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The brain has computational capabilities that surpass those of modern systems, being able to solve complex problems efficiently in a simple way. Neuromorphic engineering aims to mimic biology in order to develop new systems capable of incorporating such capabilities. Bio-inspired learning systems continue to be a challenge that must be solved, and much work needs to be done in this regard. Among all brain regions, the hippocampus stands out as an autoassociative short-term memory with the capacity to learn and recall memories from any fragment of them. These characteristics make the hippocampus an ideal candidate for developing bio-inspired learning systems that, in addition, resemble content-addressable memories. Therefore, in this work we propose a bio-inspired spiking content-addressable memory model based on the CA3 region of the hippocampus with the ability to learn, forget and recall memories, both orthogonal and non-orthogonal, from any fragment of them. The model was implemented on the SpiNNaker hardware platform using Spiking Neural Networks. A set of experiments based on functional, stress and applicability tests were performed to demonstrate its correct functioning. This work presents the first hardware implementation of a fully-functional bio-inspired spiking hippocampal content-addressable memory model, paving the way for the development of future more complex neuromorphic systems. [ABSTRACT FROM AUTHOR]

Breast brachytherapy represents a radiation technique that can be utilized as both monotherapy and as a tumor bed boost following breast conserving surgery. As monotherapy, the rationale for brachytherapy is that the majority of residual disease and therefore recurrences occur in close proximity to the lumpectomy cavity; for boost treatment, brachytherapy represents a technique that provided a more conformal approach prior to 3D treatment planning, and more recently can be used in conjunction with oncoplastic surgery. Multiple guidelines are available to assist clinicians with patient selection for accelerated partial breast irradiation (APBI), and recent guidelines support brachytherapy as an appropriate technique to deliver APBI. Modern breast brachytherapy can be performed with interstitial or applicator-based brachytherapy with multilumen and strut devices offering the ability to provide greater skin, chest wall, and normal breast sparing than previous devices. Novel strategies are being evaluated, including high dose rate perioperative/intraoperative radiotherapy, permanent breast seed implants, and noninvasive breast brachytherapy. Additionally, studies are evaluating shorter courses of brachytherapy. Multiple Level I studies are now available supporting interstitial brachytherapy to deliver APBI while prospective data and the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 trial are available with applicator brachytherapy and provide standardized prescriptions, target volume definitions, and dosimetric goals. [ABSTRACT FROM AUTHOR]

• Comparison for the first time of FEM and RC in TEM transient simulation. • RC replicates results of FEM under steady state with deviations lower than 3 % • RC replicates also values, trends and rates of variation under transient conditions. • RC presents negligible computational cost. This paper demonstrates that resistance–capacitance models provide equal results than models based on finite-element software when predicting the performance of a thermoelectric module under transient-state conditions. Previous papers on this topic fall short as comparing finite-element models with simplified versions of resistance–capacitance models. It was confirmed that resistance–capacitance models replicate results of finite-element models in the simulation of a thermoelectric module under steady-state conditions. Deviations lower than 3 % in electric power and efficiency (ratio of electric power to heat input) are obtained for temperature differences between heat source and heat sink as large as 200 K. Similarly, deviations lower than 3 % are obtained for simulation of a thermoelectric module under transient-state conditions. Resistance-capacitance models not only replicate values, trends and rates of variation predicted by finite-element models under step, linear and sinewave variations in the boundary conditions, but they also do this with negligible computational cost. [ABSTRACT FROM AUTHOR]

Summary While mitochondrial dysfunction is emerging as key in Parkinson’s disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA -related PD ( GBA -PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA -PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Thermoelectric self-cooling was firstly conceived to increase, without electricity consumption, the cooling power of passive cooling systems. This paper studies the combination of heat pipe exchangers and thermoelectric self-cooling, and demonstrates its applicability to the cooling of power electronics. Experimental tests indicate that source-to-ambient thermal resistance reduces by around 30% when thermoelectric self-cooling system is installed, compared to that of the heat pipe exchanger under natural convection. Neither additional electric power nor cooling fluids are required. This thermal resistance reaches 0.346 K/W for a heat flux of 24.1 kW/m 2 , being one order of magnitude lower than that obtained in previous designs. In addition, the system adapts to the cooling demand, reducing this thermal resistance for increasing heat. Simulation tests have indicated that simple system modifications allow relevant improvements in the cooling power. Replacement of a thermoelectric module with a thermal bridge leads to 33.54 kW/m 2 of top cooling power. Likewise, thermoelectric modules with shorter legs and higher number of pairs lead to a top cooling power of 44.17 kW/m 2 . These results demonstrate the applicability of thermoelectric self-cooling to power electronics. [ABSTRACT FROM AUTHOR]

