Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice.

PURPOSE: Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses. EXPERIMENTAL DESIGN: Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT. RESULTS: The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens. CONCLUSIONS: The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT.See related commentary by Huang and Mendonca, p. 662.

New Cardiac Abnormalities After Radiotherapy in Breast Cancer Patients Treated With Trastuzumab.

PURPOSE: To evaluate cardiac imaging abnormalities after modern radiotherapy and trastuzumab in breast cancer patients. PATIENTS AND METHODS: All patients treated with trastuzumab and radiotherapy for breast cancer between 2006 and 2014 with available cardiac imaging (echocardiogram or multigated acquisition scan) were retrospectively analyzed. Cardiac abnormalities included myocardial abnormalities (atrial or ventricular dilation, hypertrophy, hypokinesis, and impaired relaxation), decreased ejection fraction > 10%, and valvular abnormalities (thickening or stenosis of the valve leaflets). Breast laterality (left vs. right) and heart radiation dose volume parameters were analyzed for association with cardiac imaging abnormalities. RESULTS: A total of 110 patients with 57 left- and 53 right-sided breast cancers were evaluated. Overall, 37 patients (33.6%) developed a new cardiac abnormality. Left-sided radiotherapy was associated with an increase in new cardiac abnormalities (relative risk [RR] = 2.51; 95% confidence interval [CI], 1.34-4.67; P = .002). Both myocardial and valvular abnormalities were associated with left-sided radiotherapy (myocardial: RR = 2.21; 95% CI, 1.06-4.60; P = .029; valvular: RR = 3.30; 95% CI, 0.98-10.9; P = .044). There was no significant difference in decreased ejection fraction between left- and right-sided radiotherapy (9.6% vs. 2.1%; P = .207). A mean heart dose > 2 Gy as well as volume of the heart receiving 20 Gy (V20), V30, and V40 correlated with cardiac abnormalities (mean heart dose > 2 Gy: RR = 2.00; P = .040). CONCLUSION: New cardiac abnormalities, including myocardial and valvular dysfunction, are common after trastuzumab and radiotherapy. The incidence of new abnormalities correlates with tumor laterality and cardiac radiation dose exposure. Long-term follow-up is needed to understand the clinical significance of these early imaging abnormalities.

Assessment of dose to functional sub-structures in the lower urinary tract in locally advanced cervical cancer radiotherapy.

PURPOSE: To provide an analysis of dose distribution in sub-structures that could be responsible for urinary toxicity after Image-Guided Adaptive BrachyTherapy (IGABT) in Locally Advanced Cervical Cancer (LACC). METHODS: 105 LACC patients treated with radiochemotherapy and IGABT were selected. Sub-structures (bladder wall, trigone, bladder neck, urethra) were contoured on IGABT-planning MRIs. D2cm3 and D0.1cm3, ICRU Bladder-Point (ICRU BP) and Posterior-Inferior Border of Symphysis points (PIBS, PIBS + 2 cm, PIBS - 2 cm) doses were extracted. Internal-Urethral-Ostium (IUO) and PIBS-Urethra (PIBS-U) points were defined as urethral dose surrogates. Finally, the Vaginal Reference Length (VRL) was extracted. Values were converted into total EBRT + BT equivalent dose in 2 Gy fractions using α/ß = 3 and T1/2 = 1.5 h. RESULTS: Median D2cm3 for bladder and trigone were 71.7[interquartile-range:66.5;74.1]Gy and 57.8[53.3;63.6]Gy, respectively, while median D0.1cm3 were 82.2[77.6;89.1]Gy and 70.7[62.0;76.7]Gy, respectively. Median ICRU BP dose was 63.7[56.5;70.5]Gy and correlated with trigone D2cm3 and D0.1cm3, while bladder and trigone D2cm3 had poor correlation (R2 = 0.492), as well as D0.1cm3 (R2 = 0.356). Bladder neck D0.1cm3 was always lower than trigone D0.1cm3 and higher than IUO. Correlation between PIBS + 2 cm and IUO was poor (R2 = 0.273), while PIBS and PIBS-U were almost equal (R2 = 0.990). VRL correlated with dose to bladder base. CONCLUSIONS: The study confirmed that ICRU BP and trigone doses correlate. Bladder D2cm3 is not representative of trigone dose because hotspots are often placed in the bladder dome. VRL is a good indicator for bladder base sparing. In addition to D2cm3 and D0.1cm3 for whole bladder, ICRU BP, trigone D2cm3 and D0.1cm3, IUO and PIBS are useful for lower urinary tract reporting.

Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 2: Advanced delineation guidelines for FSUs.

BACKGROUND AND PURPOSE: In a separate article (PART 1), a rationale and explanation of the physiology-and-anatomy-based concept of Functional Swallowing Units (FSUs) was presented. FSUs are swallowing muscles not included in the set of commonly defined swallowing organs at risk (SWOARs). They are involved in three crucial swallowing components: hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion. This paper is a continuation of PART 1 and it provides detailed computed tomography (CT)-based delineation guidelines for FSUs, which presumably are also at risk of radiation-induced dysphagia. MATERIAL AND METHODS: Following analysis of swallowing physiology and human anatomy, presented in PART 1, CT-based delineation guidelines for defined FSUs were created. Delineation was performed by the first author and revised by a panel of experts. RESULTS AND CONCLUSIONS: Detailed delineation guidelines are presented for seven FSUs involved in HLE, TBR and tongue motion. The guidelines are supplemented by CT and MRI-based exemplary illustrations and complete CT/MRI-based delineation atlases (available online). This paper provides information essential to the implementation of the FSU concept in radiation practice, and supports uniform contouring, data collection and further improvement of swallowing sparing radiation-based strategies.

Evaluation of thyroid gland as an organ at risk after breast cancer radiotherapy: a systematic review and meta-analysis.

BACKGROUND: Radiotherapy can often lead to thyroid dysfunction. Some studies demonstrated that treatment of breast cancer by RT can expose thyroid gland to high doses of radiation. The aim of this systematic review is to evaluate consideration of thyroid gland as an organ at risk. METHODS: In this systematic review and meta-analysis to select initial studies, a comprehensive search by two independent reviewers was performed. Electronical databases following: Web of Science, Google Scholar, Scopus, PubMed, Elsevier, Embase, ProQuest and Persian databases such as Iranmedex, Magiran, and SID were searched. All searches were restricted to English language between 1985 and 2017. A random effect meta-analysis is applied to estimate pooled effect size across initial studies. Funnel plot with Egger's test is used to assess potential publication bias. RESULTS: Totally, five studies (478 samples) were included in meta-analysis. The meta-analyses of result showed that thyroid gland is affected by radiotherapy significantly and the TSH increased after radiotherapy (z = 2.68, P = 0.007). The pooled estimate of difference mean for TSH was 0.90 (95% CI 0.24, 1.55). In studies among patients with breast cancer RT, hypothyroidism was reported more than other thyroid disorders. There was not showed possibility publication bias among studies (P > 0.05). CONCLUSION: This study demonstrated that thyroid gland is affected by radiotherapy significantly and the TSH increased after radiotherapy. Protecting thyroid gland during radiation and follow-up of patients with breast cancer RT are suggested for the assessment of thyroid gland dysfunction.

Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors.

BACKGROUND: Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT). METHODS: A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices. RESULTS: The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and -0.3, respectively; P>.30). A higher left hippocampal V20GyE (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035). CONCLUSIONS: Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018;124:2238-45. © 2018 American Cancer Society.

Evaluating Which Dose-Function Metrics Are Most Critical for Functional-Guided Radiation Therapy.

PURPOSE: Four-dimensional (4D) computed tomography (CT) ventilation imaging is increasingly being used to calculate lung ventilation and implement functional-guided radiation therapy in clinical trials. There has been little exhaustive work evaluating which dose-function metrics should be used for treatment planning and plan evaluation. The purpose of our study was to evaluate which dose-function metrics best predict for radiation pneumonitis (RP). METHODS AND MATERIALS: Seventy lung cancer patients who underwent 4D CT imaging and pneumonitis grading were assessed. Pretreatment 4D CT scans of each patient were used to calculate ventilation images. We evaluated 3 types of dose-function metrics that combined the patient's 4D CT ventilation image and treatment planning dose distribution: (1) structure-based approaches; (2) image-based approaches using the dose-function histogram; and (3) nonlinear weighting schemes. Log-likelihood methods were used to generate normal tissue complication probability models predicting grade 3 or higher (ie, grade 3+) pneumonitis for all dose-function schemes. The area under the curve (AUC) was used to assess the predictive power of the models. All techniques were compared with normal tissue complication probability models based on traditional, total lung dose metrics. RESULTS: The most predictive models were structure-based approaches that focused on the volume of functional lung receiving ≥20 Gy (AUC, 0.70). Probabilities of grade 3+ RP of 20% and 10% correspond to V20 (percentage of volume receiving ≥20 Gy) to the functional subvolumes of 26.8% and 9.3%, respectively. Imaging-based analysis with the dose-function histogram and nonlinear weighted ventilation values yielded AUCs of 0.66 and 0.67, respectively, when we evaluated the percentage of functionality receiving ≥20 Gy. All dose-function metrics outperformed the traditional dose metrics (mean lung dose, AUC of 0.55). CONCLUSIONS: A full range of dose-function metrics and functional thresholds was examined. The calculated AUC values for the most predictive functional models occupied a narrow range (0.66-0.70), and all showed notable improvements over AUC from traditional lung dose metrics (0.55). Identifying the combinations most predictive of grade 3+ RP provides valuable data to inform the functional-guided radiation therapy process.

