Synergistic Impact of Xanthorrhizol and d-δ-Tocotrienol on the Proliferation of Murine B16 Melanoma Cells and Human DU145 Prostate Carcinoma Cells.

Isoprenoids suppress the mevalonate pathway that provides prenyl groups for the posttranslational modification of growth-regulating proteins. We hypothesize that xanthorrhizol and d-δ-tocotrienol synergistically suppress the growth of murine B16 melanoma and human DU145 prostate carcinoma cells. Xanthorrhizol (0-200 µmol/L; half maximal inhibitory concentration [IC50] = 65 µmol/L) and d-δ-tocotrienol (0-40 µmol/L; IC50 = 20 µmol/L) each induced a concentration-dependent suppression of the proliferation of B16 cells and concurrent cell cycle arrest at the G1 phase. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol suppressed B16 cell proliferation by 69%, an impact greater than the sum of those induced by xanthorrhizol (15%) and d-δ-tocotrienol (12%) individually. The blend cumulatively reduced the levels of cyclin-dependent kinase four and cyclin D1, key regulators of cell cycle progression at the G1 phase. The expression of RAS and extracellular signal-regulated kinase (ERK1/2) in the proliferation-stimulating RAS-RAF-MEK-ERK pathway was downregulated by the blend. Xanthorrhizol also induced a concentration-dependent suppression of the proliferation of DU145 cells with concomitant morphological changes. Isobologram confirmed the synergistic effect of xanthorrhizol and d-δ-tocotrienol on DU145 cell proliferation with combination index values ranging 0.61-0.94. Novel combinations of isoprenoids with synergistic actions may offer effective approaches in cancer prevention and therapy.

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.

Transversus abdominis plane block in robotic gynecologic oncology: a randomized, placebo-controlled trial.

OBJECTIVE: Although robotic surgery decreases pain compared to laparotomy, postoperative pain can be a concern near the site of a larger assistant trocar site. The aim of this study was to determine the efficacy of transversus abdominis plane (TAP) block on 24-hour postoperative opiate use after robotic surgery for gynecologic cancer. METHODS: Sixty-four subjects with gynecologic malignancies who were scheduled to undergo robotic surgery were enrolled into the study. They were randomized to receive a unilateral TAP block to the side of the assistant port via ultrasound guidance. The block was comprised of 30 cc of 0.25% bupivacaine with 3 mcg/mL epinephrine or saline. Opiate use was measured and converted into IV morphine equivalents. Patient-reported pain was measured using the Brief Pain Inventory (BPI) and Visual Analog Scale (VAS). RESULTS: The treatment group used a mean of 64.9 mg morphine in the first 24h compared to 69.3mg for controls (primary outcome, p=0.52). After age-adjustment, the treatment group used a mean of 11.1mg morphine less than controls (p=0.09). Postoperative pain scores assessed by the BPI (6.44 vs. 6.97, p=0.37) and the VAS (3.12 vs. 3.61, p=0.30) were equivalent. Block placement was uncomplicated in 98.4% of participants with mean BMI of 35.3 kg/m(2). Linear regression revealed an approximate 8.1mg decrease in morphine equivalents used per additional decade of life (p=0.0008). There was a positive correlation between the amount of opiates and BMI with an additional 8.8 mg of morphine per 10 kg/m(2) increase in BMI (p=0.0012). CONCLUSIONS: TAP block is safe and feasible in this patient population with a large proportion of morbid obesity. Preoperative TAP block does not significantly decrease opiate use. However; based on these data, a clinically useful nomogram has been created to aid clinicians in postoperative opiate-dosing for patients based on age and BMI.

Comparison of computed tomography and magnetic resonance imaging for the evaluation of canine intranasal neoplasia.

OBJECTIVES: Canine intranasal neoplasia is commonly evaluated using computed tomography to indicate the diagnosis, to determine disease extent, to guide histological sampling location and to plan treatment. With the expanding use of magnetic resonance imaging in veterinary medicine, this modality has been recently applied for the same purpose. The aim of this study was to compare the features of canine intranasal neoplasia using computed tomography and magnetic resonance imaging. METHODS: Twenty-one dogs with confirmed intranasal neoplasia underwent both computed tomography and magnetic resonance imaging. The images were reviewed retrospectively for the bony and soft tissue features of intranasal neoplasia. RESULTS: Overall computed tomography and magnetic resonance imaging performed very similarly. However, lysis of bones bordering the nasal cavity and mucosal thickening was found on computed tomography images more often than on magnetic resonance images. Small amounts of fluid in the nasal cavity were more often seen on magnetic resonance images. However, fluid in the frontal sinuses was seen equally well with both modalities. CLINICAL SIGNIFICANCE: We conclude that computed tomography is satisfactory for evaluation of canine intranasal neoplasia, and no clinically relevant benefit is gained using magnetic resonance imaging for intranasal neoplasia without extent into the cranial cavity.