Purpose: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy × 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy × 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. Methods and Materials: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of ≤12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. Results: The median follow-up was 17 months (range, 6–40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Conclusions: Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24–27 Gy in two fractions within 1 day have excellent tolerance with minimal acute and chronic toxicity. Longer follow-up is needed to confirm these encouraging early results. [Copyright &y& Elsevier]

Abstract: Purpose: We present 4-year results from a Phase I/II trial using balloon-based brachytherapy to deliver accelerated partial breast irradiation in 2 days. Materials/Methods: Forty-five patients received breast-conserving surgery followed by adjuvant radiation therapy using a balloon-based brachytherapy applicator delivering 2800cGy in four fractions over 2 days. Outcomes analyzed include toxicities scored using the NCI Common Toxicity Criteria v3.0 scale, ipsilateral breast tumor recurrence, regional nodal failure, distant metastasis, disease-free survival, cause-specific survival, and overall survival. Results: Median age was 66 years (range, 48–83 years) and median tumor size was 0.6cm (range, 0.2–2.3cm). Five percent of patients were node positive (n =2), whereas 73% was estrogen receptor positive (n =33). Median followup was 3.7 years (2.4–7.0 years) with greater than 2 years of followup for all patients. Only Grades 1 and 2 chronic toxicities were noted with fat necrosis (18%) and asymptomatic seromas (42%) being the most common toxicities. Seven percent of patients developed ipsilateral rib fractures (n =3), although this was not statistically associated with maximum rib dose (p =0.31). Ninety-eight percent of patients had a good or excellent radiation-related cosmetic outcome at the time of last followup. There were no ipsilateral breast tumor recurrences or regional nodal failures; however, 2 patients developed distant metastases. Four-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. Conclusions: Treatment of early-stage breast cancer patients with breast-conserving therapy using a 2-day radiation dose schedule resulted in acceptable chronic toxicity and similar clinical outcomes as standard 5-day fractionation. [Copyright &y& Elsevier]

Purpose: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients. Methods and Materials: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography–defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis–free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. Conclusions: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer. [Copyright &y& Elsevier]

Purpose: To evaluate the 10-year outcomes of intermediate- and high-risk prostate cancer patients treated with a prospective dose escalation hypofractionated trial of pelvic external beam radiation therapy (P-EBRT) with a high-dose-rate (HDR) brachytherapy boost. Methods and Materials: From 1992 to 2007, 472 patients were treated with a HDR boost at William Beaumont Hospital. They had at least one of the following: a prostate-specific antigen (PSA) level of >10 ng/ml, a Gleason score of ≥7, or clinical stage ≥T2b. Patients received 46-Gy P-EBRT and an HDR boost. The HDR dose fractionation was divided into two dose levels. The prostate biologically equivalent dose (BED) low-dose-level group received <268 Gy, and the high-dose group received >268 Gy . Phoenix biochemical failure (BF) definition was used. Results: Median follow-up was 8.2 years (range, 0.4-17 years). The 10-year biochemical failure rate of 43.1% vs. 18.9%, (p < 0.001), the clinical failure rate of 23.4% vs. 7.7%, (p < 0.001), and the distant metastasis of 12.4% vs. 5.7%, (p = 0.028) were all significantly better for the high-dose level group. On Cox multivariate analysis, higher BED levels (p = 0.017; hazard ratio [HR] = 0.586), pretreatment PSA assays (p < 0.001, HR = 1.022), and Gleason scores (p = 0.004) were significant variables for reduced biochemical failure. Higher dose levels (p, 0.002; HR, 0.397) and Gleason scores (p < 0.001) were significant for clinical failure. Grade 3 genitourinary complications were 2% and 3%, respectively, and grade 3 gastrointestinal complication was <0.5%. Conclusions: This prospective trial using P-EBRT with HDR boost and hypofractionated dose escalation demonstrates a strong dose-response relationship for intermediate- and high-risk prostate cancer patients. The improvement at 10 years for locoregional control with higher radiation doses (BED, > 268Gy) has significantly decreased biochemical and clinical failures as well as distant metastasis. [Copyright &y& Elsevier]

Purpose: Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early-stage breast cancer are presented. Materials and Methods: Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at ≥6 months. Results: The median age was 66 years (range, 48–83) and median skin spacing was 12 mm (range, 8–24). The median follow-up was 11.4 months (5.4–48 months) with 21 patients (47%) followed ≥1 year, 11 (24%) ≥2 years, and 7 (16%) ≥3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At ≥6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at ≥6 months. Persistent seroma ≥6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. Conclusions: Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule. [Copyright &y& Elsevier]

