Patient characteristics influencing the variability of distributed parameter-based models in DCE-CT kinetic analysis.

Kinetic parameter variability may be sensitive to kinetic model choice, kinetic model implementation or patient-specific effects. The purpose of this study was to assess their impact on the variability of dynamic contrast-enhanced computed tomography (DCE-CT) kinetic parameters. A total of 11 canine patients with sinonasal tumours received high signal-to-noise ratio, test-double retest DCE-CT scans. The variability for three distributed parameter (DP)-based models was assessed by analysis of variance. Mixed-effects modelling evaluated patient-specific effects. Inter-model variability (CVinter ) was comparable to or lower than intra-model variability (CVintra ) for blood flow (CVinter :[4-28%], CVintra :[28-31%]), fractional vascular volume (CVinter :[3-17%], CVintra :[16-19%]) and permeability-surface area product (CVinter :[5-12%], CVintra :[14-15%]). The kinetic models were significantly (P<0.05) impacted by patient characteristics for patient size, area underneath the curve of the artery and of the tumour. In conclusion, DP-based models demonstrated good agreement with similar differences between models and scans. However, high variability in the kinetic parameters and their sensitivity to patient size may limit certain quantitative applications.

Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment.

BACKGROUND: Adjuvant tamoxifen therapy for breast cancer has been given for a period of several years. Cardiovascular diseases increased in incidence rapidly in women older than 60 years. Favorable changes in cardiovascular risk factors have been seen with 2 years of tamoxifen therapy, and lower rates of myocardial infarction and of hospitalization for heart disease have been observed in tamoxifen-treated women. PURPOSE: We sought to evaluate changes in risk factors for cardiovascular diseases in postmenopausal women after therapy with tamoxifen for 5 years. METHODS: Five years after their initial entry in a 2-year randomized, placebo-controlled toxicity study, we re-examined 62 of the original 140 disease-free, axillary node-negative postmenopausal breast cancer patients. These 62 patients were women available for study because they had not suffered major illness and had continued on either the tamoxifen or no-tamoxifen regimen to which they had been originally randomly assigned for the entire 5 years. Patient and control blood samples were analyzed for total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and subfractions, triglycerides, apolipoprotein AI, apolipoprotein B, lipoprotein(a), fibrinogen, glucose, and platelets. RESULTS: At base line for all measurements except atherogenic lipoprotein [lipoprotein(a)], the 30 long-term tamoxifen recipients and the 32 long-term no-tamoxifen recipients were not significantly different. After 5 years, levels of total serum cholesterol (P < .001), LDL cholesterol (P < .001), and lipoprotein(a) (P = .001) were significantly lower, and apolipoprotein AI levels were significantly higher (P < .001) in the tamoxifen-treated group compared with the no-tamoxifen group. Apolipoprotein B levels increased to a greater extent in the no-tamoxifen than in the tamoxifen group (P < .001). After 5 years, fibrinogen level decrease and triglyceride level increases in the tamoxifen group compared with the no-tamoxifen group were of borderline statistical significance and HDL cholesterol levels were not different in the two groups. CONCLUSION: Favorable changes in lipid, lipoprotein, and fibrinogen levels seen early in tamoxifen therapy in postmenopausal women persist with treatment of 5 years. IMPLICATIONS: The types and magnitude of changes in cardiovascular risk factors seen here with tamoxifen are similar to a certain extent with those seen with estrogen supplements. Further risk-factor and ethnic-group data are needed to estimate the magnitude of expected benefits of tamoxifen treatment on incidence of heart disease.

Prostate-specific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer.

