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Objective To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy. Patients and Methods The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months. We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily. In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib. Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity. Results A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens. Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response. At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively. We found that the DCE-MRI variables baseline transport constant (Ktrans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly. The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities. Conclusion This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy. Keywords: castration-resistant prostate cancer, angiogenesis inhibitors, cediranib, AZD2171 Introduction Prostate cancer is the most common non-dermatological cancer in men and has the second highest cancer-related death rates in men [1]. Docetaxel and prednisone are currently the standard of therapy for patients with symptomatic metastatic castration-resistant prostate cancer (CRPC). Cabazitaxel and abiraterone are approved as second-line treatment options for patients with post-docetaxel progressive metastatic disease, but the duration of response is generally short-lived with a modest survival benefit; therefore, more effective therapeutic approaches are still needed, especially in the post-docetaxel setting. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, and its receptors have been shown to be important in promoting tumour angiogenesis, playing a critical role in prostate cancer development and progression [2–4]. In preclinical models, inhibition of angiogenesis has been shown to be an effective target in CRPC. VEGF expression is observed in prostate tumours and in plasma and urine from patients with metastatic disease, where increased expression is associated with disease progression [5, 6]. The fms-like tyrosine kinase/kinase insert domain receptor receptors are expressed in human prostate cancers and are correlated with higher grade lesions and outcome [7]. While targeting angiogenesis appears to be a rational and therapeutic approach for CRPC [8), recent phase III trial results of VEGF pathway inhibitors bevacizumab [9] and sunitinib [10] have shown no clinical benefit, suggesting the need for predictive biomarkers to identify appropriate subgroups that may more likely benefit from this targeted therapy. Cediranib (AZD2171) is a potent oral small molecule inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3 [11, 12] and also of c-kit, to a lesser extent [12]. Cediranib has been investigated in clinical trials with multiple cancers including colorectal [13], lung [14, 15], ovarian [16] and renal [17] cancer, and glioblastoma [18, 19]. Cediranib has been reported to show activity in prostate cancer. Ryan et al. [20] reported a phase I trial that established a maximum tolerated dose of 20 mg with the dose-limiting toxicities of muscle weakness and hypertension. We conducted a phase II trial using cediranib 20 mg orally, once daily to assess the clinical efficacy and side-effect profile in patients with metastatic CRPC who have progressed after therapy with docetaxel. Previous studies have reported that serum PSA level has not been a dependable marker in assessing response using non-cytotoxic drugs [21, 22]. The present study used clinical and radiographical criteria to assess response. A second part of the study added prednisone in an attempt to limit the constitutional side effects that were associated with cediranib.

Received 28 March 2007; revised 27 December 2007; accepted for publication 1 January 2008;published 12 February 2008Prostate brachytherapy is an effective treatment option for early-stage prostate cancer. During aprostate brachytherapy procedure, transrectal ultrasound TRUS and fluoroscopy imaging modali-ties complement each other by providing good visualization of soft tissue and implanted seeds,respectively. Therefore, the registration of these two imaging modalities, which are readily availablein the operating room, could facilitate intraoperative dosimetry, thus enabling physicians to implantadditional seeds into the underdosed portions of the prostate while the patient is still on the oper-ating table. It is desirable to register TRUS and fluoroscopy images by using the seeds as fiducialmarkers. Although the locations of all the implanted seeds can be reconstructed from three fluo-roscopy images, only a fraction of these seeds can be located in TRUS images. It is challenging toregister the TRUS and fluoroscopy images by using the identified seeds, since the correspondencebetween them is unknown. Furthermore, misdetection of nonseed structures as seeds can lead to theinclusion of spurious points in the data set. We developed a new method called iterative optimalassignment IOA to overcome these challenges in TRUS-fluoroscopy registration. By using theHungarian method in an optimization framework, IOAcomputes a set of transformation parametersthat yield the one-to-one correspondence with minimum cost. We have evaluated our registrationmethod at varying noise levels, seed detection rates, and number of spurious points using datacollected from 25 patients. We have found that IOA can perform registration with an average rootmean square error of about 0.2 cm even when the seed detection rate is only 10%. We believe thatIOA can offer a robust solution to seed-based TRUS-fluoroscopy registration, thus making intraop-erative dosimetry possible. ©

Dependable sediment chronologies are essential to the interpretation of the sedimentary record of past environmental change. In the present article, we use high-resolution chemical and radiochemical data as the basis for a numerical simulation of sediment accumulation, bioturbation, and episodic deposition or erosion in a dynamic estuary. We simulate episodic events by employing a time dependent sedimentation rate that we solve by finding a set of model parameters that describes depth profiles of both excess 210Pb and fallout 239,240Pu. We apply the model to depth distributions of these tracer nuclides in cores from upper-, mid- and lower-Bay sites in Chesapeake Bay. At the upper-Bay site, combining chemical and radiochemical data permits us to recognize and to quantify the sediment deposition due to tropical storm Agnes (1972). At the lower-Bay site, we demonstrate nonsteady sedimentation and propose plausible scenarios to account for it. Given adequate data, our model can provide information that is not available from steady-state models.

Purpose: (1) To develop an intra‐operative dose evaluation and optimization system for prostate brachytherapy using complementary imaging modalities (fluoroscopy for seed localization and ultrasound for prostate delineation). (2) To evaluate the usefulness of the intra‐operative dosimetry system. Method and Materials: Several algorithms were developed to realize the concept of fluoroscopy‐ultrasound based dosimetry. These include automated seed detection, 3D seed reconstruction, patient motion correction, computer‐assisted prostate contouring, and seeds‐prostate registration algorithms. In order to accelerate the seed reconstruction from multiple x‐ray projections, the dimensionality of seed matching process was reduced by strategically forming search restriction sub‐images. Problems of incomplete data due to clustering and superposition of projected seeds were solved by a pseudo‐matching technique. Patient movements between fluoroscopic image acquisitions were corrected through analysis of epipolar‐planes. Registration of seeds and prostate volume was accomplished by establishing a sparse (small subset of seeds detected on ultrasound) to full (seeds reconstructed from fluoroscopy) data set correspondence. Results: Intra‐operative dosimetry was performed on 25 patients implanted with Pd‐ 103 seeds. In nine patients, no additional seeds were implanted after intraoperative dose evaluation. In 16 patients, remedial seed were added based on the intra‐operative evaluation. Subsequently, V100 values improved from 86±8% to 93±4% (p=0.005). For all 25 patients, the post‐implant dosimetry results using our system were compared with Day 0 CT‐study. The V100 and D90 values from the fluoroscopy‐ultrasound based dosimetry were 95±4% and 120±24% while the CT‐based dosimetry computed 95±4% and 122±24%, respectively. Conclusion: We have developed and implemented an intra‐operative dosimetry system that combines the strengths of fluoroscopy and ultrasound. A clinical study has successfully demonstrated its intended utility in intra‐operative setting by significantly improving the quality of seed implant in prostate brachytherapy.