Adaptive radiotherapy has been introduced to manage an individual''s treatment by, including patient-specific treatment variation identified and quantified during the course of radiotherapy in the treatment planning and delivering optimization. Early studies have demonstrated that this technique could significantly improve the therapeutic ratio by safely reducing the large target margin that has to be used in conventional radiotherapy for prostate cancer treatment. Clinical application of off-line image-guided adaptive radiotherapy for prostate cancer has demonstrated encouraging clinical outcome. Long-term clinical follow-up has shown significant improvement in terms of tumor control and low toxicity profile, emphasizing the beneficial effect of image-guidance and adaptive treatment. Continuous development in adaptive radiotherapy has made possible additional increases in target dose by further reducing target margin when using online image-guided adaptive intensity-modulated radiation therapy. However, clinical implementation of new techniques should be explored cautiously and should include a comprehensive management strategy to address uncertainties in target definition and delineation in the preclinical implementation studies. [Copyright &y& Elsevier]

Abstract: Mercury emissions from coal-fired power plants account for 40% of the anthropogenic mercury emissions in the U.S. The speciation of mercury largely determines the amount of mercury capture in control equipments. Conversion of insoluble Hg0 into more soluble Hg2+ facilitates its removal in scrubbers. Past studies suggest that an added supply of OH radicals possibly enhance the mercury oxidation process. This study demonstrates that the application of H2O2, as source of OH radicals, accelerates the oxidation of Hg0 into Hg2+. A detailed kinetic reaction mechanism was compiled and the reaction pathways were established to analyze the effect of H2O2 addition. The optimum temperature range for the oxidation was 480–490 °C. The sensitivity analysis of the reaction mechanism indicates that the supply OH radicals increase the formation of atomic Cl, which accelerates the formation of HgCl2 enhancing the oxidation process. Also, the pathway through HOCl radical, generated by the interactions between chlorine and H2O2 was prominent in the oxidation of Hg0. The flue gas NO was found to be inhibiting the Hg0 oxidation, since it competed for the supplied H2O2. Studying the interactions with the other flue gas components and the surface chemistry with particles in the flue gas could be important and may improve the insight into the post combustion transformation of mercury in a comprehensive way. [Copyright &y& Elsevier]

Objective: To evaluate outcomes of intermediate- and high-risk prostate cancer patients on a prospective dose-escalation study of pelvic external-beam radiation therapy (EBRT) combined with high-dose-rate (HDR) brachytherapy boost. Methods: From November 1991 to April 2003, 197 patients were treated for intermediate- and high-risk disease features. All patients had prostate-specific antigen >10 ng/ml, Gleason score ≥7, or clinical stage ≥T2b, and all received pelvic EBRT (46 Gy) while receiving either two or three HDR boost treatments. HDR dose fractionation increased progressively and was divided into two dose levels. The mean prostate biologic equivalency dose was 88.2 Gy for the low-dose group and 116.8 Gy for the high-dose group (α/β = 1.2). Clinical failure was either local failure or distant metastasis; clinical event-free survival (cEFS) was defined as patients who lived free of clinical failure. Results: Median follow-up was 4.9 years. The 5-year rates were as follows: biologic failure (BF), 18.6%, clinical failure (CF), 9.8%, cEFS 84.8%, cause-specific survival (CSS), 98.3%, and overall survival (OS), 92.9%. Five-year biochemical failure (68.7% vs. 86%, p < 0.001), CF (6.1% vs. 15.6%, p = 0.04), cEFS (75.5% vs. 91.7%, p = 0.003), CSS (95.4% vs. 100%, p = 0.02), and OS (86.2% vs. 97.8%, p = 0.002) were significantly better for the high-dose group. Multivariate analysis showed that high-dose group (p = 0.01, HR 0.35) and Gleason score (p = 0.01, HR 1.84) were significant variables for cEFS. Multivariate analysis showed that high-dose group (p = 0.01, HR 0.14) and age (p = 0.03, HR 1.09 per year) were significant variables for overall survival. Conclusion: There is a strong dose–response relationship for intermediate- to high-risk prostate cancer patients. Improved locoregional control with higher radiation doses alone can significantly decrease biochemical and clinical failures. [Copyright &y& Elsevier]

