Radiation oncology investigations最新文献

Widespread replication of the favorable long-term results of prostatic conformal brachytherapy achieved by the Seattle group requires evidence that the technical quality of their implants is achievable elsewhere. Preplanning with a modified uniform loading algorithm using low activity seeds produces virtually no regions within the planning volume at less than the prescribed dose and no interconnected volumes between seeds at double the dose. The operative procedure stabilizes the prostate and locates the prostate targets, needles, and seeds and their relationship to the bladder and rectum using transverse and longitudinal ultrasound as well as contrast enhanced fluoroscopy. A detailed postoperative dosimetric analysis of patients with clinical T1/T2 adenocarcinoma of the prostate gland who underwent transperineal ultrasound conformal prostatic brachytherapy from March through June 1996 was performed. The analysis involved 7 consecutive patients implanted with 125I seeds and 5 consecutive patients implanted with 103Pd seeds. Median coverage to the full minimal peripheral dose (mPD) was 96% (range 80-99%) of the prostate volume. At 80% of the mPD, median isodose coverage was 100% (range 91-100%) of the prostate volume. Regarding hot spots to critical structures, the median maximal urethral dose was 175% of the mPD (range 115-227%) and the median maximal dose to the anterior rectal mucosa was 105% of the mPD (range 83-133%). Analysis of postoperative dose-volume histograms has shown that our maximal dose surface to any volume greater than 5 cm3 is 203% (range 175-247%). These results indicate that good quality transperineal ultrasound prostatic conformal brachytherapy can be accurately reproduced in a community hospital setting and that biochemical no evidence of disease (NED) results and local control rates will be comparable to those of the Seattle group with no unexpected urethral or rectal complications or side effects.

Inflammatory cells are involved in the pathogenesis of tissue injury through release of cytokines and biologically active compounds. This study used a novel, noninvasive method to assess the association between granulocyte transmigration and structural and molecular changes in radiation enteropathy. A 4 cm loop of rat small intestine was exposed to 0, 2.8, 12, or 23 Gy localized irradiation. Feces was collected in metabolic cages before and 3, 7, 14, 28, and 42 days after irradiation. Granulocyte marker protein (GMP) was measured in buffer extracts of feces by enzyme-linked immunosorbent assay (ELISA). Irradiated and shielded intestine were procured at 2 and 26 weeks and assessed for histopathologic injury [radiation injury score (RIS)], ED-2 positive macrophages, and interleukin-1 alpha (IL-1 alpha) positive cells. Irradiated intestine exhibited characteristic histopathologic alterations and increased numbers of macrophages and IL-1 alpha positive cells. There was a highly significant dose-dependent increase in post-radiation GMP (P < 0.0001). Maximal GMP excretion occurred 3-7 days after irradiation. Six weeks after irradiation, GMP excretion had returned to normal in the 2.8 and 12 Gy groups, but was still 3.5 times higher in the 23 Gy group than in controls. The associations between early GMP excretion and RIS and fibrosis at 26 weeks were highly significant (P < 0.001 and P < 0.0001, respectively). Post-radiation granulocyte transmigration is dose-dependent and correlates with structural and molecular changes, as well as with subsequent chronic injury. The GMP assay is a sensitive, non-invasive indicator of acute intestinal radiation injury and a promising biological predictor of chronic toxicity. Our data underscore the importance of consequential mechanisms in radiation enteropathy.

Intratumoral injection of an adenoviral vector containing radiation-inducible DNA sequences of the early growth response gene (Egr-1) promoter ligated to a cDNA encoding tumor necrosis factor-alpha (TNF-alpha; Ad.Egr-TNF) increases the radiation killing of a human radioresistant xenograft (SQ-20B). Viral dose-escalation experiments demonstrated that SQ-20B growth inhibition correlated with viral titer. Injection of 5 x 10(8) PFU Ad.Egr-TNF produced regression to a mean volume of 22 +/- 13% of the original tumor volume, 1 x 10(8) PFU to a mean of 62 +/- 24%, and 5 x 10(7) PFU to a mean of 67 +/- 27%. No regression was observed when tumors were injected with 1 x 10(7) PFU Ad.Egr-TNF or with the null viral vector (Ad.null). When two injections of vector (2 x 10(8) PFU Ad.Egr-TNF) were combined with 50 Gy, a significant increase in tumor regression was observed compared with injection of buffer, Ad.Egr-TNF, or 50 Gy. The interactive killing between TNF and radiation was enhanced significantly (P = 0.05) when the number of injections was increased from two to five while maintaining a constant viral titer (2 x 10(8) PFU Ad.Egr-TNF) and a constant radiation dose (50 Gy). Significant TNF-alpha levels were present in irradiated vs. unirradiated tumors following injection with Ad.Egr-TNF. Taken together, these data suggest that the volumetric reduction produced by the combined effects of Ad.Egr-TNF and radiation is enhanced with increasing vector concentration and the number of vector injections.

