 7 Gy; Ami(+)/Rad(+): mice received 0.5 ml of an aqueous solution of 400 mg/kg amifostine i.p.30 min prior to irradiation. All groups were assigned into subgroups sacrificed at 0.5 h, 1 h, 2 h and 4 h after irradiation. RESULTS: In oesophagus and stomach tissues, we did not observe any difference between Ami(-)/ad(-), Ami(+)/Rad(-), Ami(-)/Rad(+) and Ami(+)/Rad(+) groups in the expression of FASL, FAS and FADD. The colonic tissue was the only to exhibit any difference in the expression of FAS and caspase-3 protein in the Ami(-)/Rad(+)group at 1 and 2 h. Amifostine increased FAS and caspase-3 immunoexpression when compared to the control. Immunoexpression for FASL and FADD was not remarkably different in colonic tissue. CONCLUSION: Taken together, our results demonstrate that amifostine increases FAS and caspase-3 expression in colonic tissue of irradiated mice.

Formação óssea e contato osso-implante após irradiação e colocação do implante dentário: estudo experimental no modelo de tíbia em ratos / Bone formation and bone-implant contact after irradiation and dental implant placement: an experimental study in the rat tibiae model

Objetivo: comparar a formação óssea e o contato entre osso e implante (BIC) em osso irradiado usando um modelo de tíbia em ratos. Material e métodos: seis animais Rattus norvegicus (Wistar, 90 a 120 dias, peso entre 350 a 400 g) receberam 30 Gy de radiação ionizante (distância pele-fonte: 80 cm) na tíbia direita (grupo-experimental). A tíbia esquerda serviu como grupo-controle. Após 30 dias, implantes de titânio (2,5 mm diâmetro, 3 mm-comprimento, superfície tratada) foram colocados em ambos os grupos. Todos os animais foram sacrificados após 56 dias, e as amostras foram analisadas histomorfometricamente para área de formação óssea no espaço entre as roscas e o BIC. Resultados: para a formação óssea, as médias foram 44,91 ± 13,31% (grupo-controle), contra 43,16 ± 28,73% (grupo-experimental) (teste t; p=0,44). Para o contato entre osso e implante, o percentual foi de 39,51 ± 17,22% contra 33,36 ± 26,15%, respectivamente (teste t, p=0,31). Conclusão: dentro dos limites deste estudo, não houve diferença na formação óssea e no contato entre osso e implantes na avaliação histomorfométrica de implantes instalados em tíbias de ratos, submetidas previamente a 30 Gy de radiação ionizante.

The extrinsic apoptotic signaling pathway in gastric adenocarcinomas assessed by tissue microarray.

The purpose of this investigation was to analyze the immunoexpression of FasL, Fas, FADD, cleaved caspase 8, and cleaved caspase 3 in gastric cancer. Formalin-fixed and paraffin-embedded gastric adenocarcinoma tissues from 87 patients, including adjacent normal tissues, were included on tissue microarray by immunohistochemistry. The tumor and the adjacent normal tissues were positive for FasL in 66.7% and 90.6%, for Fas in 52.8% and 52.4%, for FADD in 67.4% and 82.3%, for cleaved caspase 8 in 27.9% and 37.7%, and for cleaved caspase 3 in 33.7% and 8.3%, respectively. FasL and the FADD from tumor were statistically different in relation to the histological type. Cleaved caspase 8 was statistically different in relation to clinical stage (p=0.031). The FADD from normal tissue was statistically different in relation to age (p=0.039), sex (p=0.055), clinical stage (p=0.019), and Fas was different in relation to tumor size (p=0.012). In the tumor, we observed a correlation between FasL and Fas, FasL and FADD, and FasL and cleaved caspase 3. In the adjacent normal tissue, a correlation was observed between FasL and Fas, FasL and FADD. There was no association of another marker with sex, age, clinical stage, and survival. Our results suggest that these proteins mediate the early extrinsic apoptotic pathway in gastric cancer and adjacent normal mucosa. FasL protein binds to Fas protein and subsequently binds to death receptor FADD signaling activation of the extrinsic apoptotic pathway. In this phase, there was inhibition of caspase 8 and, consequently, decreased apoptosis.