The continual reassessment method for multiple toxicity grades: a Bayesian quasi-likelihood approach.

We consider the case of phase I trials for treatment of cancer or other severe diseases in which grade information is available about the severity of toxicity. Most dose allocation procedures dichotomize toxicity grades based on being dose limiting, which may not work well for severe and possibly irreversible toxicities such as renal, liver, and neurological toxicities, or toxicities with long duration. We propose a simple extension to the continual reassessment method (CRM), called the Quasi-CRM, to incorporate grade information. Toxicity grades are first converted to numeric scores that reflect their impacts on the dose allocation procedure, and then incorporated into the CRM using the quasi-Bernoulli likelihood. A simulation study demonstrates that the Quasi-CRM is superior to the standard CRM and comparable to a univariate version of the Bekele and Thall method (2004, Journal of the American Statistical Association 99, 26-35). We also present sensitivity analysis of the new method with respect to toxicity scores, and discuss practical issues such as extending the simple algorithmic up-and-down designs.

Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin.

PURPOSE: The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites. EXPERIMENTAL DESIGN: In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood vessel formation in nonneoplastic tissue was evaluated by creating a skin wound site on the arm with a punch biopsy device. The wound site was sampled with a second biopsy after a 7-day interval. This sequential biopsy procedure was performed prior to and 3 weeks after initiation of endostatin treatment. Vascular density, endothelial cell kinetics, and blood vessel maturity were determined in tumor and skin wound samples. The ultrastructure of tumor blood vessels was examined by electron microscopy. RESULTS: As expected, the tumors were of variable vascular density. Skin wounding induced a vascular granulation tissue containing a high percentage of proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistically significant difference was detected between pretreatment and treatment samples of tumors and of skin wounds for any of the parameters tested. CONCLUSIONS: Endostatin treatment was not associated with any recognizable vascular changes in tumor samples and did not perturb wound healing at the doses and the treatment schedule used.

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.

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.

Is alpha/beta for prostate tumors really low?

PURPOSE: Brenner and Hall's 1999 paper estimating an alpha/beta value of 1.5 Gy for prostate tumors has stimulated much interest in the question of whether this ratio (of intrinsic radiosensitivity to repair capacity) is much lower in prostate tumors than in other types of tumors that proliferate faster. The implications for possibly treating prostatic cancer using fewer and larger fractions are important. In this paper we review updated clinical data and present somewhat different calculations to estimate alpha/beta. METHODS AND MATERIALS: Seventeen clinical papers published from 1995 to 2000 were reviewed to obtain estimates of biochemical control from radiotherapy alone using external beam, I-125 implants, or Pd-103 implants. The focus was on intermediate risk patients. Three methods of estimating alpha/beta were employed. First, a simple two-step graphical comparison of isoeffective doses from external beam and implant modalities was made, to see which value of alpha/beta predicted the observed identity of biologic effect. Second, the same data were subjected to Direct Analysis (maximum likelihood estimation), from which an estimate of alpha/beta and also of the T(12) of repair of sublethal damage in the tumors (both with confidence intervals) were obtained. Third, preliminary clinical data comparing two different sizes of high-dose boost doses were analyzed in which significantly different bNED was observed at 2 years. RESULTS: The second method gave the definitive result of alpha/beta = 1.49 Gy (95% CI 1.25-1.76) and T(12) = 1.90 h (95% CI 1.42-2.86 h). The first method gave a range from 1.4 to 1.9 Gy and showed that if mean or median dose were used instead of prescribed dose, the estimate of alpha/beta would be substantially below 1 Gy. The third method, although based on early follow-up, was consistent with low values of alpha/beta in the region of 2 Gy or below. The estimate for T(12) is the first value reported for prostate tumors in situ. CONCLUSIONS: All the estimates point toward low values of alpha/beta, at least as low as the estimates of Brenner and Hall, and possibly lower than the expected values of about 3 Gy for late complications. Hypofractionation trials for intermediate-risk prostatic cancer appear to be indicated.