Whole-brain Irradiation Field Design: A Comparison of Parotid Dose.

Whole-brain radiation therapy (WBRT) plays an important role in patients with diffusely metastatic intracranial disease. Whether the extent of the radiation field design to C1 or C2 affects parotid dose and risk for developing xerostomia is unknown. The goal of this study is to examine the parotid dose based off of the inferior extent of WBRT field to either C1 or C2. Patients treated with WBRT with either 30 Gy or 37.5 Gy from 2011 to 2014 at a single institution were examined. Parotid dose constraints were compared with Radiation Therapy Oncology Group (RTOG) 0615 nasopharyngeal carcinoma for a 33-fraction treatment: mean <26 Gy, volume constraint at 20 Gy (V20) < 20 cc, and dose at 50% of the parotid volume (D50) < 30 Gy. Biologically effective dose (BED) conversions with an α/ß of 3 for normal parotid were performed to compare with 10-fraction and 15-fraction treatments of WBRT. The constraints are as follows: mean < BED 32.83 Gy, V15.76 (for 10-fraction WBRT) or V17.35 (for 15-fraction WBRT) < 20 cc, and D50 < BED 39.09 Gy. Nineteen patients treated to C1 and 26 patients treated to C2 were analyzed. Comparing WBRT to C1 with WBRT to C2, the mean left, right, and both parotids' doses were lower when treated to C1. Converting mean dose to BED3, the parotid doses were lower than BED3 constraint of 32.83 Gy: left (30.12 Gy), right (30.69 Gy), and both parotids (30.32 Gy). V20 to combined parotids was lower in patients treated to C1. When accounting for fractionation of WBRT received, the mean corrected V20 volume was less than 20 cc when treating to C1. D50 for C1 was lower than C2 for the left parotid, right parotid, and both parotids. BED3 conversion for the mean D50 of the left, right, and both parotids was less than 39.09 Gy. In conclusion, WBRT to C1 limits parotid dose, and parotid dose constraints are achievable compared with inferior border at C2. A possible mean parotid dose constraint with BED3 should be less than 32.83 Gy.

Heart Dose Is an Independent Dosimetric Predictor of Overall Survival in Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: In the randomized trial of standard- versus high-dose chemoradiotherapy for locally advanced (LA) NSCLC (Radiation Therapy Oncology Group 0617), overall survival (OS) was worse in the high-dose arm. Although heart dose was suggested as a contributing factor, actionable parameters have not been established. We present an analysis of clinical and dosimetric parameters affecting OS in this patient population, focusing on heart dose. METHODS: Clinical data were collected on 416 patients with LA NSCLC treated at a single institution, with a subset of 333 available treatment plans recontoured using Radiation Therapy Oncology Group 0617 normal tissue guidelines. Toxicity and dosimetry data were analyzed for 322 patients; multivariate analysis was performed on 251 patients. Dosimetric parameters of radiation to tumor and organs at risk were analyzed with clinical data pertaining to OS, disease-free survival, and toxicity. RESULTS: Patients were treated with radiation therapy to prescribed doses of 50.0 to 84.9 Gy (median 66.0 Gy). Median follow-up was 14.5 months. Median OS was 16.8 months. The 1- and 2-year OS rates were 61.4% and 38.8%, respectively. On multivariate analysis, factors independently associated with worse OS were increasing heart V50 (volume receiving ≥50 Gy), heart volume, lung V5 (proportion of the lung structure [excluding the target volume]) receiving at least 5 Gy), bilateral mediastinal lymph node involvement, and lack of concurrent chemotherapy. When stratified by heart V50 less than 25% versus 25% or greater, the 1-year OS rates were 70.2% versus 46.8% and the 2-year OS rates were 45.9% versus 26.7% (p < 0.0001). Median heart V50 was significantly higher (20.8% versus 13.9%, p < 0.0001) for patients with cardiac toxicity with a Common Terminology Criteria for Adverse Events grade of 1 or higher. CONCLUSIONS: Heart dose is associated with OS and cardiac toxicity for patients with LA NSCLC treated with chemoradiotherapy.

