Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasis

BACKGROUND: Tumor metastasis and relapse are major obstacles in combating human malignant diseases. Neither radiotherapy alone nor injection of dendritic cells (DCs) can successfully overcome this problem. Radiation induces tumor cell apoptosis and necrosis, resulting in the release of tumor antigen and danger signals, which are favorable for DC capturing antigens and maturation. Hence, the strategy of combined irradiation and DC vaccine may be a novel approach for treating human malignancies and early metastasis. METHODS: To develop an effective combined therapeutic approach, we established a novel concomitant local tumor and liver metastases model through subcutaneous (s.c.) and intravenous (i.v.) injection. We selected the optimal time for DC injection after irradiation and investigated the antitumor effect of combining irradiation with DC intratumoral injection and the related mechanism. RESULTS: Combined treatment with radiotherapy and DC vaccine could induce a potent antitumor immune response, resulting in a significant decrease in the rate of local tumor relapse and the numbers of liver metastases. The related mechanisms for this strong antitumor immunity of this combined therapy might be associated with the production of apoptotic and necrotic tumor antigens and heat shock proteins after irradiation, phagocytosis, migration and maturation of DCs, and induction of more efficient tumor-specific cytotoxic T lymphocyte activity through a cross-presentation pathway. CONCLUSIONS: Co-administration of local irradiation and intratumoral DC injection may be a promising strategy for treating radiosensitive tumors and eliminating metastasis in the clinic.     

Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors

We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.     

Quality of use of parenteral metronidazole therapy in a teaching hospital

The recent release, relatively high cost and potential adverse effects of parenterally administered metronidazole prompted a quality-of-use audit at a 1000-bed teaching hospital. Ninety-two courses of treatment in 81 inpatients during a 6-week period were studied. Appropriateness of therapy was assessed on the basis of published indications. Parenterally administered metronidazole was prescribed primarily in anaerobic and anaerobic-aerobic infections. It was used as frequently for prophylaxis as for therapy. Surgical services accounted for 95% of the treatment courses. Inappropriate use was noted in 27 (29%) of the courses: agents other than parenterally administered metronidazole were indicated in 12 (13%), while the dose, dosing interval or duration of treatment was suboptimal in 15 (16%). Substantial savings would be achieved if oral or rectal metronidazole therapy were substituted for intravenous therapy for perioperative prophylaxis in elective colorectal surgery. Written justification for use and automatic stop orders are recommended to improve the cost effectiveness of both prophylactic and therapeutic use of selected antimicrobial agents.     

Pancreatic islet blood flow in conscious rats during hyperglycemia and hypoglycemia

Anesthesia affects general hemodynamics and regulation of organ perfusion. We used colored microspheres to measure pancreatic islet blood flow in conscious rats at two time points, during either hyperglycemia or hypoglycemia. This method, using black and green microspheres, was validated by comparison with previous microsphere experiments and by lack of effect of a nonmetabolizable glucose analog, 3-O-methylglucose, on islet perfusion. Basal and glucose-stimulated islet blood flow levels were similar in pentobarbital sodium-anesthetized and conscious rats. However, the basal distribution of pancreatic blood flow was altered by anesthesia (fractional islet blood flow 5.8 +/- 0.4% in conscious rats, 7.9 +/- 0.8% in pentobarbital-anesthetized rats, P < 0.05). Insulin-induced hypoglycemia significantly increased whole pancreatic blood flow in conscious rats, whereas islet blood flow remained unchanged and fractional islet blood flow was decreased (5.8 +/- 0.5% in the basal state, 4.2 +/- 0.4% during hypoglycemia, P < 0.001). Methylatropine pretreatment significantly increased islet blood flow during hypoglycemia by 181%. This result suggests that prevention of hypoglycemia-induced increase in islet perfusion may be mediated, at least in part, by a cholinergic, vagal muscarinic mechanism.     

The use of mexamine to reduce radiation injuries during embryogenesis of Wistar rats

In experiments with 330 Wistar rats experiencing their first pregnancy and 1430 neonatal rats of the first generation a study was made on the toxicity and radioprotective efficiency of a single subcutaneous injection of 10 mg/kg mexamine on days 3, 11 and 19 of pregnancy. The agent caused various abnormalities in pregnancy, delivery and postnatal development of the offspring of nonirradiated animals, and it was almost ineffective when used for the prevention of radiation damages during the antenatal ontogenesis.     

Effect of hypoxic cell sensitizer metronidazole on the radiation reaction of clonogenic cells from solid tumors

The clonogenic capacity of cells from peripheral and central zones of solid NKLy tumors of mice treated with metronidazole, a sensitizer of hypoxic cells, and with a mixture of metronidazole and radiation was studied by cloning in diffusion chambers. The cytotoxic effect of metronidazole was only noted during the prolonged interaction with cells under acute hypoxia that was observed in central tumor zones. Metronidazole increased by more than two times the radiosensitivity of cells from the central zones of the tumor and did not influence the radiation response of cells from the peripheral zones. Metronidazole was shown to inhibit the repair of potentially lethal radiation damages.     

