Precision assessment of bowel motion quantification using 3D cine-MRI for radiotherapy.

Objective. The bowel is an important organ at risk for toxicity during pelvic and abdominal radiotherapy. Identifying regions of high and low bowel motion with MRI during radiotherapy may help to understand the development of bowel toxicity, but the acquisition time of MRI is rather long. The aim of this study is to retrospectively evaluate the precision of bowel motion quantification and to estimate the minimum MRI acquisition time.Approach. We included 22 gynaecologic cancer patients receiving definitive radiotherapy with curative intent. The 10 min pre-treatment 3D cine-MRI scan consisted of 160 dynamics with an acquisition time of 3.7 s per volume. Deformable registration of consecutive images generated 159 deformation vector fields (DVFs). We defined two motion metrics, the 50th percentile vector lengths (VL50) of the complete set of DVFs was used to measure median bowel motion. The 95th percentile vector lengths (VL95) was used to quantify high motion of the bowel. The precision of these metrics was assessed by calculating their variation (interquartile range) in three different time frames, defined as subsets of 40, 80, and 120 consecutive images, corresponding to acquisition times of 2.5, 5.0, and 7.5 min, respectively.Main results. For the full 10 min scan, the minimum motion per frame of 50% of the bowel volume (M50%) ranged from 0.6-3.5 mm for the VL50 motion metric and 2.3-9.0 mm for the VL95 motion metric, across all patients. At 7.5 min scan time, the variation in M50% was less than 0.5 mm in 100% (VL50) and 95% (VL95) of the subsets. A scan time of 5.0 and 2.5 min achieved a variation within 0.5 mm in 95.2%/81% and 85.7%/57.1% of the subsets, respectively.Significance. Our 3D cine-MRI technique quantifies bowel loop motion with 95%-100% confidence with a precision of 0.5 mm variation or less, using a 7.5 min scan time.

Clinical and imaging findings in cervical cancer and their impact on FIGO and TNM staging - An analysis from the EMBRACE study.

OBJECTIVE: To investigate differences in local tumour staging between clinical examination and MRI and differences between FIGO 2009, FIGO 2018 and TNM in patients with primary cervical cancer undergoing definitive radio-chemotherapy. METHODS: Patients from the prospective observational multi-centre study "EMBRACE" were considered for analysis. All patients had gynaecological examination and pelvic MRI before treatment. Nodal status was assessed by MRI, CT, PET-CT or lymphadenectomy. For this analysis, patients were restaged according to the FIGO 2009, FIGO 2018 and TNM staging system. The local tumour stage was evaluated for MRI and clinical examination separately. Descriptive statistics were used to compare local tumour stages and different staging systems. RESULTS: Data was available from 1338 patients. For local tumour staging, differences between MRI and clinical examination were found in 364 patients (27.2%). Affected lymph nodes were detected in 52%. The two most frequent stages with FIGO 2009 are IIB (54%) and IIIB (16%), with FIGO 2018 IIIC1 (43%) and IIB (27%) and with TNM T2b N0 M0 (27%) and T2b N1 M0 (23%) in this cohort. CONCLUSIONS: MRI and clinical examination resulted in a different local tumour staging in approximately one quarter of patients. Comprehensive knowledge of the differential value of clinical examination and MRI is necessary to define one final local stage, especially when a decision about treatment options is to be taken. The use of FIGO 2009, FIGO 2018 and TNM staging system leads to differences in stage distributions complicating comparability of treatment results. TNM provides the most differentiated stage allocation.

Automatic bi-objective parameter tuning for inverse planning of high-dose-rate prostate brachytherapy.