Phosphorylation and cytoplasmic localization of MAPK p38 during apoptosis signaling in bone marrow granulocytes of mice irradiated in vivo and the role of amifostine in reducing these effects.

We studied p38 phosphorylation and its intracellular localization during p53 and Puma (a p53 upregulated modulator of apoptosis) apoptotic signaling pathway in bone marrow granulocytes in mice irradiated in vivo and the role of the radioprotector amifostine in ameliorating these responses. Sixty-four C57BL mice were randomly assigned in two non-irradiated (Ami-/rad- and Ami+/rad-) and two irradiated (Ami-/rad+ and Ami+/rad+) groups. Animals received 400mg/kg of amifostine i.p. 30 min prior to a single whole body radiation dose of 7Gy. The experiments were performed using immunohistochemistry for caspase-3, cleaved caspase-3, p53, p-p53 (Ser 15), Puma, p38 and p-p38 (Thr 180/Tyr 182) protein expression. In addition transmission electron microscopy was used for ultrastructural characterization of apoptosis. Data showed that: (i) amifostine significantly reduced the number of apoptotic cells, (ii) p-p53 and Puma proteins were strongly immunostained in granulocytes after irradiation (Ami-/rad+), (iii) amifostine decreased the immunostaining of the proteins (Ami+/rad+), (iv) p38 was immunolocalized in physiological conditions in the nucleus and cytoplasm of granulocytes and neither radiation nor amifostine changed the protein immunostaining or its subcellular distribution, but influenced its activation, (v) radiation-induced p38 phosphorylation and its cytoplasmic accumulation during apoptosis signaling in granulocytes after whole body high radiation dose and amifostine markedly reduced these effects.

Resident peritoneal inflammatory cells are pivotal in the development of experimental atherosclerosis.

AIM: Based on evidence that ionizing radiation can ameliorate chronic and autoimmune diseases in patients and experimental animals, we investigated the effects of radiation on the induction and development of experimental atherogenesis. METHODS: Male New Zealand rabbits were divided into 5 groups and given an atherogenic diet for 90 days. Peritoneal and thoracic areas (9 Gy) were irradiated on the 1st and 45th days for groups 1 and 2, the 45th day for groups 3 and 4, and not at all for group 5. Prior to irradiation, the peritoneal cavity of animals from groups 1 and 3 was washed with buffered saline. Cells collected by peritoneal washing were reinfused into the peritoneal cavity of the same animal after irradiation. Animals from groups 2 and 4 were intraperitoneally injected with saline as a control. RESULTS: Despite similar lipid profiles among the experimental groups, the percentage of aortas covered by plaques was remarkably reduced (p<0.001) among animals submitted to irradiation (groups 2 and 4). These differences were completely abolished in irradiated animals reconstituted with their own peritoneal cells. CONCLUSIONS: These findings point to an important role of resident inflammatory peritoneal cells in experimental atherogenesis.

Amifostine does not prevent activation of TGFbeta1 but induces smad 7 activation in megakaryocytes irradiated in vivo.

Experiments were undertaken to assess the role of amifostine in the activation of latent TGFbeta1 and in the smad proteins cascade (smad 2/3, smad4, smad7), focusing on megakaryocytes, in the bone marrow irradiated in vivo. Non-irradiated megakaryocytes were negative for active TGFbeta1. Immunopositivity to active TGFbeta1 was detected in megakaryocytes 10 days after irradiation in amifostine- treated and untreated marrows. Smad 2/3 and smad 4 were strongly positive in the nucleus of megakaryocytes 10 days after irradiation. At the same time, a predominant hypocellular bone marrow with foci of hematopoiesis was observed with few megakaryocytes. An increase in the number of reticulin fibers was also seen. In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation. Coincidentally, bone marrows were cellular with megakaryocytes. Smad7 immunoexpression was detected in the cytoplasm of megakaryocytes in the non-irradiated, amifostine-treated and in the irradiated, amifostine-treated marrows. Data indicate that amifostine does not prevent latent TGFbeta1 activation in irradiated megakaryocytes. While TGFbeta1 signal transduction occurs in megakaryocytes in untreated bone marrows, it is inhibited in megakaryocytes in amifostine-treated marrows due to the induction of smad 7 activation. This is the first report showing smad 7 activation by amifostine. Our results also suggest a role for TGFbeta1 as an inhibitor of megakaryocytes in vivo.