Combined effects of short-term calorie restriction and exercise on insulin action in normal rats

The present study examined the effect of combination of short-term calorie restriction (CR) and moderate exercise on insulin action in normal rats. Rats were divided randomly into 4 groups: ad libitum, sedentary (A-Sed); calorie restriction, sedentary (CR-Sed); ad libitum, exercise (A-Ex); and calorie restriction, exercise (CR-Ex). Rats in the exercise groups were run on a rodent treadmill. Rats in the CR groups were fed every alternate day. Oral glucose tolerance test (OGTT) showed improvements in both CR-Sed and A-Ex groups compared with the A-Sed group; no further improvement in glucose tolerance was observed in the CR-Ex group. In contrast, glucose infusion rates (GIRs) determined by the hyperinsulinemic-euglycemic clamp method indicated that the GIR of the CR and exercise combination was significantly better than that of the sole intervention of CR or exercise. There was no difference in the levels of fasting glucose, insulin, or high-molecular weight forms of adiponectin among the 4 groups. Protein expression of GLUT-4 in the skeletal muscle increased by exercise, but not by CR. Our findings indicate that the combination of exercise and CR may be effective in enhancing insulin sensitivity at the skeletal muscle in normal subjects.     

Complex use of radiation diagnostic techniques in tumors of the pancreatoduodenal area

In the work are summarized the results of the examination of the 500 patients with tumors of pancreas (141), tumors of biliary ducts (9), tumor of duodenum (1), chronic pancreatitis (315), choledocholithiasis (12) and non-specific biliary dilatation (13). The are show the possibilities different methods of radiation diagnosis (ultrasonography, CT, MRI, MR cholangiopancreatography) in the differential diagnosis tumors of pancreatico-duodenal region, estimation of the localization, specification, degree of invasion into the neoplasms gathering round the cells. The paper presents algorithm, used in the Regional hospital of Chelyabinsk.     

Liver glycogen metabolism during short-term insulin-induced hypoglycemia in fed rats

The activities of glycogen phosphorylase and synthase during infusions of glucagon, isoproterenol, or cyanide in isolated liver of fed rats submitted to short-term insulin-induced hypoglycemia (IIH) was investigated. A condition of hyperinsulinemia/hypoglycemia was obtained with an intraperitoneal injection of regular insulin (1.0 U kg(-1)). The control group received ip saline. The experiments were carried out 60 min after insulin (IIH group) or saline (COG group) injection. The rats were anesthetized and after laparotomy, blood was collected from the vena cava for glucose and insulin measurements. The liver was then infused with glucagon (1 nM), isoproterenol (2 microM), or cyanide (0.5 mM) during 20 min and a sample of the organ was collected for determination of the activities of glycogen phosphorylase and synthase 5 min after starting and 10 min after stopping the infusions. The infusions of cyanide, glucagons, and isoproterenol did not change the activities of glycogen synthase and glycogen phosphorylase. However, glycogen catabolism was decreased during the infusions of glucagon and isoproterenol in IIH rats, being more intense with isoproterenol (p < 0.05), than glucagon. It was concluded that short-term IIH promoted changes in the liver responsiveness of glycogen degradation induced by glucagon and isoproterenol without a change in the activities of glycogen phosphorylase and synthase.     

Intraventricular cholecystokinin-octapeptide produces hyperglycemia in rats

The effect of intraventricular cholecystokinin-octapeptide (CCK-8) on blood glucose was evaluated. Intraventricular CCK-8 in rats produces hyperglycemia. The highest dose of CCK-8 (250 ng) increased plasma glucagon levels but at lower doses (2.5 and 25 ng) increases in glucose occurred without alteration in the glucagon levels. None of the doses of CCK-8 altered insulin levels. Using ¹⁴C-glucose tracer we showed that the hyperglycemia produced by CCK-8 was not due to alterations in glucose clearance.     

Impact of hyperglycemia on the expression of GLUT1 during oral carcinogenesis in rats

Molecular Biology Reports - On the background of the epidemiological link between diabetes and oral cancer, the present study aimed to analyze the potential involvement of selected glucose...     

Some behavioral effects of short-term exposure of rats to 2.45 GHz microwave radiation

Rats were tested for neurobehavioral alterations immediately after exposure to 2.45-GHz (CW) microwave radiation at 10 mW/cm2 for 7 h. Behavioral tests used were locomotor activity, startle to an acoustic stimulus and acquisition and retention of a shock-motivated passive avoidance task. Both horizontal and vertical components of locomotor activity were assessed in 5-min epochs for a period of 30 min using photoelectric detectors. Microwave-exposed animals exhibited less activity than sham-exposed animals. This was most evident during the last 10-15 min of the 30-min test session. Twenty identical acoustical stimuli (8 KHz, 110 dB) were delivered to each rat at 40-s intervals. The microwave-exposed animals were less responsive to the stimuli than sham-exposed animals. Microwave exposure had no effect on the retention of a passive avoidance procedure when tested at 1 week after training. Both the locomotor activity and acoustic startle data demonstrate that, under the conditions of this experiment, microwave exposure may alter responsiveness of rats to novel environmental conditions or stimuli.     