We present an automatic bi-objective parameter-tuning approach for inverse planning methods for high-dose-rate prostate brachytherapy, which aims to overcome the difficult and time-consuming manual parameter tuning that is currently required to obtain patient-specific high-quality treatment plans. We modelled treatment planning as a bi-objective optimization problem, in which dose-volume-based planning criteria related to target coverage are explicitly separated from organ-sparing criteria. When this model is optimized, a large set of high-quality plans with different trade-offs can be obtained. This set can be visualized as an insightful patient-specific trade-off curve. In our parameter-tuning approach, the parameters of inverse planning methods are automatically tuned, aimed to maximize the two objectives of the bi-objective planning model. By generating trade-off curves for different inverse planning methods, their maximally achievable plan quality can be insightfully compared. Automatic parameter tuning furthermore allows to construct standard parameter sets (class solutions) representing different trade-offs in a principled way, which can be directly used in current clinical practice. In this work, we considered the inverse planning methods IPSA and HIPO. Thirty-nine previously treated prostate cancer patients were included. We compared automatic parameter tuning, random parameter sampling, and the maximally achievable plan quality obtained by directly optimizing the bi-objective planning model with the state-of-the-art optimization software GOMEA. We showed that for each patient, a set of plans with a wide range of trade-offs could be obtained using automatic parameter tuning for both IPSA and HIPO. By tuning HIPO, better trade-offs were obtained than by tuning IPSA. For most patients, automatic tuning of HIPO resulted in plans close to the maximally achievable plan quality obtained by optimizing the bi-objective planning model directly. Automatic parameter tuning was shown to improve plan quality significantly compared to random parameter sampling. Finally, from the automatically-tuned plans, three class solutions were successfully constructed representing different trade-offs.

Socioeconomic status as an independent risk factor for severe late bowel toxicity after primary radiotherapy for cervical cancer.

OBJECTIVE: To evaluate the frequency of and risk factors for severe late bowel toxicity after curative radiotherapy in women treated for locally advanced cervical cancer. METHODS: Included were 515 women treated for locally advanced cervical cancer with primary radiotherapy with curative intent from 1992 to 2013. Bowel toxicity was graded according to the Common Terminology Criteria for Adverse Events. Associations between risk factors and severe late bowel toxicity were assessed using Cox proportional hazards regression models. RESULTS: Median follow-up was 78months. Fifty-nine patients developed severe late bowel toxicity. The actuarial 3-year and 5-year severe late bowel toxicity rates were both 13%. In the multivariable analysis, factors significantly associated with severe late bowel toxicity were: smoking (HR 2.59 [1.48-4.55]), severe acute bowel toxicity (HR 2.46 [1.24-4.49]), previous major abdominal surgery (HR 2.35 [1.20-4.60]), hypertension (HR 2.33 [1.23-4.40]), parametrial boost (HR 2.18 [1.10-4.33]), low socioeconomic status (HR 2.05 [1.17-3.59]) and low BMI (HR 0.93 [0.88-0.99]). First symptoms of severe late bowel toxicity were reported after a median follow-up of 9months, but occurred up to 10years after end of treatment. Only one third of the patients with severe late bowel toxicity were referred to a gastroenterologist. CONCLUSIONS: Severe late bowel toxicity is a frequent complication of definitive radiotherapy for cervical cancer. Several independent risk factors were found which warrant further research. A standardized and structured approach in the early diagnostics and management of bowel toxicity is needed.

Improving postoperative radiotherapy following radical prostatectomy.

INTRODUCTION: Prostate cancer has one of the highest incidences in the world, with good curative treatment options like radiotherapy and radical prostatectomy. Unfortunately, about 30% of the patients initially treated with curative intent will develop a recurrence and need adjuvant treatment. Five randomized trials covered the role of postoperative radiotherapy after radical prostatectomy, but there is still a lot of debate about which patients should receive postoperative radiotherapy. Areas covered: This review will give an overview on the available literature concerning post-operative radiotherapy following radical prostatectomy with an emphasis on the five randomized trials. Also, new imaging techniques like prostate-specific membrane antigen positron emission tomography (PSMA-PET) and multiparametric magnetic resonance imaging (mp-MRI) and the development of biomarkers like genomic classifiers will be discussed in the search for an improved selection of patients who will benefit from postoperative radiotherapy following radical prostatectomy. With new treatment techniques like Intensity Modulated Radiotherapy, toxicity profiles will be kept low. Expert commentary: Patients with biochemical recurrence following radical prostatectomy with an early rise in prostate-specific antigen (PSA) will benefit most from postoperative radiotherapy. In this way, patients with only high risk pathological features can avoid unnecessary treatment and toxicity, and early intervention in progressing patients would not compromise the outcome.

Postoperative single-dose interstitial high-dose-rate brachytherapy in therapy-resistant keloids.