Purpose: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of ≤6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered. Methods and Materials: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36–50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an α /β of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen ≥10, Gleason score ≥7, or clinical stage ≥T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 × 3 to 15 Gy × 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used. Results: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5–14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G0. Conclusions: Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of ≤6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation. [Copyright &y& Elsevier]

Purpose We analyzed our experience treating localized prostate cancer with image-guided off-line correction with adaptive high-dose radiotherapy (ART) in our Phase II dose escalation study to identify factors predictive of chronic rectal toxicity. Materials and Methods From 1999–2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated in our Phase II 3D conformal dose escalation ART study to a median dose of 75.6 Gy (range, 63.0–79.2 Gy), minimum dose to confidence limited-planning target volume (cl-PTV) in 1.8 Gy fractions (median isocenter dose = 79.7 Gy). Seventy-four patients (22%) also received neoadjuvant/adjuvant androgen deprivation therapy. A patient-specific cl-PTV was constructed using 5 computed tomography scans and 4 sets of electronic portal images by applying an adaptive process to assure target accuracy and minimize PTV margin. For each case, the rectum (rectal solid) was contoured from the sacroiliac joints or rectosigmoid junction (whichever was higher) to the anal verge or ischial tuberosities (whichever was lower), with a median volume of 81.2 cc. The rectal wall was defined using the rectal solid with an individualized 3-mm wall thickness (median volume = 29.8 cc). Rectal wall dose-volume histogram was used to determine the prescribed dose. Toxicity was quantified using the National Cancer Institute Common Toxicity Criteria 2.0. Multiple dose-volume endpoints were evaluated for their association with chronic rectal toxicity. Results Median follow-up was 1.6 years. Thirty-four patients (crude rate = 10.3%) experienced Grade 2 chronic rectal toxicity at a median interval of 1.1 years. Nine patients (crude rate = 2.7%) experienced Grade ≥3 chronic rectal toxicity (1 was Grade 4) at a median interval of 1.2 years. The 3-year rates of Grade ≥2 and Grade ≥3 chronic rectal toxicity were 20% and 4%, respectively. Acute toxicity predicted for chronic: Acute Grade 2–3 rectal toxicity (p &#60; 0.001) including any acute rectal Grade 2–3 tenesmus (p = 0.02) and pain (p = 0.008) were significant predictors of chronic Grade ≥2 rectal toxicity. Any acute rectal toxicity (p = 0.001), any acute tenesmus (p = 0.03), and any acute diarrhea (p &#60; 0.001) were also found to be predictive for chronic toxicity, as continuous variables. Dose-volume histogram predicted for chronic toxicity: Rectal wall absolute and relative V50, V60, V66.6, V70, and V72 and rectal solid relative V60-V72 were significantly associated with chronic Grade ≥2 rectal toxicity both as categorical and continuous variables (t test, linear regression) and when divided into subgroups (chi-square table). The chronic rectal toxicity Grade ≥2 risk was 9%, 18%, and 25% for the rectal wall relative V70 &#60;15%, 25%–40%, and >40% respectively. The volume of rectum or rectal wall radiated to ≥50 Gy was a strong predictor for chronic rectal toxicity. Nonpredictive factors: Rectal solid/wall absolute or relative volumes irradiated to ≤40 Gy, dose level, and use of androgen deprivation were not found predictive. Conclusions In our ART dose escalation study, rectal wall or rectum relative ≥V50 are closely predictive for chronic rectal toxicity. If rectal dose-volume histogram constraints are used to select the dose level, the risk of chronic rectal toxicity will reflect the risk of toxicity of the selected constraint rather than the dose selected as found in our study using an adaptive process. To select the prescribed dose, different dose-volume histogram constraints may be used including the rectal wall V70. Patients experiencing acute rectal toxicity are more likely to experience chronic toxicity. [Copyright &y& Elsevier]