In vivo radioprotection of mouse bone marrow: protection from apoptotic death by WR-2721

Apoptotic cell death is an important phenomenon in radiation bone marrow injury and the compound WR-2721 can protect hematopoietic tissue against such injury. In this study, we assessed the ability of WR-2721 to prevent radiation-induced apoptosis in bone marrow cells. Femoral bone marrow from C57BL male mice was used. The marrow was studied 4 h, 12 h, 24 h and 10 days after a single whole-body radiation dose of 7 Gy. Mice which received WR-2721 (400 mg/kg, i.p.) 30 min before irradiation were compared with unprotected mice. Less injury and a significant reduction in the number of apoptotic cells were observed 4 h (49.6 per cent less) and 12 h (40.8 per cent less) after irradiation in the group that received WR-2721 compared to the unprotected mice. An earlier than expected recovery was also observed 10 days after irradiation in the protected group. This is the first study in vivo to report the protection by WR-2721 of bone marrow cells from apoptosis following exposure to radiation.

WR2721 (amifostina) e radioproteçäo da medula óssea / WR2721 (amifostina) and bone marrow radioprotection

A medula óssea é bastante radiosensível e dependendo da intensidade, suas alteraçöes podem causar a morte de indivíduos expostos, pela Síndrome Aguda da Radiaçäo.Constitui-se também num tecido crítico para a interaçäo de drogas e radiaçäo, durante o tratamento de doenças malignas, às vezes, limitando tais procedimentos. No presente artigo säo abordadas as características do radioprotetor amifostina e seu papel na proteçäo da medula óssea irradiada.

Apoptose e radiaçäo: revisäo / Apoptosis and radiation

A apoptose é um mecanismo de morte celular que ocorre espontaneamente e promove a remoçäo de células dos tecidos normais. É essencial para o desenvolvimento normal e homeostase. Pode ocorrer também, naturalmente, em certo tumores. Este processo pode ainda ser desencadeado nos diferentes tecidos, pela radiaçäo e drogas quimioterapicas. Morfologicamente, caracteriza-se por condensaçäo e fragmentaçäo da cromatina nuclear e fragmentaçäo em escada do DNA. Alguns genes estäo envolvidos nesse mecanismo de morte celular. Vários fatores de crescimento e o sistema de transduçäo modulam o processo. No presente artigo säo abordados aspectos gerais da morte celular apoptótica e a apoptose radioinduzida em células normais e neoplásicas

Radiação ionizante e resposta celular - atualidades / Ionizing radiation and cell response

A radiação ionizante pode interagir diretamente com os componentes celulares (efeito direto) ou de modo indireto, por meio dos radicais livres produzidos pela radiólise da água (efeito indireto). A interação da radiação com as células acarreta diferentes tipos de resposta, que podem comprometer ou não a vida dessas células. No presente artigo são abordadas as alterações no DNA, cromossomos, membranas, fatores de crescimento, sistema de transdução e ciclo celular. As alterações radioinduzidas não reparadas ou reparadas de modo errado podem provocar transformações ou morte celular por falência reprodutiva, necrose ou apoptose.

Ultrastructure of convoluted proximal tubule of kidney mice before and after X-ray exposure

Ultrastructural initial changes study of convoluted proximal tubule after single dose of 154.8 mC/Kg (600R), X, ray whole body radiation was performed in 12C57BL mice. Twenty-four hours later, mitochondria evidenced proeminent changes such as cristolyses, dilatation and vacuolization. Within 72 hours, heterochromatin nuclei increased and vanished 144 hours after X-ray exposure. Such findings suggest that recovery probably happened because convoluted proximal tubules take place, regeneration occurs in aslow rate