PURPOSE: Patients with keloids complain of the cosmetic aspect, pain, and pruritus. Many different therapies are being used for keloids. The aim of this study was to evaluate the recurrence rate and outcome after resection followed by a single-dose brachytherapy. METHODS AND MATERIALS: Patients treated by resection of the keloid plus a single dose of 13 Gy high-dose-rate brachytherapy were evaluated at least 1 year after treatment. Clinical response and cosmesis were assessed by a plastic surgeon and by the patients using the Patient and Observer Scar Assessment Scale. RESULTS: Only 24 of the 61 invited patients responded to participate with the study; 29 keloids were evaluated. The recurrence rate was 24.1% after a median followup of 53 months (19-95 months). Patients scored on average 24.3 for their total Patient and Observer Scar Assessment Scale score (range 6-52), whereas the observer scored on average 14.6 (range 6-42). CONCLUSIONS: This treatment has a higher recurrence rate than that reported in most other studies. This may be explained by differences in recurrence definition, differences in followup time among studies, and selection bias because of not contributing to the study. The cosmetic outcome for evaluated patients is relatively good. This treatment policy has the advantage that patients are treated in a single day.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

Quantification of image distortions on the Utrecht interstitial CT/MR brachytherapy applicator at 3T MRI.

PURPOSE: To quantify distortions on MR images of the Utrecht interstitial CT/MR applicator at a field strength of 3T using an MRI-only method. MATERIALS AND METHODS: An MR-compatible phantom suspending the applicator in water was built and imaged on a Philips Ingenia 3T MRI scanner. A map of the magnetic field (B0) was calculated from multiecho images and used to quantify the field inhomogeneity. The expected displacements of the applicator could be quantified using the measured field inhomogeneity and sequence bandwidth. Additionally, two scans were acquired using opposing readout gradients. These scans were rigidly matched and their displacement was compared with the expected displacements from the B0 map. These same methods were applied in 4 patients. By rigid matching of the scans acquired with opposing readout direction the applicator displacement due to image distortion from B0 inhomogeneity as well as patient movement and organ deformation was determined. RESULTS: According to the B0 map, the displacement on the intrauterine device of the plastic brachytherapy applicator was <0.4 mm for both the phantom and patients. Displacements obtained by the opposing readout method were ≤0.8 mm for each patient with a mean ± SD over the patients of 0.3 ± 0.1 mm. CONCLUSION: The results of our study indicate that the B0 method agrees with the opposing readout method. Displacements caused by magnetic field inhomogeneity on 3T MRI were small compared with displacements due to patient movement and organ deformation.

Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma.

PURPOSE: Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. METHODS: Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. RESULTS: Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90). CONCLUSIONS: Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population.

Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study.

OBJECTIVES: To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. DESIGN: Cross-sectional long-term follow-up study. SETTING: Tertiary comprehensive cancer centre. PARTICIPANTS: Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). MAIN OUTCOME MEASURES: We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. METHODS: We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). RESULTS: Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. CONCLUSIONS: One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

Variability in target volume delineation on CT scans of the breast.

PURPOSE: To determine the intra- and interobserver variation in delineation of the target volume of breast tumors on computed tomography (CT) scans in order to perform conformal radiotherapy. MATERIALS AND METHODS: The clinical target volume (CTV) of the breast was delineated in CT slices by four radiation oncologists on our clinically used delineation system. The palpable glandular breast tissue was marked with a lead wire on 6 patients before CT scanning, whereas 4 patients were scanned without a lead wire. The CTV was drawn by each observer on three separate occasions. Planning target volumes (PTVs) were constructed by expanding the CTV by 7 mm in each direction, except toward the skin. The deviation in the PTV extent from the average extent was quantified in each orthogonal direction for each patient to find a possible directional dependence in the observer variations. In addition, the standard deviation of the intra- and interobserver variation in the PTV volume was quantified. For each patient, the common volumes delineated by all observers and the smallest volume encompassing all PTVs were also calculated. RESULTS: The patient-averaged deviations in PTV extent were larger in the posterior (42 mm), cranial (28 mm), and medial (24 mm) directions than in the anterior (6 mm), caudal (15 mm), and lateral (8 mm) directions. The mean intraobserver variation in volume percentage (5.5%, 1 SD) was much smaller than the interobserver variation (17.5%, 1 SD). The average ratio between the common and encompassing volume for the four observers separately was 0.82, 0.74, 0.82, and 0.80. A much lower combined average ratio of 0.43 was found because of the large interobserver variations. For the observer who placed the lead wire, the intraobserver variation in volume was decreased by a factor of 4 on scans made with a lead wire in comparison to scans made without a lead wire. For the other observers, no improvement was seen. Based on these results, an improved delineation protocol was designed. CONCLUSIONS: Intra- and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large. A detailed delineation protocol making use of CT scans with lead wires placed on the skin around the palpable breast by the delineating observer reduces the intraobserver variation. To reduce the interobserver variation, better imaging techniques and pathology studies relating glandular breast tissue to imaging may be needed to provide more information on the extent of the clinical target volume.