PURPOSE: A study of preradiation and postradiation, serial serum prostate-specific antigen (PSA) levels was performed in patients who had clinically localized prostate cancer. The prognostic value of the PSA in pretreatment evaluation and posttreatment follow-up was assessed. PATIENTS AND METHODS: Sixty-three patients who presented with clinically localized prostate cancer and who were treated with external-beam radiation therapy were followed-up for a median of 25 months. A serum PSA and physical examination were performed at 3-month intervals, and a bone scan was done yearly. An increase in PSA triggered an additional metastatic workup. Prostate rebiopsy was performed for new, palpable nodules or for a serial increase in PSA in the context of a negative metastatic workup. RESULTS: Forty-one patients remained recurrence-free and 22 recurred clinically, 15 distantly and seven locally. The PSA was the strongest, independent, pretreatment prognostic indicator (P = .019) among pretreatment PSA, stage, and grade, but lost significance when the serum prostatic acid phosphatase (PAP) status was included. The initial rate of the PSA decrease after radiation (median half-life, 2.6 months) failed to predict outcome. Recurrence-free patients reached postradiation PSA levels that were equivalent to those reported in disease-free male populations; failure of the PSA to reach such normal levels was a multivariate predictor of subsequent failure (P less than .037). All clinicopathologic documentations of failure were preceded by an increase in PSA levels during follow-up. Delayed versus early PSA increase was associated with clinically localized versus metastatic first recurrence. CONCLUSIONS: The serum PSA is an independent pretreatment and posttreatment predictor of outcome. Additionally, for a median follow-up of 25 months, delayed PSA failure is associated with clinically localized rather than metastatic recurrence, a relationship that may help in selection for local salvage therapy.

Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years.

BACKGROUND: Because adjuvant tamoxifen citrate is given to women with early-stage breast cancer for long periods, it is important to know how it affects risk factors for osteoporotic bone fractures, particularly since rates of bone fracture increase rapidly with age in postmenopausal women. In a 2-year randomized placebo-controlled toxicity study in 140 subjects, we demonstrated that tamoxifen was associated with preservation of bone mineral density (BMD), a major risk factor for fractures, in the lumbar spine. METHODS: Five years after entry on this study we reexamined 62 of the original subjects with lumbar spine BMD and serum osteocalcin measurements. These were women available for study because they had not suffered major illnesses and had continued to receive (1) tamoxifen or (2) the no-tamoxifen regimen that they had originally been randomized to receive for the entire 5 years. RESULTS: For lumbar spine BMD at baseline, the 30 subjects in the long-term tamoxifen group and the 32 subjects in the long-term no-tamoxifen group were not significantly different (P = .26). During the first 2 years of follow-up, the 30 subjects in the long-term tamoxifen group showed the same BMD pattern as the entire 70-patient tamoxifen cohort, and similarly the 32 subjects in the long-term no-tamoxifen group showed the same pattern as the entire 70-patient cohort who received placebo. Five-year mean BMD measurements for each long-term follow-up group showed no significant changes from their respective 2-year levels. However, 5-year BMD measurements between the two groups differed (tamoxifen group, +0.8%; placebo group, -0.7%) (P = .06), and the mean regression lines for the changes in BMD over 5 years differed significantly between the two groups (P = .0005). Adjustment for differences in body mass index, reported exercise, and calcium supplementation between these two groups did not change these results. Osteocalcin levels, also comparable at baseline in the two groups, were significantly lower in tamoxifen-treated subjects at 5 years (P = .0005). CONCLUSIONS: While remodeling of bone may be lower, resorption of lumbar spine bone mineral is also lower, and tamoxifen preserves BMD in the lumbar spine over 5 years of treatment in postmenopausal women. Over longer periods, this preservation of BMD might be expected to be associated with lower fracture rates.

Perioperative morbidity and mortality of high-dose-rate gynecologic brachytherapy.