We have previously described the development of radiation transformed human fetal prostate epithelial cells, 267B1. Using this in vitro model system, we investigated the molecular mechanisms of prostate carcinogenic progression by comparing nontumorigenic (267B1/B) and tumorigenic (267B1/D) cells. We examined the G1- to S-phase transition in synchronized cells to determine if the progression of 267B1 cells from nontumorigenic to tumorigenic was the consequence of a perturbation in the G1- to S-phase transition involving p53, pRb, p21, or p16. Nontumorigenic 267B1/B cells showed a time-dependent increase in the expression of p53 and a corresponding increase in p21 following exposure to ionizing radiation (6 Gy). The levels of pRb and p16 protein were virtually unchanged. In contrast, tumorigenic 267B1/D cells exhibited a p53-independent induction of p21 protein with a parallel increase in p16 protein in response to ionizing radiation, but no change in pRb was observed. These results suggest that the progression of 267B1 cells from nontumorigenic to tumorigenic involves p53-independent processes.

In this paper, an attempt is made to identify endpoints that might be of potential use in the quantification of radiation effects in human tissues. Irradiated cultures of cells that are not selected for clonogenic survival but are left in situ to grow after irradiation show a wide variety of morphological and biochemical abnormalities. These include nuclear fragmentation and other evidence of programmed cell death, but they also include a considerable amount of lysis, necrosis, and persistent abnormal growth and function, which are expressed in the progeny of irradiated cells. Induction of proteins associated with stress or shock responses, growth and cell cycle control, and control of apoptosis are also seen and may persist. The dose dependence of these various responses is documented, because it probably determines to a large extent the outcome of radiation exposure in terms of whether a cell dies, divides normally, or develops genomic instability, mutation, and ultimate carcinogenic progression of the progeny. Clearly, a cell that dies presents no further threat to the organism, nor does a fully repaired cell. Therefore, a major challenge facing radiation protection research is to define the population at risk of surviving with damage. The results show that there is a variation in response to radiation between different patient cultures that is detectable in an explant culture system of primary normal human urothelium. The growth pattern and protein expression postirradiation is consistent with apoptosis being a major determinant of low dose response to radiation. This form of death appears to be suppressed at higher doses and, in the majority of subjects, results in the presence of a highly abnormal population of cells, even though the population size is the same whether their progenitors were irradiated or not.

Brain masses diagnosed in 47 pet dogs as tumors by CT scans, and confirmed in 12 dogs by necropsies, were injected with iodinated contrast media and treated by a modified CT scanner, the CTRx. Twenty-six dogs that received six or more weekly treatments of about 5.6 Gy per fraction, of which about 25% was contributed by radiation from the iodine, for a median total dose of 39 Gy, had a median survival of 230 days. This compares well with the 150 days reported for 25 dogs given 46-48 Gy of cobalt-60 radiation to the whole brain, and is significantly greater than the 6 to 13 days in untreated historic controls.

