Ivan Yeung

Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation

PURPOSE To look for factors predictive of acute urinary retention (AUR) after permanent seed prostate brachytherapy. METHODS AND MATERIALS From March 1999 to February 2001, 150 permanent seed prostate implants were performed at Princess Margaret Hospital (Stage T1c, n = 113; T2a, n = 37; mean prostate-specific antigen level 5.9 ng/mL, prescription dose 145 Gy per Task Group No. 43). alpha-Blockers were used routinely after implantation. Dosimetry was based on the 1-month postimplant CT scan. The International Prostate Symptom Score (IPSS) and catheterization were recorded at 1 month and 3 months and then every 3 months. The following variables were examined: age, baseline IPSS, prior androgen ablation, prostate transrectal ultrasound volume, number of seeds, D(90), V(100), V(200), and urethral dose. RESULTS Twenty patients (13%) experienced AUR. No difference was seen in the mean D(90) (149 Gy vs. 152 Gy, p = 0.6), V(100) (90% vs. 91%, p = 0.6), V(200) (23% vs. 25% p = 0.4), IPSS (6.4 vs. 5.9, p = 0.8), or maximal urethral dose (204 Gy vs. 210 Gy, p = 0.5). The prostate volume was significantly larger in men with AUR (39.8 cm(3) vs. 34.3 cm(3), p = 0.003), and the mean number of seeds was higher (112 vs. 103, p = 0.006). Of the 20 patients experiencing AUR, 11 (55%) had received prior antiandrogen therapy to downsize their prostates vs. 35 (27%) of the 130 who did not have AUR (p = 0.02). Multivariate analysis showed prostate volume and prior hormone use to be independent predictors of AUR. CONCLUSIONS Implant quality as determined by D(90), V(100), V(200), and urethral dose did not predict AUR. Prostate size was the major determinant of AUR. For any given prostate size, prior androgen ablation increased the risk of AUR. Men with larger prostates should be aware of the increased risk when contemplating brachytherapy.

Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers

PURPOSE These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage. METHODS AND MATERIALS The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy. RESULTS Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung. CONCLUSIONS With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.

Interobserver variation in postimplant computed tomography contouring affects quality assessment of prostate brachytherapy

PURPOSE Permanent seed implants are accepted treatment of early stage prostate cancer. Implant quality is assessed by post implant CT-based dosimetry but prostate contours on CT images are obscured by metallic seed artefact and edema. Outcome depends on implant quality, but perceived implant quality depends on accurate prostate contouring. This study documents inter observer variation in prostate contouring on post implant CT scans. METHODS AND MATERIALS Ten patients had implant dosimetry calculated on 4 copies of the post implant CT scan. Prostate contours from MRI-CT fusion were the gold standard for prostate edge identification. CTs were contoured by an experienced prostate brachytherapist matching CT images to the pre implant TRUS, and by 2 GU radiation oncologists experienced in conformal radiotherapy planning. Dosimetry was compared to that obtained using MRI-CT fusion in terms of D90 and V100. RESULTS Contours and dosimetry were not reproducible among the 3 observers. The V100s of the experienced brachytherapist differed from that of MRI-CT fusion by a mean of 2.4% compared to 9.1% and 4.4% for observers 1 and 2, and the D90 by a mean of 9.3 Gy compared to 30.3 and 14.4 Gy for observers 1 and 2. CONCLUSIONS Quality assessment of prostate brachytherapy based on 1 month post implant CT is difficult. This may obscure the dose-response relationship in brachytherapy as well as create problems for quality assurance in multicentre trials evaluating brachytherapy against standard modalities. Whenever possible, MRI-CT fusion should be employed to verify prostate contours post implant.

Partial volume rat lung irradiation: Temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation

Purpose: The current study investigated the early activation of inflammatory cytokines and macrophages in different regions of the lung following partial volume irradiation. We examined temporal fluctuations in DNA damage, cytokine expression and macrophage activation during 16 weeks post-irradiation. Materials and methods: We irradiated the lower lung of Sprague-Dawley rats with 10 Gy. A micronucleus assay was used to examine DNA damage. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to analyse the RNA expression of Interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNF-α) and Transforming Growth Factor beta (TGF-β) relative to Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH). The activation of macrophages was determined using the antibody ED-1 for immunohistochemical analysis. Results: The expression of DNA damage, the activation of macrophages and the expression of inflammatory cytokines all fluctuated in a cyclic pattern. The initial induction of cytokine expression and the activation of macrophages occurred at very early times (1 h) following irradiation. Waves of cytokine expression and macrophage activation were also seen at later times (up to 16 weeks) following irradiation. DNA damage also occurred in a cyclic pattern though this was less pronounced out-of-field. The levels of cytokines and activated macrophages were elevated to a similar degree both in- and out-of-field, whereas there was a greater micronuclei yield in-field than out-of-field. Conclusions: An inflammatory response triggered by the partial volume irradiation occurs in the whole rat lung at very early times following irradiation and is maintained in a cyclic pattern to later times when the onset of functional symptoms is expected. We hypothesize that Reactive Oxygen Species (ROS) induced by this response play an important role in the induction of both in-field and out-of-field DNA damage.