Purpose: Kilovoltage cone-beam CT (CBCT) implemented on board a medical accelerator is available for image-guidance applications in our clinic. The objective of this work was to assess the magnitude and stability of the residual setup error associated with CBCT online-guided prostate cancer patient setup. Residual error pertains to the uncertainty in image registration, the limited mechanical accuracy, and the intrafraction motion during imaging and treatment. Methods and Materials: The residual error for CBCT online-guided correction was first determined in a phantom study. After online correction, the phantom residual error was determined by comparing megavoltage portal images acquired every 90 degrees to the corresponding digitally reconstructed radiographs. In the clinical study, 8 prostate cancer patients were implanted with three radiopaque markers made of high-winding coils. After positioning the patient using the skin marks, a CBCT scan was acquired and the setup error determined by fusing the coils on the CBCT and planning CT scans. The patient setup was then corrected by moving the couch accordingly. A second CBCT scan was acquired immediately after the correction to evaluate the residual target setup error. Intrafraction motion was evaluated by tracking the coils and the bony landmarks on kilovoltage radiographs acquired every 30 s between the two CBCT scans. Corrections based on soft-tissue registration were evaluated offline by aligning the prostate contours defined on both planning CT and CBCT images. Results: For ideal rigid phantoms, CBCT image-guided treatment can usually achieve setup accuracy of 1 mm or better. For the patients, after CBCT correction, the target setup error was reduced in almost all cases and was generally within +/-1.5 mm. The image guidance process took 23-35 min, dictated by the computer speed and network configuration. The contribution of the intrafraction motion to the residual setup error was small, with a standard deviation of +/-0.9 mm. The average difference between the setup corrections obtained with coil and soft-tissue registration was greatest in the superoinferior direction and was equal to -1.1 +/- 2.9 mm. Conclusion: On the basis of the residual setup error measurements, the margin required after online CBCT correction for the patients enrolled in this study would be approximatively 3 mm and is considered to be a lower limit owing to the small intrafraction motion observed. The discrepancy between setup corrections derived from registration using coils or soft tissue can be due in part to the lack of complete three-dimensional information with the coils or to the difficulty in prostate delineation and requires further study. [ABSTRACT FROM AUTHOR]

Interfractional patient variation occurs regularly and considerably during the radiotherapy course. Consequently, a generic but large planning target margin has to be applied when patient treatment plan design based on a single pre-treatment computed tomography scan is used to guide multifraction radiation treatment, which creates a major limiting factor for radiotherapy improvement. Planning target margins can be significantly reduced using multiple (or 4-dimensional) image feedback management in the routine treatment process. The most effective method in multiple-image feedback management of radiotherapy is the adaptive control methodology. The adaptive radiotherapy technique aims to customize each patient’s treatment plan to patient-specific variation by evaluating and characterizing the systematic and random variations through image feedback and including them in adaptive planning. Adaptive radiotherapy will become a new treatment standard, in which a predesigned adaptive treatment strategy, including the schedules of imaging and replanning, will eventually replace the predesigned treatment plan in the routine clinical practice. [Copyright &y& Elsevier]

Purpose: To evaluate the validity of the chosen adaptive radiotherapy (ART) dose–volume constraints while testing the hypothesis that toxicity would not be greater at higher tumor dose levels. Materials and methods: In the ART dose escalation/selection trial, treatment was initiated with a generic planning target volume (PTV) formed as a 1-cm expansion of the clinical target volume (CTV). After the first week of therapy, the patient was replanned with a patient-specific PTV, constructed with CT and electronic portal images obtained in the first 4 days of treatment. A new multileaf collimator beam aperture was used. A minimum dose prescribed to the patient-specific PTV, ranging 70.2–79.2 Gy, was determined on the basis of the following rectal and bladder constraints: <5% of the rectal wall has a dose >82 Gy, <30% of the rectal wall has a dose >75.6 Gy, <50% of the bladder volume has a dose >75.6 Gy, and the maximum bladder dose is 85 Gy. A conformal four-field and/or intensity-modulated radiotherapy (IMRT) technique was used. Independent reviewers scored toxicities. The worst toxicity score seen was used as per the Common Toxicity Criteria grade scale (version 2). We divided the patients into three separate groups: 70.2–72 Gy, >72–75.6 Gy, and >75.6–79.2 Gy. Toxicities in each group were quantified and compared by the Pearson chi-squared test to validate our dose escalation/selection model. Grades 0, 1, 2, and 3 were censored as none vs. each category and none vs. any. Results: We analyzed patients with follow-up greater than 1 year. The mean duration of follow-up was 29 months (range, 12–46 months). We report on 280 patients, mean age 72 years (range, 51–87 years). Only 60 patients received adjuvant hormones. Mean pretreatment prostate-specific antigen level was 9.3 ng/mL (range, 0.6–120 ng/mL). Mean Gleason score was 6 (range, 3–9). The lowest dose level was given to 49 patients, the intermediate dose to 131 patients, and 100 patients received the highest dose escalation. One hundred eighty-one patients (65%) were treated to a prostate field only and 99 patients (35%) to prostate and seminal vesicles. Chronic genitourinary and/or gastrointestinal categories were incontinence, persistent urinary retention, increased urinary frequency/urgency, urethral stricture, hematuria, diarrhea, rectal pain, bleeding, ulcer, fistula, incontinence, and proctitis. Toxicity at the high dose level was not different from toxicity at the intermediate or lower dose levels. No significant difference was observed in any of the individual toxicity categories. Conclusions: By applying the ART process—namely, developing a patient-specific PTV—to prostate cancer patients, significant dose escalation can be achieved without increases in genitourinary or gastrointestinal toxicity. Our data validate the rectal and bladder dose–volume constraints chosen for our three-dimensional conformal and IMRT prostrate radiotherapy planning. [Copyright &y& Elsevier]

