A GPU-based multi-criteria optimization algorithm for HDR brachytherapy

Currently in HDR brachytherapy planning, a manual fine-tuning of an objective function is necessary to obtain case-specific valid plans. This study intends to facilitate this process by proposing a patient-specific inverse planning algorithm for HDR prostate brachytherapy: GPU-based multi-criteria optimization (gMCO). Two GPU-based optimization engines including simulated annealing (gSA) and a quasi-Newton optimizer (gL-BFGS) were implemented to compute multiple plans in parallel. After evaluating the equivalence and the computation performance of these two optimization engines, one preferred optimization engine was selected for the gMCO algorithm. Five hundred sixty-two previously treated prostate HDR cases were divided into validation set (100) and test set (462). In the validation set, the number of Pareto optimal plans to achieve the best plan quality was determined for the gMCO algorithm. In the test set, gMCO plans were compared with the physician-approved clinical plans. Over 462 cases, the number of clinically valid plans was 428 (92.6%) for clinical plans and 461 (99.8%) for gMCO plans. The number of valid plans with target V100 coverage greater than 95% was 288 (62.3%) for clinical plans and 414 (89.6%) for gMCO plans. The mean planning time was 9.4 s for the gMCO algorithm to generate 1000 Pareto optimal plans. In conclusion, gL-BFGS is able to compute thousands of SA equivalent treatment plans within a short time frame. Powered by gL-BFGS, an ultra-fast and robust multi-criteria optimization algorithm was implemented for HDR prostate brachytherapy. A large-scale comparison against physician approved clinical plans showed that treatment plan quality could be improved and planning time could be significantly reduced with the proposed gMCO algorithm.Comment: 18 pages, 7 figure

Clinical applications of custom-made vaginal cylinders constructed using three-dimensional printing technology.

PurposeThree-dimensional (3D) printing technology allows physicians to rapidly create customized devices for patients. We report our initial clinical experience using this technology to create custom applicators for vaginal brachytherapy.Material and methodsThree brachytherapy patients with unique clinical needs were identified as likely to benefit from a customized vaginal applicator. Patient 1 underwent intracavitary vaginal cuff brachytherapy after hysterectomy and chemotherapy for stage IA papillary serous endometrial cancer using a custom printed 2.75 cm diameter segmented vaginal cylinder with a central channel. Patient 2 underwent interstitial brachytherapy for a vaginal cuff recurrence of endometrial cancer after prior hysterectomy, whole pelvis radiotherapy, and brachytherapy boost. We printed a 2 cm diameter vaginal cylinder with one central and six peripheral catheter channels to fit a narrow vaginal canal. Patient 3 underwent interstitial brachytherapy boost for stage IIIA vulvar cancer with vaginal extension. For more secure applicator fit within a wide vaginal canal, we printed a 3.5 cm diameter solid cylinder with one central tandem channel and ten peripheral catheter channels. The applicators were printed in a biocompatible, sterilizable thermoplastic.ResultsPatient 1 received 31.5 Gy to the surface in three fractions over two weeks. Patient 2 received 36 Gy to the CTV in six fractions over two implants one week apart, with interstitial hyperthermia once per implant. Patient 3 received 18 Gy in three fractions over one implant after 45 Gy external beam radiotherapy. Brachytherapy was tolerated well with no grade 3 or higher toxicity and no local recurrences.ConclusionsWe established a workflow to rapidly manufacture and implement customized vaginal applicators that can be sterilized and are made of biocompatible material, resulting in high-quality brachytherapy for patients whose anatomy is not ideally suited for standard, commercially available applicators

Phase I study of dose escalation to dominant intraprostatic lesions using high-dose-rate brachytherapy.

PurposeRadiation dose escalation for prostate cancer improves biochemical control but is limited by toxicity. Magnetic resonance spectroscopic imaging (MRSI) can define dominant intraprostatic lesions (DIL). This phase I study evaluated dose escalation to MRSI-defined DIL using high-dose-rate (HDR) brachytherapy.Material and methodsEnrollment was closed early due to low accrual. Ten patients with prostate cancer (T2a-3b, Gleason 6-9, PSA < 20) underwent pre-treatment MRSI, and eight patients had one to three DIL identified. The eight enrolled patients received external beam radiation therapy to 45 Gy and HDR brachytherapy boost to the prostate of 19 Gy in 2 fractions. MRSI images were registered to planning CT images and DIL dose-escalated up to 150% of prescription dose while maintaining normal tissue constraints. The primary endpoint was genitourinary (GU) toxicity.ResultsThe median total DIL volume was 1.31 ml (range, 0.67-6.33 ml). Median DIL boost was 130% of prescription dose (range, 110-150%). Median urethra V120 was 0.15 ml (range, 0-0.4 ml) and median rectum V75 was 0.74 ml (range, 0.1-1.0 ml). Three patients had acute grade 2 GU toxicity, and two patients had late grade 2 GU toxicity. No patients had grade 2 or higher gastrointestinal toxicity, and no grade 3 or higher toxicities were noted. There were no biochemical failures with median follow-up of 4.9 years (range, 2-8.5 years).ConclusionsDose escalation to MRSI-defined DIL is feasible. Toxicity was low but incompletely assessed due to limited patients' enrollment

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.

Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium

Evaluation Of Phenyl-propanedione On Yellowing And Chemical-mechanical Properties Of Experimental Dental Resin-based Materials

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)To evaluate the influence of phenyl-propanedione on yellowing and chemical-mechanical properties of experimental resin-based materials photoactivated using different light curing units (LCUs). Material and Methods: Experimental resin-based materials with the same organic matrix (60:40 wt% BisGMA:TEGDMA) were mechanically blended using a centrifugal mixing device. To this blend, different photoinitiator systems were added in equimolar concentrations with aliphatic amine doubled by wt%: 0.4 wt% CQ; 0.38 wt% PPD; or 0.2 wt% CQ and 0.19 wt% PPD. The degree of conversion (DC), flexural strength (FS), Youngs modulus (YM), Knoop hardness (KNH), crosslinking density (CLD), and yellowing (Y) were evaluated (n=10). All samples were light cured with the following LCUs: a halogen lamp (XL 2500), a monowave LED (Radii), or a polywave LED (Valo) with 16 J/cm2. The results were analysed by two-way ANOVA and Tukeys test (alpha=0.05). Results: No statistical differences were found between the different photoinitiator systems to KNH, CLS, FS, and YM properties (p >= 0.05). PPD/CQ association showed the higher DC values compared with CQ and PPD isolated systems when photoactivated by a polywave LED (p <= 0.05). Y values were highest for the CQ compared with the PPD systems (p?0.05). Conclusion: PPD isolated system promoted similar chemical and mechanical properties and less yellowing compared with the CQ isolated system, regardless of the LCU used.246555560FAPESP - Sao Paulo Research Foundation [2013/04241-2]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

How do proteins search for their specific sites on coiled or globular DNA

It is known since the early days of molecular biology that proteins locate their specific targets on DNA up to two orders of magnitude faster than the Smoluchowski 3D diffusion rate. It was the idea due to Delbruck that they are non-specifically adsorbed on DNA, and sliding along DNA provides for the faster 1D search. Surprisingly, the role of DNA conformation was never considered in this context. In this article, we explicitly address the relative role of 3D diffusion and 1D sliding along coiled or globular DNA and the possibility of correlated re-adsorbtion of desorbed proteins. We have identified a wealth of new different scaling regimes. We also found the maximal possible acceleration of the reaction due to sliding, we found that the maximum on the rate-versus-ionic strength curve is asymmetric, and that sliding can lead not only to acceleration, but in some regimes to dramatic deceleration of the reaction.Comment: 16 pages, 5 figure

Successful Treatment and Management of Canine Ehrlichiosis-Leishmaniosis-Heartworm Comorbidity

 Background: Canine vector borne diseases (CVBD) are common in tropical countries where the climate favors arthropods abundance. Comorbidity with one or more CVBD are reported as clinical complication and worsen prognostic. Canine visceral leishmaniosis (CanL) is an endemic zoonotic disease in Brazil caused by Leishmania infantum, with several restrictions to canine treatment and suggestion of reservoirs euthanasia for disease control. Heart worm (HW) is a helminthic disease caused by Dirofilaria immitis infection in dogs. It is a chronic heart disease, which can lead to death by congestive heart failure. Canine ehrlichiosis (CE) is caused by Ehrlichia canis bacterial infection with a zoonotic potential and fatal to dogs in acute and chronic presentations. Exposed the above, this study aims to describe a successful treatment and management of a dog with CanL, CE, and HW comorbidity. Case: A 3-year-old male uncastrated black Labrador dog, weighing 35 kg, was admitted to the veterinary clinic due to immunochromatographic CanL positive test performed by municipal zoonosis control center active surveillance in August 2014. Clinical exam showed a mild shedding, intermittent eye white/yellow discharge and popliteal lymph nodes enlargement. After positive for CanL, veterinary requested more laboratorial exams. IFAT and ELISA were positive for CanL, blood smear showed presence of microfilaria, and bone marrow cytology showed Ehrlichia spp. morulae and microfilaria. Initial treatment prescribed was oral doxycycline, omeprazole, ranitidine, and domperidone for 30 days, and allopurinol and ivermectin until further recommendation. Additionally, repellent collar, repellent spray and vitamin supplement was indicated. After first month, marbofloxacin for 30 days and three doses of immune stimulant protocol were administrated. After three months of treatment, dog still positive for heartworm, ehrlichiosis, and CanL. Doxycycline protocol was repeated. Dog became consistently negative for all pathogens one year later with persistent thrombocytopenia but without clinical signs, ergo allopurinol and ivermectin were discontinued. After four years of follow up, the animal had an acute pancreatitis and died, with unremarkable total blood count and negative for all pathogens. Discussion: CVBD coinfections are commonly reported as worsen prognostic in endemic regions. The pathogens reported here share a host immunomodulation competence. L. infantum and Ehrlichia spp.downregulates Th1 response, whereas D. immitis increase as Th2 profile. The therapeutic protocol was iniciated by staging CanL. Since the patient had clinical signs, allopurinol was prescribed as a well-established drug for CanL. Marbofloxacin was added due to its high safety drug in clinical improvement of infected dogs with and without renal disease and in vitro effectiveness against L. infantum. Domperidone was used to promote Th1 cytokine profile as INF-γ, IL-2, IL-12, and TNF-α. We used an immunostimulant protocol to favor polarization to the Th1 profile comprised by 30 days of domperidone protocol followed by a vaccine and an immunomodulator. Doxycycline was used successfully for Ehrlichia spp. and HE clearance after two treatment courses and one year of ivermectin every 15 days. The animal presented intermittent coughing episodes on the first treatment course, but no medical intervention was needed besides exercise restriction. Our report shows the successful management of one dog with CanL, CE and HE comorbidity. This success was possible due to early detection and good therapeutic choice.Keywords: canine visceral leishmaniosis, coinfection, Dirofilaria immitis, Erhlichia canis, Leishmania infantum, treatment