Prognostic factors in glioblastoma multiforme patients receiving high-dose particle radiotherapy or conventional radiotherapy.

The aim of this study was to evaluate the influence of prognostic factors related to patient selection on survival outcomes. Survival outcomes were retrospectively analysed in a consecutive series of 67 newly diagnosed glioblastoma multiforme (GBM) patients who had received either conventional fractionated photon radiotherapy (CRT) or high-dose particle radiotherapy (HDT). In the CRT protocol, a total dose of 60.0-61.2 Gy was administered. In the HDT protocol, an average dose of approximately 30 GyE in a single session and additional fractionated photon irradiation of total dose 30 Gy were administered to patients receiving boron neutron capture therapy; and a total dose of 96.6 GyE was administered to patients receiving proton therapy. Most of the patients had received chemotherapy with nimustine hydrochloride (ACNU) alone or with ACNU, procarbazine and vincristine. The median overall survival (OS) and progression-free survival times for all patients were 17.7 months [95% confidence interval (CI), 14.6-20.9 months] and 7.8 months (95% CI, 5.7-9.9 months), respectively. The 1- and 2-year survival rates were 67.2% and 33.7%, respectively. For patients treated with HDT, the median OS was 24.4 months (95% CI, 18.2-30.5 months), compared with 14.2 months (95% CI, 10.0-18.3 months) for those treated with CRT. The Cox proportional hazards model revealed radiation modality (HDT vs CRT) and European Organisation for Research and Treatment of Cancer recursive partitioning analysis class to be the significant prognostic factors. Age, sex, pre-operative performance status, treatment with or without advanced neuroimaging, extent of surgery and regimen of chemotherapy were not statistically significant factors in predicting prognosis. The median OS was 18.5 months (95% CI, 9.9-27.1 months) in patients of 65 years and older, compared with 16.8 months (95% CI, 13.6-20.1 months) in those 64 years and younger (p=0.871). The positive effect of HDT treatment is unlikely to reflect patient selection alone. Randomised trials with strictly controlled inclusion criteria to ensure the comparable selection of patients are required to demonstrate conclusively that prolonged survival can be attributed to high-dose particle radiotherapies.

Promotion of survival and regeneration of nigral dopamine neurons in a rat model of Parkinson's disease after implantation of embryonal carcinoma-derived neurons genetically engineered to produce glial cell line-derived neurotrophic factor.

OBJECT: The P19 embryonal carcinoma-derived cell line consists of undifferentiated multipotential cells, which irreversibly differentiate into mature neurons after exposure to retinoic acid (RA). In the present study, the authors genetically engineered P19 cells to produce glial cell line-derived neurotrophic factor (GDNF), and grafted the cells in a rat model that had been rendered parkinsonian. METHODS: Undifferentiated P19 cells were grown in vitro and transduced with GDNF complementary DNA. The level of GDNF released from the transduced cells was measured using an enzyme-linked immunosorbent assay, and its neurotrophic activities were assessed by testing the effects on rat embryonic dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours and allowed to differentiate into postmitotic neurons, the GDNF gene-transduced cells were implanted into the midbrain of immunosuppressed rats. A unilateral nigrostriatal lesion was then induced by intrastriatal infusions of 6-hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting revealed that the GDNF-producing cells expressed several neuronal markers without evidence of overgrowth. The grafts expressed GDNF protein and prevented the death of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks after nigrostriatal lesions restored the expression of tyrosine hydroxylase in injured DA neurons and induced their dendritic sprouting. CONCLUSIONS: The results indicate that the P19 cell line transduced with the GDNF gene can stably secrete functional levels of GDNF, even after being converted to postmitotic neurons. Because it is has been established that GDNF exerts trophic effects on DA neurons, the means currently used to deliver GDNF into the brain could be a viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's disease.

Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: possible roles of interferon alpha, tumor necrosis factor alpha and transforming growth factor beta in Mn-SOD induction by polysaccharide K.

Previously we reported the malignant progression of QR-32, a regressor-type tumor clone, following co-implantation with foreign bodies (gelatin sponge or plastic plate) in normal syngeneic C57BL/6 mice. We also reported that the progression of QR-32 cells by a gelatin sponge was significantly inhibited in the mice administered polysaccharide K (PSK) and that PSK induced an increase of radical scavengers, especially manganese superoxide dismutase (Mn-SOD), locally at the site of tumor tissues. In this study, to reveal the possible mechanism by which PSK induced Mn-SOD in the tumor tissues, we examined the mRNA expression and protein levels of inflammatory cytokines in the tissues. We found that mRNAs of tumor necrosis factor alpha (TNFalpha) and interleukin-1alpha (IL-1alpha) were considerably expressed in both PSK-treated and phosphate-buffered-saline-treated tumors, and that the mRNA expression and protein level of interferon gamma (IFNgamma) increased in the tumor tissues treated with PSK. In vitro treatment of QR-32 cells with IFNgamma did not significantly increase the production of Mn-SOD; however, the combination of IFNgamma with TNFalpha increased the Mn-SOD production more effectively than did any of the cytokines used singly. Furthermore, we observed the down-regulation of the mRNA expression and protein level of transforming growth factor beta (TGFbeta) in the tumor tissues treated with PSK, and that in vitro treatment of QR-32 cells with TGFbeta decreased the production of Mn-SOD. These results suggest that PSK suppresses the progression of QR-32 cells by increasing Mn-SOD via the modulation of inflammatory cytokines; that is, by decreasing TGF-beta and increasing IFN-gamma.