: PurposeThe aim of this study is to analyze, during the prostate-specific antigen (PSA) era, the long-term outcome of patients treated with conformal high-dose-rate (HDR) brachytherapy boost to the prostate with or without androgen deprivation therapy (ADT) when patients are stratified by risk factors for failure.: Methods and materialsBetween 1986 and 2000, 611 patients were treated for clinically localized prostate cancer in three prospective trials of external beam radiation therapy (EBRT) and dose-escalating HDR brachytherapy (BT) boost. There were 104 patients treated at Seattle, 198 at Kiel University, and 309 at William Beaumont Hospital. Of the 611 patients, 177 received a short course of neoadjuvant/concurrent ADT. The patients were divided into three risk groups. Group I, comprised of 46 patients, had stage ≤T2a, Gleason score (GS) ≤ 6, and initial PSA (iPSA) ≤ 10 ng/mL. Group II comprised 188 patients with stage ≥T2b, GS ≥ 7, and iPSA ≥ 10, with any one factor higher. Group III included 359 patients with any two risk factors higher. The American Society for Therapeutic Radiology and Oncology definition for biochemical failure was used.: ResultsThe mean follow-up was 5 years (range, 0.2–15.3). For the 611 patients, the 5-year and 10-year biochemical control (BC) rates were 77% and 73%, disease-free survival (DFS) was 67% and 49%, and cause-specific survival (CSS) was 96% and 92%, respectively. BC at 5 years for Group I patients was 96%, for Group II 88%, and for Group III patients 69%. CSS at 5 years was 100% in Group I, 99% in Group II, and 95% in Group III patients. In univariate and multiple regression analyses for BC, risk group, stage, iPSA, and GS were significant in predicting failure. However, age, follow-up interval, and ADT did not.: ConclusionsEBRT with HDR-BT produced excellent long-term outcomes in terms of BC, DFS, and CSS in patients with prostate cancer even for those at highest risk. Conformal HDR-BT is both a precise dose delivery system and an effective treatment for both favorable and unfavorable prostate cancer. The addition of a short course of neoadjuvant/concurrent ADT failed to improve outcome. The results were similar at all three institutions, giving credence to the reproducibility of the brachytherapy treatment. [Copyright &y& Elsevier]

Purpose: To evaluate the long-term results of treatment using adjuvant whole abdominal irradiation (WAPI) with a pelvic/vaginal boost in patients with Stage I–III endometrial carcinoma at high risk of intra-abdominopelvic recurrence, including clear cell (CC) and serous-papillary (SP) histologic features.Methods and Materials: In a prospective nonrandomized trial, 119 patients were treated with adjuvant WAPI between November 1981 and April 2000. All patients were analyzed, including those who did not complete therapy. The mean age at diagnosis was 66 years (range 39–88). Thirty-eight patients (32%) had 1989 FIGO Stage I–II disease and 81 (68%) had Stage III. The pathologic features included the following: 64 (54%) with deep myometrial invasion, 48 (40%) with positive peritoneal cytologic findings, 69 (58%) with high-grade lesions, 21 (18%) with positive pelvic/para-aortic lymph nodes, and 44 (37%) with SP or CC histologic findings.Results: The mean follow-up was 5.8 years (range 0.2–14.7). For the entire group, the 5- and 10-year cause-specific survival (CSS) rate was 75% and 69% and the disease-free survival (DFS) rate was 58% and 48%, respectively. When stratified by histologic features, the 5- and 10-year CSS rate for adenocarcinoma was 76% and 71%, and for serous papillary/CC subtypes, it was 74% and 63%, respectively (p = 0.917). The 5- and 10-year DFS rate for adenocarcinoma was 60% and 50% and was 54% and 37% serous papillary/CC subtypes, respectively (p = 0.498). For surgical Stage I–II, the 5-year CSS rate was 82% for adenocarcinoma and 87% for SP/CC features (p = 0.480). For Stage III, it was 75% and 57%, respectively (p = 0.129). Thirty-seven patients had a relapse, with the first site of failure the abdomen/pelvis in 14 (38%), lung in 8 (22%), extraabdominal lymph nodes in 7 (19%), vagina in 6 (16%), and other in 2 (5%). When stratified by histologic variant, 32% of patients with adenocarcinoma and 30% with the SP/CC subtype developed recurrent disease. Most failures for either histologic group occurred within the abdominopelvic region. However, one-third of the adenocarcinoma recurrences were in the lung. Multivariate regression analysis (age, surgical stage, grade, myometrial invasion, histologic type, lymph node status, and peritoneal cytology) demonstrated age (p = 0.019) and surgical stage (p = 0.036) to be of prognostic significance for CSS; age (p = 0.036) was the only significant prognostic factor for DFS. Grade 1–2 gastrointestinal and hematologic acute toxicities were common. Asymptomatic bibasilar scarring on chest X-ray and mild elevation of liver enzymes were seen in almost 50% of the patients. Even though chronic toxicities were less frequent, 12% developed Grade 3–4 gastrointestinal and 2% Grade 3 renal toxicities.Conclusion: Adjuvant WAPI is very effective treatment with excellent 10-year results for Stage I–III endometrial carcinoma with risk factors for intra-abdominopelvic recurrence, including SP or CC histologic variants, deep myometrial invasion, high grade, nodal involvement, and positive peritoneal cytology. The low long-term complication rate with high CSS rate makes WAPI the treatment of choice for these patients with significant comorbidities. [Copyright &y& Elsevier]

Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed.Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50–11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure.Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%.Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment. [Copyright &y& Elsevier]

• No difference in mean values of results provided by all modelling techniques • Significant differences in the uncertainty, always higher than 8% • The simple model and expressions for thermoelectric properties is recommended • Performance parameters in datasheets lead to high uncertainties • No experimental testing of heat exchangers is needed for low thermal resistance The use of thermoelectric heat pumps for heat, ventilation, and air conditioning in nearly-zero-energy buildings is one of the most promising applications of thermoelectrics. However, simulation works in the literature are predominately based on the simple model, which was proven to exhibit significant deviations from experimental results. Nine modelling techniques have been compared in this work, according to statistical methods based on uncertainty analysis, in terms of predicted coefficient of performance and cooling power. These techniques come from the combination of three simulation models for thermoelectric modules (simple model, improved model, electric analogy) and five methods for implementing the thermoelectric properties. The main conclusion is that there is no statistical difference in the mean values of coefficient of performance and cooling power provided by these modelling techniques under all the scenarios, at 95% level of confidence. However, differences appear in the precision of these results in terms of uncertainty of the confidence intervals. Minimum values of uncertainty are obtained when the thermal resistance ratio approaches 0.1, being ±8% when using temperature-dependent expressions for the thermoelectric properties, ±18% when using Lineykin's method, and ± 25% when using Chen's method. The best combination is that composed of the simple model and temperature-dependent expressions for the thermoelectric properties. Additionally, if low values of resistance ratio are anticipated, empirical expressions from the literature can be used for the thermal resistance of the heat exchangers; for high values, though, experimental tests should be deployed, especially for the heat exchanger on the hot side. [ABSTRACT FROM AUTHOR]

Purpose: To prospectively evaluate the use of a single Arbeitsgemeinschaft für Osteosynthesefragen (AO) 2.0-mm locking reconstruction plate for linear noncomminuted mandibular fractures without the use of a second plate. Patients and Methods: We analyzed the clinical and radiologic data of 45 patients with 74 fractures (21 single fractures, 22 double fractures, and 2 triple fractures). Fracture locations were the symphysis (n = 35, 47.3%), body (n = 15, 20.3%), and angle (n = 24, 32.4%). We recorded the mechanism of injury, time between admission to the hospital and surgery, gender and age, temporary maxillomandibular fixation and its duration, and the surgical approach. Postsurgical complications that were recorded as minor did not require surgical intervention, whereas major complications required further surgical intervention. Results: All patients had satisfactory fracture reduction and a successful treatment outcome without major complications. Ten patients (22.2%) developed minor complications. Conclusion: The present study has demonstrated that treating linear noncomminuted mandibular fractures with a single AO 2.0-mm locking reconstruction plates is associated with no major complications and sound bone healing in all patients. [Copyright &y& Elsevier]