Responses of small- and large-field bipolar cells to GABA and glycine.

Morphologically distinct subtypes of retinal bipolar cells transmit information along parallel pathways to convey different aspects of the visual scene, but the synaptic mechanisms that regulate signal transmission are largely unknown. The all-rod retina of skate provides a comparatively simple system in which to correlate bipolar cell morphology with responses to the inhibitory neurotransmitters GABA and glycine. Two subtypes of bipolar cells can be identified when isolated in culture: large-field bipolar cells with extensive dendritic arbors, and small-field bipolar cells with one or two dendritic branches. Under voltage-clamp, glycine elicited significant current responses from small-field cells, but not from large-field bipolar cells. Although all bipolar cells displayed GABA-activated chloride currents mediated by both GABA(A) and GABA(C) receptors, the small-field bipolar cells showed a significantly greater contribution from GABA(A) receptors. The results of the present study reveal for the first time that the relative expression of the two classes of GABA receptor on each bipolar cell type correlates with cell morphology and the presence of the glycine receptor.

A new approach to dose escalation in non-small-cell lung cancer.

PURPOSE: To describe the radiobiological rationale for dose-per-fraction escalation in non-small-cell lung cancer (NSCLC) and to devise a novel Phase I scheme to implement this strategy using advanced radiotherapy delivery technologies. METHODS AND MATERIALS: The data from previous dose escalation trials in NSCLC are reanalyzed to establish a dose-response relationship in this disease. We also use data relating prolongation in treatment time to survival to compute the potential doubling time for lung tumors. On the basis of these results, and using a Bayesian model to determine the probability of pneumonitis as a function of mean normalized lung dose, a dose-per-fraction escalation strategy is developed. RESULTS: Standard approaches to dose escalation using 2 Gy per fraction, five fractions per week, require doses in excess of 85 Gy to achieve 50% long-term control rate. This is partly because NSCLCs repopulate rapidly, with a 1.6% per day loss in survival from prolongation in overall treatment time beyond 6 weeks, and a cell doubling time of only 2.5 to 3.3 days. A dose-per-fraction escalation strategy, with a constant number of fractions, 25, and overall time, 5 weeks, is projected to produce tumor control rates predicted to be 10%-15% better than 2 Gy per fraction dose escalation, with equivalent late effects. This Phase I clinical study is divided into three parts. Step 1 examines the feasibility of the maximum breath-holding technique and junctioning of tomotherapy slices. Step 2 treats 10 patients with 30 fractions of 2 Gy over 6 weeks and then reduces duration to 5 weeks using fewer but larger fractions in 10 patients. Step 3 will consist of a dose-per-fraction escalation study on roughly 50 patients, maintaining 25 fractions in 5 weeks. Bayesian methodology (a modification of the Continual Reassessment Method) will be used in Step 3 to allow consistent and efficient escalation within five volume bins. CONCLUSION: A dose-per-fraction escalation approach in NSCLC should yield superior outcomes, compared to standard dose escalation approaches using a fixed dose per fraction, for a given level of pneumonitis and late toxicity. Highly conformal radiotherapy techniques, such as intensity modulated radiotherapy (IMRT) and helical tomotherapy with its adaptive capabilities, will be necessary to achieve significant dose-per-fraction escalation without unacceptable lung and esophageal morbidity.

Retrospective analysis on treating nasopharyngeal carcinoma with accelerated fractionation (6 fractions per week) in comparison with conventional fractionation (5 fractions per week): report on 3-year tumor control and normal tissue toxicity.