The purpose of this study was to update the experience and demonstrate the effectiveness and limitations of 241Am applicators for previously irradiated patients and for selected patients with primary gynecologic malignancies. Between October 1986 and May 1994, 30 patients were treated with 241Am. The median patient age was 68 years, ranging from 41 to 91 years. Patients were retrospectively categorized by treatment intent, i.e., palliative vs. curative. Patients undergoing curative therapy were further classified as to whether 241Am brachytherapy was directed at microscopic residua after surgery or to gross primary tumor. Of the 30 patients, 18 had recurrent pelvic malignancies from various primary sites and were reirradiated with 241Am for palliation. Six patients had microscopic disease after surgical resection and were managed with postoperative radiotherapy (RT) that included 241Am. Six patients had gynecologic cancers managed with primary RT that included treatment with 241Am. Overall, 50% (9/18) of the patients with recurrent pelvic malignancies were locally controlled after reirradiation with 241Am. Including surgical salvage, the ultimate local control rate was 61% (11/18). Postoperative 241Am with or without external beam radiation therapy (XRT) was effective in 83% (5/6) of the patients with microscopic disease. Including surgical salvage, 100% (6/6) of the patients were ultimately free of disease. Fifty percent (3/6) of the patients treated with primary RT that included 241Am brachytherapy experienced local control. Including surgical salvage, 67% (4/6) of the patients were ultimately controlled with 241Am. In conclusion, reirradiation utilizing 241Am was effective in palliating patients with recurrent pelvic malignancies. 241Am was effective in 83% (5/6) of the patients with microscopic disease managed with postoperative RT. 241Am was of marginal benefit in patients with gynecologic tumors managed with primary RT.

By using the atomic force microscope (AFM), three-dimensional structures of biological specimens may be imaged at nanometer resolution. Furthermore, samples can be imaged in air or in fluid environments. The tapping mode of AFM operation for imaging has offered a significant advance in visualizing soft biological structures, such as DNA, proteins, and membranes. Here, we review the principles underlying the application of this instrument to radiation biological investigations. We focus on examples of proteins involved in the processes of repair of damaged DNA, including poly(ADP-ribose) polymerase, Ku protein, and DNA protein kinase. Novel observations on the character of DNA damage and repair have been addressed by direct visualization of DNA and protein-DNA interactions, such as the observation that the Ku protein is capable of physically joining DNA fragments in vitro. The AFM offers a powerful tool for investigating biologically important molecular interactions that are relevant to DNA damage and repair processes.

We have investigated the oncogenic alterations in murine lymphomas induced by in utero exposure to gamma-radiation. The expression of the myc oncogene increased in 23% of the tumors. Alterations in the expression of the ras oncogenes and in the p53 tumor suppressor gene were not characteristic. The p53 gene was mutated in a low percentage of the tumors (12%). Ras mutations were not detected. Loss of heterozygosity (LOH) at the p53 locus was found in 30% of the tumors, and LOH at the mts tumor suppressor gene was detected in 23% of lymphomas. Multiple oncogenic changes were infrequent in the investigated tumors. There were no essential differences in the frequency of carcinogenic alterations in spontaneous and gamma-radiation-induced lymphomas.

With three-dimensional conformal therapy, doses > 75 Gy have been delivered to the prostate with acceptable levels of morbidity; however, higher doses do appear to increase late gastrointestinal (GI) and genitourinary (GU) morbidity. Because patients with pretreatment prostate-specific antigen (PSA) values < 10 ng/ml can achieve 3-year actuarial bNED control rates of 90% after treatment with external beam radiotherapy to doses < 71 Gy, one might question the need for further dose escalation in this population. In this report, we examined the relationship between dose and PSA nadir for 90 patients with pretreatment PSA values < 10 ng/ml entered into a dose escalation study from March 1987 to October 1992. We wanted to see if nadir response data would predict a different outcome from our 3-year bNED control reports. All patients were treated with external beam radiotherapy to ICRU reporting point doses of 6,598 cGy to 7,895 cGy (median of 7,068 cGy). Minimum follow-up was 36 months (median, 47 months). Seven hundred thirty-nine posttreatment PSA nadir values were analyzed, yielding an average of 8.2 values per patient. Estimates of rates of bNED control and time to reach a posttreatment PSA of 1.0 ng/ml were calculated using the Kaplan-Meier product limit method. The log-rank test was used to evaluate differences in rates according to dose levels. Linear regression and Cox proportional hazard modeling were used to relate dose to bNED control on a continuum. Escalating doses from 66 to 79 Gy failed to increase the percentage of patients achieving nadir values < 1 ng/ml and similarly failed to increase the 3-year actuarial bNED control. Linear regression (P = .81) and the chi-square test of association (P = .23) supported the lack of a dose effect on nadir continuously and categorically, respectively, and the Cox regression model supported the conclusion that dose on a continuum has no effect on bNED control (P = .34). Furthermore, time to reach a posttreatment PSA level of 1.0 ng/ml was not statistically dependent on dose level (P = .13). Based on this study and prior reports demonstrating a dose response for late GI/GU morbidity, we question whether further dose escalation in this subgroup of patients is justified.