Sequential Comparison of Seed Loss and Prostate Dosimetry of Stranded Seeds With Loose Seeds in 125I Permanent Implant for Low-Risk Prostate Cancer

PURPOSE To compare stranded seeds (SSs) with loose seeds (LSs) in terms of prostate edema, dosimetry, and seed loss after (125)I brachytherapy. METHODS AND MATERIALS Two prospective cohorts of 20 men participated in an institutional review board-approved protocols to study postimplant prostate edema and its effect on dosimetry. The LS cohort underwent brachytherapy between September 2002 and July 2003 and the SS cohort between April 2006 and January 2007. Both cohorts were evaluated sequentially using computed tomography-magnetic resonance imaging fusion-based dosimetry on Days 0, 7, and 30. No hormonal therapy or supplemental beam radiotherapy was used. RESULTS Prostate edema was less in the SS cohort at all points (p = NS). On Day 0, all the prostate dosimetric factors were greater in the LS group than in the SS group (p = 0.003). However, by Days 7 and 30, the dosimetry was similar between the two cohorts. No seeds migrated to the lung in the SS cohort compared with a total of five seeds in 4 patients in the LS cohort. However, the overall seed loss was greater in the SS cohort (24 seeds in 6 patients; 1.1% of total vs. 0.6% for LSs), with most seeds lost through urine (22 seeds in 5 patients). CONCLUSION Despite elimination of venous seed migration, greater seed loss was observed with SSs compared with LSs, with the primary site of loss being the urinary tract. Modification of the technique might be necessary to minimize this. Prostate dosimetry on Days 7 and 30 was similar between the SS and LS cohorts.

Genistein Can Mitigate the Effect of Radiation on Rat Lung Tissue

Abstract We investigated whether genistein could protect the lung from radiation-induced injury. We hypothesized that genistein would reduce the levels of inflammatory cytokines and ROS after irradiation and therefore lead to reduced DNA damage and functional deficits. Whole lungs of Sprague-Dawley rats were irradiated with 18 Gy at ∼0.5 Gy/min. At 28 weeks a micronucleus assay was used to examine DNA damage and, using immunohistochemical analysis, expression of IL-1α, IL-1β, IL-6, TNF-α and TGF-β, macrophage activation, oxidative stress (8-OHdG) and collagen levels were measured. A TBARS assay was used to measure the level of malondialdehyde. Functional damage was assessed by measuring the breathing rate of the rats over the course of the experiment. The increase in breathing rate after irradiation was damped in rats receiving genistein during the phase of pneumonitis (6–10 weeks), and there was a 50–80-day delay in lethality in this group. Genistein treatment also decreased the levels of the inflammatory cytokines TNF-α, IL-1β and TGF-β and led to a reduction in collagen content, a reduction in 8-OHdG levels, and complete protection against DNA damage measured in surviving rats at 28 weeks after irradiation. These results demonstrates that genistein treatment can provide partial protection against the early (pneumonitis) effects of lung irradiation and reduce the extent of fibrosis, although not sufficiently to prevent lethality at the radiation dose used in this study.

A Mathematical Model of the Enhanced Permeability and Retention Effect for Liposome Transport in Solid Tumors

The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect based on fundamental properties of the tumor microenvironment and forms the basis for transport modeling of liposome drug delivery.

Loose seeds vs. stranded seeds: A comparison of critical organ dosimetry and acute toxicity in 125I permanent implant for low-risk prostate cancer