A method to improve the dose distribution of interstitial breast implants using geometrically optimized stepping source techniques and dose normalization.

BACKGROUND AND PURPOSE: The standard linear source breast implant of our institution was compared with alternative linear source implant geometries and a stepping source implant, to evaluate the possibility of minimizing the treated volume. Normalization to a higher isodose than the conventional 85% of the mean central dose (MCD) was investigated for the stepping source implant to reduce the thickness of the treated volume and to increase dose uniformity. The purpose of this study was to develop an implant geometry yielding a high conformity and a more uniform dose distribution over the target volume. MATERIALS AND METHODS: The dose distributions of four implant geometries were compared for a planning target volume (PTV) of 48 cm(3). Implants #1 (standard) and #2 had linear sources arranged in a triangular pattern of equal lengths and lengths adapted to the shape of the PTV. Implants #3 and #4 were squared pattern arranged implants with linear sources and a stepping source with geometric optimized dwell times. The active lengths were adapted to the shape of the PTV. Using implant #4 for PTVs of different volumes, the reference dose (RD) was normalized to 85 and 91% of the MCD. RESULTS: Comparing implants #2, #3, and #4 with #1, the treated volume (V(100)) encompassed by the reference isodose was reduced by 22, 35, and 37%, respectively. The volumes receiving a dose of at least 125% (V(125)) of the reference dose was reduced by 16, 30, and 30%, respectively. The conformation number increased being 0.30, 0.39, 0.47, and 0.48 for implants #1, #2, #3, and #4, respectively. The average reduction of V(125) when the dose was normalized to 91% compared with 85% of the MCD was 18%. CONCLUSIONS: A conformal treatment to a PTV could be best achieved with a geometrically optimized stepping source plan with needles arranged in a squared pattern. Reduction of high dose volumes within the implant was obtained by normalizing the RD to 91% instead of 85% of the MCD.

An improved technique for breast cancer irradiation including the locoregional lymph nodes.

PURPOSE: To find an irradiation technique for locoregional irradiation of breast cancer patients which, compared with a standard technique, improves the dose distribution to the internal mammary-medial supraclavicular (IM-MS) lymph nodes. The improved technique is intended to minimize the lung dose and reduce the dose to the heart. METHODS AND MATERIALS: The standard technique consists of an anterior mixed electron/photon IM-MS field. In the improved technique, an oblique electron and an oblique asymmetric photon field are combined to irradiate the IM lymph nodes. To irradiate the MS lymph nodes, a combination of an anterior electron and an anterior asymmetric photon field is used. For both the standard and the improved technique, tangential photon fields are used to irradiate the breast. Three-dimensional (3D) treatment planning was performed for 8 patients with various breast sizes for these two techniques. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) were compared for both techniques. The field dimensions and energy of the standard technique were determined at simulation, whereas for the improved technique the fields were designed by CT-based treatment planning. RESULTS: The dose in the breast planning target volume was essentially the same for both techniques. For the improved technique, combined with 3D localization information, an improvement in the IM-MS planning target coverage is seen. The volume within the 95% isodose surface was on average 25% (range, 0-64%) and 74% (range, 43-90%) for the standard and improved technique, respectively. The heart generally receives less dose with the improved technique. However, sometimes a small but acceptable increase in lung dose is found. CONCLUSION: The improved technique, combined with localization information of the IM-MS lymph nodes, greatly improves the dose distribution in the planning target volume for a large group of patients without significantly increasing the dose to organs at risk.

Cardiac and lung complication probabilities after breast cancer irradiation.