PURPOSE: To determine the 30-day morbidity and mortality rates for patients with an intact uterus undergoing high-dose-rate (HDR) brachytherapy, and to assess risk factors which may predict for these potentially life-threatening complications. METHODS AND MATERIALS: From August 1989 to December 1994, 128 cervical and 41 medically inoperable endometrial cancer patients were treated with 5 outpatient weekly HDR brachytherapy insertions. Patients with cervical cancer also were treated with external beam radiotherapy. Acute events that resulted in either hospitalization (morbidity) or death (mortality) within 30 days of the implant were analyzed. Univariate and multivariate analyses were performed to identify risk factors. RESULTS: Overall there were 16 acute events in 169 patients (9.5%). The overall morbidity and mortality rates for the cervical and endometrial patients were 5.5%, 1.6%, 7.3%, and 9.8%, respectively. The following factors were significant by univariate analysis: age per decade, American Society of Anesthesiologists (ASA) score, Karnofsky Performance Status (KPS), significant medical history, diagnosis of cervical vs. endometrial cancer, and mean time exceeding 160 minutes for the procedure. Since age was the most significant predictive factor (p = 0.0003), bivariate analyses were performed by adjusting for age. In these analyses only ASA and KPS maintained significance, while a positive medical history was of borderline significance (p = 0.07). CONCLUSION: The morbidity and mortality rates observed in gynecologic patients selected for HDR brachytherapy were similar to low-dose-rate, but higher than other HDR reports. Reasons for this include a higher risk population, especially those with medically inoperable endometrial cancer. In the cervical cancer patients, some of the complications may have also been a result of the external beam portion of the radiation. In order to minimize the acute complications observed in the present HDR brachytherapy system, the following changes have been implemented: appropriate patient selection, anesthesiology involvement to monitor conscious sedation for high-risk patients, external beam radiotherapy alone in patients at extremely high risk, deep vein thrombosis (DVT) prophylaxis, use of intraoperative ultrasound, shorter duration in the brachytherapy suite, and preradiation treatment plans (plans executed prior to the insertion) if applicable. Finally, this analysis suggests that these procedures should be performed in a hospital-based setting where appropriate support is available.

Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Radiation Therapy Oncology Group.

PURPOSE: To evaluate the impact of stereotactic radiosurgery on the survival of patients treated with malignant gliomas. METHODS AND MATERIALS: A total of 115 patients from three institutions (75 from the Joint Center for Radiation Therapy, 30 from the University of Wisconsin, and 10 from the University of Florida) were treated with a combination of surgery, external beam radiation therapy, and linac-based radiosurgery as part of similar institutional protocols from March 1988 through July 1993. Patients were stratified into six prognostic classes (classes 1-6) based on the recursive partitioning analysis of multiple prognostic factors previously reported by the Radiation Therapy Oncology Group. RESULTS: The actuarial 2-year and median survival for all patients analyzed was 45% and 96 weeks, respectively. In comparison to the results from a previously published analysis of 1578 patients entered on three Radiation Therapy Oncology Group external beam radiotherapy protocols from 1974 to 1989, those patients treated with radiosurgery had a significantly improved 2-year and median survival (p = 0.01) corresponding with a standardized mortality risk ratio of 0.51 [95% confidence interval (CI): 0.31, 0.85]. This improvement in survival was seen predominantly for the worse prognostic classes (classes 3-6). The 2-year survival for the radiosurgical patients compared with the previously reported patients was 81% vs. 76% for classes 1/2, 75% vs. 35% for class 3, 34% vs. 15% for class 4, and 21% vs. 6% for classes 5/6, respectively. Although Karnofsky performance status and prognostic class were significant on univariate analysis, only the Karnofsky score was a significant predictor of outcome on multivariate analysis. Median and 2-year survival for patients with a Karnofsky score > or = 70 was 106 weeks and 51%, respectively, as compared to 38 weeks and 0% for patients with a Karnofsky score < 70% (p = 0.001). CONCLUSIONS: The addition of radiosurgery to conventional treatment (surgery and external beam radiotherapy) of malignant gliomas appears to improve survival when compared to historical reports. These results should be interpreted with caution because the recursive partitioning model does not completely predict the prognosis of the patients treated in the present study. Although this study suggests that radiosurgery may prolong survival in patients with malignant gliomas, the role of radiosurgery in the management of these patients remains to be defined by a prospective randomized trial.

Pattern of age-related maculopathy in the macular area. The Beaver Dam Eye Study.