In vivo evaluating skin doses for lung cancer patients undergoing volumetric modulated arc therapy treatment.

This study is the first to use 10- to 90-kg tissue-equivalent phantoms as patient surrogates to measure peripheral skin doses (Dskin) in lung cancer treatment through Volumetric Modulated Arc Therapy of the Axesse linac. Five tissue-equivalent and Rando phantoms were used to simulate lung cancer patients using the thermoluminescent dosimetry (TLD-100H) approach. TLD-100H was calibrated using 6 MV photons coming from the Axesse linac. Then it was inserted into phantom positions that closely corresponded with the position of the represented organs and tissues. TLDs were measured using the Harshaw 3500 TLD reader. The ICRP 60 evaluated the mean Dskin to the lung cancer for 1 fraction (7 Gy) undergoing VMAT. The Dskin of these phantoms ranged from 0.51±0.08 (10-kg) to 0.22±0.03 (90-kg) mSv/Gy. Each experiment examined the relationship between the Dskin and the distance from the treatment field. These revealed strong variations in positions close to the tumor center. The correlation between Dskin and body weight was Dskin (mSv) = -0.0034x + 0.5296, where x was phantom's weight in kg. R2 is equal to 0.9788. This equation can be used to derive an equation for lung cancer in males. Finally, the results are compared to other published research. These findings are pertinent to patients, physicians, radiologists, and the public.

Dosimetric analysis of rectal filling on rectal doses during vaginal cuff brachytherapy.

PURPOSE: Several studies have analyzed the effect of bladder filling during vaginal cuff brachytherapy (VCB), but the effect of rectum filling has not been studied. We sought to evaluate the effects of rectal volume on rectal doses during postoperative VCB. METHODS AND MATERIALS: Brachytherapy planning CT scans (334 sets) obtained from 92 consecutive patients treated with VCB were resegmented (bladder and rectum) and replanned retrospectively using the same parameters to homogenize data and improve analysis. Rectal volume and a set of values derived from dose-volume histograms (DVHs) were extracted (maximal dose [Dmax], D0.1cc, D1cc, and D2cc). Univariate and multivariate analyses were carried out to evaluate the association between rectal volume and DVH metrics after adjusting for other clinical factors. RESULTS: A positive significant correlation was observed between rectal volume correlated and Dmax, D0.1cc, D1cc, and D2cc. Multiple linear regression models found that rectal volume, cylinder angle position, and cylinder diameter variables correlated significantly with the different DVH parameters analyzed. These variables explained the 14.5% and 18% of variance on regression models. CONCLUSIONS: Larger rectal volumes are associated with higher rectal dose parameters during VCB fractions. Prospective studies are needed to investigate whether these data are linked to differences in rectal toxicity.

Crisis hipertensivas: seudocrisis, urgencias y emergencias / Hypertensive crisis: Pseudocrises, urgencies and emergencies

Las crisis hipertensivas se definen como elevaciones agudas de la presión arterial capaces de producir alteraciones funcionales o estructurales en los órganos diana de la hipertensión. Históricamente se han dividido en 2 tipos, urgencias y emergencias hipertensivas, con diferente clínica, tratamiento y pronóstico. En esta revisión se sigue dicha clasificación pero considerando un tercer tipo, las llamadas seudocrisis o falsas crisis hipertensivas. Las urgencias hipertensivas no provocan afectación de los órganos diana o si esta se produce es leve-moderada, permitiendo un descenso tensional lento y progresivo (horas-días) con fármacos por vía oral, habitualmente en el ámbito extrahospitalario. Las emergencias hipertensivas provocan lesiones agudas y graves de los órganos diana, con riesgo de compromiso vital, precisando un descenso tensional rápido (minutos-horas) pero muy controlado con fármacos por vía intravenosa en el ámbito hospitalario. Las elevaciones tensionales agudas que no pueden llegar a clasificarse ni como urgencias ni como emergencias se consideran seudocrisis hipertensivas