PURPOSE To compare the critical organ dosimetry and toxicity of loose seeds (LS) with stranded seeds (SS) in (125)I permanent implant for low-risk prostate cancer. METHODS AND MATERIALS Two cohorts of 20 patients each were treated in Institutional Review Board-approved protocols designed to assess prostate edema and seed stability using MR-CT fusion on Days 0, 7, and 30 after permanent implant. (125)I LS were used for one cohort and (125)I SS for the other. Rectal wall dosimetry was compared for the two cohorts using RV100 and RD1cc and urethral dosimetry using UD5, UD30, and UV150. Statistical comparisons were performed using unpaired Students t test. RESULTS At each time point (Days 0, 7, and 30), both the mean RD1 cc (SS: 123.1, 139.7, and 156.1 Gy vs. LS: 90.2, 104, and 129.4 Gy, respectively) and the mean RV100 (SS: 0.63, 1.0, and 1.4 cc vs. LS: 0.2, 0.4, and 0.73 cc, respectively) were significantly higher for strands (all p-values<0.01). Only 1 patient developed radiotherapy oncology group (RTOG) Grade 1 acute rectal toxicity in the loose seed cohort, whereas 3 patients had Grade 1 and 1 patient had Grade 2 toxicity with strands. The mean percentage increase of UD5 (7.7% LS vs. 24.6% SS; p=0.004) and UD30 (5% LS vs. 15.9% SS; p=0.02) from preplan to Day 30 was higher for strands. The increase in UV150 from baseline to Day 30 was significantly higher for strands (0.2 vs. 0.06 cc; p=0.01). Urinary toxicity was similar in both cohorts. CONCLUSIONS SS resulted in higher dose to urethra and rectal wall compared with LS on postimplant dosimetry. A trend toward higher acute rectal toxicity rate was observed for SS.

Assessing perfusion changes during whole brain irradiation for patients with cerebral metastases

AbstractPurpose: To assess perfusion changes within brain and correlate these with clinical symptoms during whole brain radiotherapy (WBRT) for cerebral metastases. Materials and methods: Fourteen patients with cerebral metastases underwent dynamic CT perfusion scans during palliative whole brain irradiation. Perfusion scans were performed on Day 1 prior to initial radiotherapy treatment, then on Day 2, and on Day 5 immediately after completion of radiotherapy. Measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and capillary surface area permeability product (PS) were performed for each perfusion scan, and daily symptom assessment was taken prior to initial perfusion scan and thereafter prior to each daily radiation treatment. Results: Utilizing Day 1 as baseline, a 19% increase (P=0.033) was noted in PS at Day 2, (median 1.47 ml/100 g/min), which returned to Day 1 range at Day 5 (median 1.31 ml/100 g/min). When symptoms were correlated with perfusion parameters, a statistically significant association between change in MTT with change in headache scores was observed, baseline to Day 2 (P=0.019), and a trend between change in nausea scores with change in CBV (P=0.059) as well as change in MTT (P=0.098), baseline to Day 5. Conclusion: This study has demonstrated the feasibility of a non-invasive technique to assess changes occurring within the human brain during a course of radiation treatment. Dynamic perfusion tomography provides insight into the pathophysiological processes taking place and allows correlation with patient symptomatology.

Interindividual variability of arterial impulse response to intravenous injection of nonionic contrast agent (Iohexol) in DCE-CT study

PURPOSE It is known that the arterial input function (AIF) in dynamic contrast-enhanced (DCE)-CT differs among patients even for fixed contrast injection protocols. Therefore, a study has been performed to investigate the interindividual variability of the AIF with respect to patient factors (such as weight, height, and age). In addition, it has been demonstrated that the relations from the interindividual variability investigation can be further used for the estimation of AIF for a patient without the requirement of measurement. METHODS DCE-CT data for a cohort of 34 patients with cervical carcinoma were used for the investigation of interindividual variability of the AIF. To dissociate the effect of different durations of contrast injection, the arterial impulse response (AIR) to intravenous contrast injection was calculated and examined for its correlations with these patient factors. An empirical functional form was proposed to model the AIR with temporal intensity of a first pass of contrast agent followed by recirculation and quasiequilibrium state of contrast concentration. Specific features (onset time, peak time, and amplitudes) of the AIR were tested for correlations with the patient factors. Linear regression was applied to cases that show significant strong correlation between the AIR amplitudes and patient factors. The results were then used to predict the AIR for any given patient based on the patient factors. It was shown that using the predicted AIR, the AIF of the patient can be estimated without the requirement of measurement given the injection protocol is known. The method of AIF estimation was tested in DCE-CT data from another group of 14 patients. The efficacy of individually estimated AIF on pharmacokinetic analysis was assessed against the use of measured AIF and population-averaged AIF as the latter is another possible strategy for AIF generation if AIF measurement is not available. RESULTS It was found that the amplitudes of AIR postonset time were significantly correlated with patient bodyweight at most time points(r<-0.44,P<0.01) except 8-17 s (P>0.01). When the adiabatic tissue homogeneity (ATH) and the Kety models were applied to the pharmacokinetic analysis, the mean percentage errors in kinetic parameter estimates induced by using the estimated AIF instead of the measured one for both models ranged from -4.98% to 11.19 %. CONCLUSIONS It was found that there are strong linear relationships between AIR and patient weight; thereby the AIR of a patient can be estimated with patient weight. The proposed method of AIF estimation is potentially applicable in cases where AIF measurement is not possible.