BACKGROUND AND PURPOSE: To assess the therapeutic gain achieved by accelerated fractionation for non-keratinizing/undifferentiated nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: During January 1994 to October 1997, 325 patients were treated to a total dose of 66 Gy in 33-37 fractions: 167 (irradiated before mid-January 1996) with 5 daily fractions (CF) and subsequent 158 with 6 daily fractions (AF) per week. Their median treatment times were 46 and 39 days, respectively. Additional boost to parapharyngeal extension had been given to 181 and Cisplatin-based chemotherapy to 57 patients (24 concurrent with radiotherapy). RESULTS: The AF group had significantly higher progression-free rate than the CF group (74 vs. 63% at 3 years, P=0.02 by the log-rank test). However, the difference in disease-specific survival (86 vs. 80%, P=0.39) and overall survival (81 vs. 78%, P=0.9) did not reach statistical significance. Strongly significant improvement in local failure-free rate was achieved for patients with T3-4 tumors (87 vs. 62%, P<0.01). Multivariate analyses showed that fractionation was an independent significant factor for overall progression: hazard ratio=0.63, 95% confidence interval: 0.41-0.98, P=0.04. Among the 268 patients treated with radiotherapy alone, those treated by AF had significantly higher incidence of acute reaction grade > or=3 (72 vs. 13%, P<0.01). However, all patients completed the scheduled dose without excessive prolongation, and no significant increase in late complications was observed (20 vs. 15% at 3 years, P=0.19). CONCLUSIONS: The current analyses suggested that acceleration to 6 daily fractions per week could significantly improve the progression-free rate for NPC without excessive late toxicity. Improvement in local control was confined to T3-4 tumors.

Sport in Latin America from past to present: a European perspective.

This chapter examines sport in Latin America in its social, cultural, and political contexts. An analysis of the development of sport in Latin America suggests that there have been a number of distinct phases influenced by the cultures of the Spanish, British and French. More recently, the games and pastimes of the United States have made a significant impact. It is suggested that the further development of sport in Latin America is hindered by a number of significant problems. It concludes that the problems faced by some countries are immense and that governments and international organizations in the developed world should offer help where appropriate.

Sequential designs for phase I clinical trials with late-onset toxicities.

Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.

Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) who had bulky disease (lymphomatous features) at diagnosis had the highest rate of testicular relapse (20%) of any ALL subgroup on previous Children's Cancer Group (CCG) studies in the late 1980s. To limit curative, but sterilizing, testicular irradiation to those with testicular disease, testicular biopsies were performed to detect occult testicular disease within the first 6 months of treatment. Testicular irradiation then was provided to those with occult disease to increase disease-free survival. Identification of those with occult disease was believed to be a factor that would influence ultimate survival in such patients in that era. PATIENTS AND METHODS: One hundred ninety-nine patients had bilateral testicular wedge biopsies performed during the first maintenance therapy phase of the four different chemotherapy regimens. Patients with positive biopsy results were treated with testicular irradiation and continued on therapy. RESULTS: Eleven of 199 biopsy results (5.5%) were judged positive. Patients with positive biopsy results given testicular radiation had a 45% subsequent adverse event rate, compared with 36% for those with a negative biopsy results (P = 0.4). The survival rates for the two groups were similar. The low rate of positive biopsy specimens resulted in discontinuation of the procedure before closure of the study. CONCLUSION: Positive testicular biopsy results early in remission identified patients at a slightly higher risk of subsequent adverse events but did not influence survival. However, because negative biopsy results (94.5%) did not alter the prescribed treatment, the small number of positive biopsy results did not warrant undertaking the procedure in most male patients with ALL, and this procedure was abandoned.

Total biological effect on late reactive tissues following reirradiation for recurrent nasopharyngeal carcinoma.

PURPOSE: To assess the additional damage of normal tissues attributable to reirradiation and the magnitude of partial recovery following the initial course. METHODS AND MATERIALS: Symptomatic late complication rates (excluding xerostomia) in 3635 patients receiving one course (Group 1) and 487 patients receiving two courses of external radiotherapy (Group 2) for nasopharyngeal carcinoma were retrospectively analyzed and compared. RESULTS: Group 2 had significantly lower actuarial complication-free survival rates than Group 1: 48% versus 81% at 5 years. The post-retreatment incidence was significantly affected by biologically effective dose (BED) (assuming an alpha/beta ratio of 3 Gy) of the first course: hazard ratio (HR) = 1.04 per Gy(3) (p = 0.01), but only marginally by that of the second course: HR = 1.01 per Gy(3) (p = 0.06). If the summated BED was taken as the dose unit, it was estimated that a total BED of 143 Gy(3) would induce a 20% incidence at 5 years, while the corresponding dose projected from Group 1 was 111 Gy(3). The gap effect was insignificant in the overall analyses, but a trend of decreasing risk with increasing interval was observed in patients with gap > or = 2 years: HR = 0.86 per year (p = 0.07). CONCLUSION: The major determinant of post-retreatment complication is the severity of damage during the initial course. The sum of total doses tolerated is higher than that expected with a single-course treatment, suggesting occurrence of partial recovery (particularly in those reirradiated after an interval of 2 years or more).