PURPOSE: To describe the distribution of lesions associated with age-related maculopathy by location in the macula in a population of adult Americans. METHODS: Four thousand nine hundred twenty-six persons ranging in age from 43 to 84 years and living in Beaver Dam, Wisconsin, at the time of a census (1987-1988) were examined from 1988 to 1990. Lesions typical of age-related maculopathy were determined by masked grading of stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. The extent and prevalence of different types of lesions were determined for each of nine macular subfield regions: central, inner superior, inner nasal, inner inferior, inner temporal, outer superior, outer nasal, outer inferior, and outer temporal. RESULTS: Lesions associated with early age-related maculopathy were distributed in specific patterns. Soft indistinct drusen were more prevalent in the temporal and superior quadrants than in the nasal and inferior quadrants, whereas pigmentary abnormalities associated with age-related maculopathy were more prevalent in the superior or nasal quadrants than in the inferior or temporal quadrants. After weighting for subfield area, all types of lesions were most prevalent in the central macular region. CONCLUSION: Various lesions associated with early age-related maculopathy were located in specific patterns in the macula. It is not known whether these patterns resulted from environmental, anatomic, or physiologic factors.

Antineoplastic effect of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in transgenic mice with retinoblastoma.

OBJECTIVE: To evaluate the in vivo efficacy and clinical toxic effects of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in beta-luteinizing hormone-Tag (LH beta-Tag) transgenic mice with heritable retinoblastoma. METHODS: Forty-two mice (8-10 weeks old), randomly assigned to experimental (n = 21) or control (n = 21) groups, received intraperitoneal injections of 0.05 microgram of 1,25-dihydroxy-16-ene-23-yne-D3 in 0.5-mL mineral oil vehicle (experimental group) or 0.5 mL of mineral oil vehicle (control group) for 5 weeks. One experimental and 3 control animals died of injection-related trauma. Eyes were enucleated 1 week after treatment and were examined histologically in a masked fashion. RESULTS: All experimental and control animals showed evidence of tumor. The tumors in the experimental mice showed a significantly smaller cross-sectional area (0.88 +/- 0.08 mm2) compared with that in the control mice (1.12 +/- 0.12 mm2) (P = .02). All mice completed the treatment and showed no clinical evidence of toxic effects. CONCLUSIONS: Tumors in transgenic mice with retinoblastoma treated with 1,25(OH)2-16-ene-23-yne-D3 showed a 21% smaller cross-sectional area compared with that in the control mice, without producing clinically apparent toxic effects. This compound may be useful as adjunctive therapy in the treatment of retinoblastoma.

Changes in visual acuity in a population over a 10-year period : The Beaver Dam Eye Study.

PURPOSE: To describe the change in visual acuity in a 10-year period. DESIGN: Population-based cohort study. PARTICIPANTS: Included 3684 persons 43 to 86 years of age at the time of a baseline examination in 1988 to 1990, living in Beaver Dam, Wisconsin, at a follow-up examination in 1993 to 1995 and/or 1998 to 2000. METHODS: Best-corrected visual acuity was measured, after refraction, with logarithm of the minimum angle of resolution charts using a modification of the Early Treatment Diabetic Retinopathy Study protocol. MAIN OUTCOMES MEASURES: Doubling of the visual angle and incidence of visual impairment. RESULTS: The change in the mean number of letters read correctly over the 10-year period varied in the right eye from -0.9 (standard deviation [SD] = 5.5) and in the left eye from -1.2 (SD = 6.6) in people between 43 and 54 years of age to -11.0 (SD = 20.0) in the right eye and -12.6 (SD = 20.4) in the left eye in people 75 years of age or older (n = 184) at baseline. Over the 10-year period, 5.9% of the population had impaired vision (20/40 or worse in the better eye) develop, 0.8% had severe visual impairment (20/200 or worse in the better eye) develop, 4.8% had doubling of the visual angle, and 3.9% had improved vision. People who were 75 years of age or older at baseline were 15.0 times (95% confidence interval [CI], 10.9-20.6; P < 0.001) as likely to have impaired vision develop, 9.3 times (95% CI, 6.5-13.3; P < 0.001) as likely to have doubling of the visual angle, and 19.8 times as likely (95% CI, 8.4-46.4; P < or = 0.001) to have severe visual impairment develop than people younger than 75 years of age at baseline. For the 82 persons 75 years of age or older, currently residing in a nursing or group home at follow-up, they were 2.6 times (95% CI, 1.45-4.52) as likely to have impaired vision develop, 1.6 times (95% CI, 0.47-5.62) as likely to have severely impaired vision develop, and 3.6 times (95% CI, 1.96-6.78) as likely to have had a doubling of the visual angle than those not residing in a nursing or group home at follow-up. CONCLUSIONS: These data provide precise population-based estimates of the 10-year incidence of loss of vision over a wide spectrum of ages and show that decreased visual acuity in people 75 years of age after 10 years is a common finding, especially in those who are admitted to nursing or group homes.