Meniere's disease (MD) is a complex disorder of the inner ear that causes vertigo attacks, fluctuating sensorineural hearing loss (SNHL), tinnitus and aural fullness. MD has been attributed to an accumulation of endolymph in the cochlear duct. The diagnosis of MD is based on the phenomenological association of clinical symptoms and the demonstration of SNHL during the vertigo attacks. Several evidences support a genetic contribution to MD including differences in the prevalence according to the ethnic background and familial aggregation in European and Asian populations in multiplex families with autosomal dominant inheritance. The genetic underpinnings of MD may include some rare monogenic forms in isolated families and a polygenic contribution in most familial and sporadic cases. So, familial MD has been reported in 6–8% of sporadic cases and several genes have been described in single Familial MD including FAM136A, DTNA, PRKCB, SEMA3D and DPT , suggesting genetic heterogeneity. Multiplex rare missense variants in OTOG gene have been reported in 33% of familial MD, suggesting multiallelic inheritance. Moreover, the genetic landscape of sporadic MD is more complex and it involves multiplex rare variants in several SNHL genes such as GJB2, USH1G, SLC26A4, ESRRB, and CLDN14 and axonal-guidance signalling genes such as NTN4 and NOX3. This review summarizes evidence to support a genetic contribution in MD and the start of deciphering the genetic architecture to design and develop a molecular map of MD. • Meniere disease (MD) is a complex genetic disorder which involves multiplex rare and common variants in several genes. • Epidemiological and molecular evidence support a genetic contribution to MD. • Clinical and genetic heterogeneity suggest the existence of different endophenotypes and multiplex mechanisms leading to MD. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia and fetal growth restriction share some pathophysiologic features and are both associated with placental insufficiency. Fetal cardiac remodeling has been described extensively in fetal growth restriction, whereas little is known about preeclampsia with a normally grown fetus.Objective: To describe fetal cardiac structure and function in pregnancies complicated by preeclampsia and/or fetal growth restriction as compared with uncomplicated pregnancies.Study Design: This was a prospective, observational study including pregnancies complicated by normotensive fetal growth restriction (n=36), preeclampsia with a normally grown fetus (n=35), preeclampsia with fetal growth restriction (preeclampsia with a normally grown fetus-fetal growth restriction, n=42), and 111 uncomplicated pregnancies matched by gestational age at ultrasound. Fetal echocardiography was performed at diagnosis for cases and recruitment for uncomplicated pregnancies. Cord blood concentrations of B-type natriuretic peptide and troponin I were measured at delivery. Univariate and multiple regression analysis were conducted.Results: Pregnancies complicated by preeclampsia and/or fetal growth restriction showed similar patterns of fetal cardiac remodeling with larger hearts (cardiothoracic ratio, median [interquartile range]: uncomplicated pregnancies 0.27 [0.23-0.29], fetal growth restriction 0.31 [0.26-0.34], preeclampsia with a normally grown fetus 0.31 [0.29-0.33), and preeclampsia with fetal growth restriction 0.28 [0.26-0.33]; P<.001) and more spherical right ventricles (right ventricular sphericity index: uncomplicated pregnancies 1.42 [1.25-1.72], fetal growth restriction 1.29 [1.22-1.72], preeclampsia with a normally grown fetus 1.30 [1.33-1.51], and preeclampsia with fetal growth restriction 1.35 [1.27-1.46]; P=.04) and hypertrophic ventricles (relative wall thickness: uncomplicated pregnancies 0.55 [0.48-0.61], fetal growth restriction 0.67 [0.58-0.8], preeclampsia with a normally grown fetus 0.68 [0.61-0.76], and preeclampsia with fetal growth restriction 0.66 [0.58-0.77]; P<.001). Signs of myocardial dysfunction also were observed, with increased myocardial performance index (uncomplicated pregnancies 0.78 z scores [0.32-1.41], fetal growth restriction 1.48 [0.97-2.08], preeclampsia with a normally grown fetus 1.15 [0.75-2.17], and preeclampsia with fetal growth restriction 0.45 [0.54-1.94]; P<.001) and greater cord blood B-type natriuretic peptide (uncomplicated pregnancies 14.2 [8.4-30.9] pg/mL, fetal growth restriction 20.8 [13.1-33.5] pg/mL, preeclampsia with a normally grown fetus 31.8 [16.4-45.8] pg/mL and preeclampsia with fetal growth restriction 37.9 [15.7-105.4] pg/mL; P<.001) and troponin I as compared with uncomplicated pregnancies.Conclusion: Fetuses of preeclamptic mothers, independently of their growth patterns, presented cardiovascular remodeling and dysfunction in a similar fashion to what has been previously described for fetal growth restriction. Future research is warranted to better elucidate the mechanism(s) underlying fetal cardiac adaptation in these conditions. [ABSTRACT FROM AUTHOR]