Combined antibiotic therapy of acute radiation disease in persons affected during the accident at the Chernobyl nuclear power station

One hundred and fifteen patients with acute radiation disease of degrees I to IV affected during the accident at the Chernobyl APS were treated in a specialized hospital. The anti-infection regimen included isolation, air sterilization with ultraviolet light, intravenous administration of broad spectrum of antibiotics (gentamicin, cephalosporins and carbenicillin) and nystatin. Some cases were treated with amphotericin. Some cases were treated with amphotericin B. Out of 22 patients who died at the early periods (days 14 to 34) or at the period of agranulocytosis in 7 patients sepsis was stated. In 5 of them it was complicated by pneumonia. In 5 patients who died at the late periods (days 48 to 99) or at the period of hemopoiesis normalization infectious complications by the death moment were stated: sepsis in 3 patients and pneumonia in 2 patients. The aspect of the microbiological diagnosis and therapy efficacy is discussed.     

Factors influencing the use of adaptive radiation therapy in vulvar carcinoma

AimWe aim to evaluate the variables affecting the frequency of adaptive radiotherapy (ART) in vulvar cancer.BackgroundART may be needed throughout a definitive RT course for vulvar carcinoma due to changes in patient’s anatomy and tumor response.Materials and methodsCharts of patients charts who had been treated with definitive concurrent chemo-radiotherapy for vulvar carcinoma, between January 2015 and December 2019 were inquired. Radiation therapy was delivered using intensity modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT). ART was defined as re-simulation and re-planning based on deformation in the irradiated volume by more than 1 cm. Univariate analysis was conducted to study the impact of patient’s demographics as well as tumor characteristics on the frequency of ART.Results22 patients were eligible for analysis. Median age at diagnosis was 55 years (range 43–82). Radiotherapy dose was 60−66 Gy over 30–35 fractions (fx). Median primary tumor volume was 30cc (9–140). Median Body Mass Index (BMI) was 32 (range 21–40). Thirteen out of 22 patients (59%) required ART, with median timing at 25 fx (19–31). On univariate analysis, larger primary tumor volume (> = 30cc) was associated significantly with increased frequency of ART (p value = 0.0005). There was no significant impact of ART on the frequency with respect to patient’s age, BMI, tumor stage, grade and location.ConclusionChanges in radiation target volume are common among vulvar carcinoma patients who are treated with definitive radiotherapy, especially large primary tumors. This review highlights the importance of ART for patients with vulvar carcinoma treated with definitive radiotherapy.     

Efficiency of radiation or chemoradiation therapy for diffusely growing brainstem tumors in children

Radiation or chemoradiation therapy was performed in 97 children with diffusely growing brainstem tumors. A reduction in the severity of neurological disorders was achieved in 92 (94.8%) patients. The course of the disease was traced in 79 patients. Control studies recorded no complete tumor regression. Following 4-8 months, there was growth resumption of a tumor with its lysis and cyst formation in most children. The principal cause of death was local tumor progression. Six-month survivors were 64 (81%) patients; one-, two-, and three-survivors were 21 (26.5%), 8 (10.1%), and 3 (7.65) patients, respectively; one (2.8%) patient survived 5 years. A combination of radiotherapy and monochemotherapy with temodal, vincristine, oncofer, and theraloc failed to improve immediate and long-term results     

Secondary brain tumors after cranial radiation therapy: A single-institution study

AimTo study the probability of developing secondary brain tumors after cranial radiotherapy.Background Patients treated with cranial radiotherapy are at risk for developing secondary brain tumors.Patients and methodsWe planned an institutional survey for secondary brain tumors in survivors after cranial irradiation and reviewed the 30-year duration data. Event analysis and cumulative proportion curves were performed to generally estimate the cumulative proportion of developing secondary brain tumors, cavernoma and meningioma at different periods of time.ResultsSecondary brain tumors occurred in 21% of cases: 10% were cavernomas, 6% were meningiomas, 3% were skull osteomas, and 1% were anaplastic astrocytoma. The cumulative proportion of developing secondary brain tumor was 6% at 10 years and 20% at 20 years, while the cumulative proportion for developing cavernomas and meningiomas was 16% and 7% at 20 years, respectively.ConclusionOur study shows that patients who received cranial irradiation were at risk of secondary brain tumors such as cavernomas and meningiomas. Thus, a meticulous follow-up of cancer survivors with history of cranial irradiation by an annual MRI scan is justifiable. This will help clinicians to detect secondary brain tumors early and make its management much easier.     

Combined action of gamma and UHF radiation on conditioned reflex behavior of rats

Dynamics of the conditioned behaviour of rats in a shuttle box was studied after combined exposure to Cs-gamma radiation (1 Gy, 1.32 Gy/min) and microwave radiation (2450 MHz, 1 mW/cm2, 3 h). The number of conditioned and interstimulus responses was found to decrease on day 5 after microwave + gamma irradiation and to increase on day 30 after gamma + microwave irradiation.