PURPOSE: To assess for locoregional irradiation of breast cancer patients, the dependence of cardiac (cardiac mortality) and lung (radiation pneumonitis) complications on treatment technique and individual patient anatomy. MATERIALS AND METHODS: Three-dimensional treatment planning was performed for 30 patients with left-sided breast cancer and various breast sizes. Two locoregional techniques (Techniques A and B) and a tangential field technique, including only the breast in the target volume, were planned and evaluated for each patient. In both locoregional techniques tangential photon fields were used to irradiate the breast. The internal mammary (IM)-medial supraclavicular (MS) lymph nodes were treated with an anterior mixed electron/photon field (Technique A) or with an obliquely incident mixed electron/photon IM field and an anterior electron/photon MS field (Technique B). The optimal IM and MS electron field dimensions and energies were chosen on the basis of the IM-MS lymph node target volume as delineated on CT-slices. The position of the tangential fields was adapted to match the IM-MS fields. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) for the heart and lung were compared for the three techniques. In the beam's eye view of the medial tangential fields the maximum distance of the heart contour to the posterior field border was measured; this value was scored as the Maximum Heart Distance. RESULTS: The lymph node target volume receiving more than 85% of the prescribed dose was on average 99% for both locoregional irradiation techniques. The breast PTV receiving more than 95% of the prescribed dose was generally smaller using Technique A (mean: 90%, range: 69-99%) than using Technique B (mean: 98%, range: 82-100%) or for the tangential field technique (mean: 98%, range: 91-100%). NTCP values for excess cardiac mortality due to acute myocardial ischemia varied considerably between patients, with minimum and maximum values of 0.1 and 7.5% (Technique A), 0.1 and 5.8% (Technique B) and 0.0 and 6.1% (tangential tech.). The NTCP values were on average significantly higher (P<0.001) by 1.7% (Technique A) and 1.0% (Technique B) when locoregional breast irradiation was given, compared with irradiation of the left breast only. The NTCP values for the tangential field technique could be estimated using the Maximum Heart Distance. NTCP values for radiation pneumonitis were very low for all techniques; between 0.0 and 1.0%. CONCLUSIONS: Technique B results in a good coverage of the breast and locoregional lymph nodes, while Technique A sometimes results in an underdosage of part of the target volume. Both techniques result in a higher probability of heart complications compared with tangential irradiation of the breast only. Irradiation toxicity for the lung is low in all techniques. The Maximum Heart Distance is a simple and useful parameter to estimate the NTCP values for cardiac mortality for tangential breast irradiation.

Enzyme immobilization on a low-cost magnetic support: kinetic studies on immobilized and coimmobilized glucose oxidase and glucoamylase.

Glucose oxidase (GOx) and glucoamylase (GA) were immobilized and coimmobilized through their carbohydrate moieties onto polyethyleneimine-coated magnetite crosslinked with glutaraldehyde and derivatized with adipic dihydrazide. The carbohydrates were oxidized with sodium periodate, and at optimal concentration, their Vm increased up to 18% for GOx and up to 16% for GA. After immobilization, a remaining activity as high as 88% and 70% for GA with maltose and maltodextrin respectively as substrates was obtained, independently of the particle loading. On the contrary, the remaining activity of GOx strongly decreased at high particle loading. Nevertheless, half of its initial activity was recovered at low loading and was not significantly affected when GA was coimmobilized by saturating the reactive groups left on the particle. The Vm of both immobilized enzymes was improved by crosslinking their carbohydrates with adipic dihydrazide, a treatment which allows further coimmobilization of the other enzyme on a second layer.

Glucoamylase immobilization on a magnetic microparticle for the continuous hydrolysis of maltodextrin in a fluidized bed reactor.

Glucoamylase (GA) has been successfully immobilized through its carbohydrates previously oxidized with periodate onto a low-cost magnetic microparticle made of polyethyleneimine-coated magnetite crosslinked with glutaraldehyde (M-GAD) and derivatized with adipic dihydrazide (ADH). A stabilization posttreatment consisting of crosslinking its carbohydrates with ADH, increased the remaining activity from 54 to 71%, calculated on the Vm values and measured at 50 degrees C and pH 4.5 with maltodextrin (DE 11-14) as substrate. This treatment also improved the enzyme stability and lowered the deactivation rate constant kd to a third of its value. A 30% maltodextrin solution has been continuously hydrolyzed at 50 degrees C and pH 4.5 in a recycled, fluidized bed reactor (FBR) containing GA immobilized on these magnetic microparticles. They easily settled in this highly viscous medium because of their high density (5 g/mL), and washout of ultrafines was prevented by surrounding the top of the bed with an electromagnet. The small particle size (20 microns) allowed a high enzyme loading in the reactor and also a high bed voidage, which is recommended to avoid extensive pressure drop and consequent channeling problems. The kinetic of hydrolysis fitted with the plug-flow model; this is explained by the insignificant backmixing effects observed. After 2 wk of hydrolysis under process conditions leading to a conversion of 70%, which corresponds to a high-conversion syrup, the immobilized GA only lost 4% of its initial activity.