Treatment of spontaneously arising retinoblastoma tumors in transgenic mice with an attenuated herpes simplex virus mutant.

The use of viruses to treat tumors has received renewed interest with the availability of genetically defined attenuated mutants. Herpes simplex virus (HSV) type 1 in particular has been shown to be effective for tumors of neuronal origin. However, the model systems used for these studies rely on the use of explanted tumor cells in immunodeficient animals. We have used a recently developed transgenic mouse model, wherein mice spontaneously develop retinoblastomas, to determine if a mutant HSV has a therapeutic effect against an endogenously arising tumor in an immunocompetent host. The injection of 1 x 10(6) PFU of the neuroattenuated HSV-1/HSV-2 recombinant RE6 into the vitreous of transgenic mice resulted in a significant inhibition of tumor growth compared to injection of medium alone (P = 0.0063). Immunohistochemical analysis of viral antigen showed that viral replication was restricted to focal areas of the tumors and the retinal pigment epithelium. Viral growth was not significantly different in the eyes of transgene-positive and transgene-negative mice, suggesting that enhanced replication in tumor cells may not explain the effects. Tumor cells in the treated eyes were significantly less differentiated than those in the untreated eyes (P = 0.04), suggesting that the virus may replicate better in certain cell types in the tumors. Although the injection of RE6 resulted in a difference in tumor size, the treatment did not result in the elimination of tumors in any of the mice improvements in the efficacy of tumor control are needed if this therapy is to be of use.

Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience.

BACKGROUND: Childhood acute lymphoblastic leukemia is the single most common childhood malignancy. Despite substantial improvements in therapy, cases in which relapse occurs are still more common than newly diagnosed cases of many other childhood cancers. The survival of patients who relapse despite improved therapy continues to be of interest. METHODS: One thousand one hundred forty-four relapses and 28 second malignant neoplasms were identified among the 3712 eligible patients enrolled on Children's Cancer Group trials between 1983 and 1989. The details of treatment after relapse were not accessible. Subsequent secondary event free survival and overall survival were examined by the site of and time to initial relapse. A variety of potential prognostic factors were examined employing the log rank statistic and Wilcoxon regression model. RESULTS: Rates of 6-year survival (+/- standard error) after isolated bone marrow, isolated central nervous system (CNS), and isolated testis relapse were 20%+/-2%, 48%+/-4%, and 70%+/-5%, respectively. Rates of survival after isolated bone marrow relapse at 0-17 months, 18-35 months, and after 36 months were 6%+/-2%, 11%+/-2%, and 43%+/-4%, respectively. Rates of survival after isolated CNS relapse at 0-17 months, 18-35 months, and after 36 months were 33%+/-4%, 59%+/-5%, and 72%+/-8%, respectively. Rates of survival after isolated testis relapse at 0-17 months, 18-35 months, and after 36 months were 52%+/-11%, 57%+/-10%, and 81%+/-5%, respectively. Rates of survival after combined bone marrow and CNS or testis relapse at 0-17 months, 18-35 months, and after 36 months were 9%+/-5%, 11%+/-6%, and 49%+/-7%, respectively. CONCLUSIONS: Substantial survival at 6 years is evident among several subsets of this unselected group of heterogeneously treated children, namely, those with isolated or combined bone marrow relapse after 36 months and those with isolated extramedullary relapse at any time. Second malignant neoplasms are rare thus far.