[Clinical studies on autologous blood transfusion].

To study the present status of blood transfusion in head and neck surgery, we investigated recent cases of intraoperative transfusion in our department. In addition, we present our autologous blood transfusion cases, presently involved in an ongoing clinical trial for patients with head and neck cancer in our department which began in 1989. 1. Investigation of intraoperative blood transfusion cases There were 37 cases of intraoperative blood transfusion among 677 cases who underwent surgery under general anesthesia during the period from May, 1991 to December, 1993. We divided these 37 cases into three groups according to the amount of intraoperative blood loss: less than 600ml (10 cases), more than 600ml and less than 1200ml (11 cases), and more than 1200ml (16 cases). Average amounts of intraoperative blood transfusion in each group were 195ml, 475ml and 780ml, respectively. As we noted that most of these 37 cases received a blood transfusion of less than 800ml, the majority needing intraoperative blood transfusion during head and neck surgery are potential candidates for autologous blood transfusion. Therefore, we have promoted autologous blood transfusion for intraoperative blood transfusion in head and neck surgery. Thus, the patients undergoing intraoperative autologous blood transfusion increased to seven annually as of 1994. 2. Clinical studies on autologous blood transfusion Among 677 cases of head and neck surgery conducted during a six year period (1989-1994), we experienced ten cases of autologous blood transfusion. For the prevention of anemia due to repeated blood withdrawal, we administered an iron preparation. Patients who preoperatively showed a low value of Hb (less than 11g/ dl) received intravenous drip infusion of erythropoietin. Since some patients selected for autologous blood transfusion, who also received neo-adjuvant chemotherapy and preoperative radiotherapy, exhibited a generally chronic anemia status, an iron preparation and erythropoietin should be preoperatively administered in combination.

Plasma serotonin and platelet aggregation during ischemia-reperfusion in dogs: effect of dipyridamole and coenzyme Q10.

Platelet aggregation and plasma serotonin were studied during ischemia-reperfusion of the small intestine in dogs. Blood was withdrawn from the superior mesenteric vein before and 1 h after ischemia, then 5, 30 and 60 min after reperfusion. Dipyridamole (5 mg/kg body weight) and coenzyme Q10 (CoQ10; 10 mg/kg body weight) were administered intravenously 5 min before reperfusion, following 1 h ischemia, in order to investigate their effects on platelet function and free serotonin. Ischemia-reperfusion resulted in an increased local free serotonin concentration together with an enhanced platelet response to ADP, collagen and arachidonic acid. Administration of dipyridamole and CoQ10 prior to reperfusion prevented, at least in part, augmented platelet activation and serotonin release. It appeared that dipyridamole was more potent than CoQ10. Our results may indicate a possible protective effect of dipyridamole on enhanced platelet activation during ischemia-reperfusion in dogs.

Effect of atrial natriuretic peptide on ischemic brain edema: changes in brain water and electrolytes.

The effects of intraventricularly administered atrial natriuretic peptide (ANP) on the brain water, sodium, and potassium contents in ischemic brain edema were investigated. By use of a three-vessel occlusion model, ischemic brain edema was produced in the rat brain by 15 minutes of global ischemia followed by recirculation. Water content was measured by means of a drying/weighing method; sodium and potassium contents were measured by means of flame photometry. The effects of intraventricular administration of ANP were evaluated by a comparison between the groups given 2 and 5 micrograms of atriopeptin II (treated) and those given 0.9% NaCl (sham-treated). The treated groups showed significant decreases in brain water (P less than 0.02) and sodium (P less than 0.01) contents at 15 and 30 minutes after recirculation, whereas the brain potassium contents remained unaltered. Before ischemia and immediately after 15 minutes of ischemia, intraventricularly administered ANP did not significantly change the brain water, sodium, or potassium contents. There was no significant difference in the effect on the amount of brain water and sodium between the two doses (2 and 5 micrograms). These effects of ANP were thought not to be mediated by primary changes in serum osmolality and sodium and potassium concentrations, because intraventricular administration of ANP did not change them significantly. The present results reveal that, in ischemic brain edema, ANP may act directly on the central nervous system to inhibit brain water and sodium accumulation.