Hypertensive crises are defined as acute blood pressure elevations that can cause functional or structural alterations in hypertension target organs. Historically, they have been divided into two types, urgencies and hypertensive emergencies, with different symptoms, treatment and prognosis. This review follows this classification but also considers a third type, the so-called pseudocrises or false hypertensive crisis. Hypertensive urgencies do not cause organ involvement target or if this does occur, the involvement is slight-moderate, allowing a slow and progressive decrease in pressure (hours-days) with oral drugs usually in the outpatient setting (primary care).Hypertensive emergencies cause acute and severe injuries of the target organs, with life threatening risk, and require a rapid, but very controlled drop with intravenous drugs in blood pressure (minutes-hours) within the hospital setting. Acute blood pressure elevations that cannot be classified as urgencies or emergencies are considered hypertensive pseudocrises

Transabdominal high-intensity focused ultrasound therapy of the prostate and determination of the protective effect of rectal cooling: an experimental study using canine prostates.

OBJECTIVES: The purpose of this study was to report our initial experience with transabdominal high-intensity focused ultrasound (HIFU) therapy of the canine prostate and to determine the protective effect of rectal cooling during HIFU therapy. METHODS: Fifteen male dogs underwent transabdominal HIFU therapy of the prostate. Transabdominal HIFU was performed on 9 dogs without using a rectal cooling device, and the remaining 6 dogs underwent transabdominal HIFU with introduction of the rectal cooling device. Magnetic resonance imaging (MRI) was performed before, immediately after, and 1 week after the HIFU procedure. Rectal changes on MRI were classified into 4 grades (grades 0-3), and a comparison of the rectal change grades on MRI between the two groups was performed with the Mann-Whitney U test. RESULTS: The procedure failed for the first dog because of inadequate skin preparation. Of the remaining 14 dogs (8 without rectal cooling and 6 with rectal cooling), 4 showed focal signal changes in the prostate. The average rectal change grades on immediate postprocedural MRI were 2.63 for the non-rectal cooling group and 1.17 for the rectal cooling group (P = .0216). On 1-week follow-up MRI, the average grades were 1.20 for the non-rectal cooling group and 0.33 for the rectal cooling group (P = .1956). CONCLUSIONS: Transabdominal HIFU of the canine prostate was technically feasible, but the effect was limited because of anatomic and physiologic factors of the canine prostate. The rectal cooling device seems to have a protective effect on the rectum during the transabdominal HIFU procedure.

Is there a dose-response relationship for heart disease with low-dose radiation therapy?

PURPOSE: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. METHODS AND MATERIALS: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. RESULTS: The mean difference in pre- and post-RT PD was -0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. CONCLUSIONS: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

Predicting dose-volume histograms for organs-at-risk in IMRT planning.

PURPOSE: The objective of this work was to develop a quality control (QC) tool to reduce intensity modulated radiotherapy (IMRT) planning variability and improve treatment plan quality using mathematical models that predict achievable organ-at-risk (OAR) dose-volume histograms (DVHs) based on individual patient anatomy. METHODS: A mathematical framework to predict achievable OAR DVHs was derived based on the correlation of expected dose to the minimum distance from a voxel to the PTV surface. OAR voxels sharing a range of minimum distances were computed as subvolumes. A three-parameter, skew-normal probability distribution was used to fit subvolume dose distributions, and DVH prediction models were developed by fitting the evolution of the skew-normal parameters as a function of distance with polynomials. Cohorts of 20 prostate and 24 head-and-neck IMRT plans with identical clinical objectives were used to train organ-specific average models for rectum, bladder, and parotids. A sum of residuals analysis quantifying the integrated difference between the clinically approved DVH and predicted DVH evaluated similarity between DVHs. The ability of the average models to prospectively predict DVHs was evaluated on an independent validation cohort of 20 prostate plans. Statistical comparison of the sums of residuals between training and validation cohorts quantified the accuracy of the average model. Restricted sums of residuals (RSR) were used to identify potential outliers, where large values of RSR indicate a clinical DVH that exceeds the predicted DVH by a considerable amount. A refined model was obtained for each organ by excluding outliers with large RSR values from the training cohort. The refined model was applied to the original training cohort and restricted sums of residuals were utilized to estimate potential DVH improvements. All cases were replanned and evaluated by the physician that approved the original plan. The ability of the refined models to correctly identify outliers was assessed using the residual sum between the original and replanned DVHs to quantify dosimetric gains realized under replanning. RESULTS: Statistical analysis of average sum of residuals for rectum (SR(rectum)=0.003±0.037), bladder (SR(bladder)=-0.008±0.037), and parotid (SR(parotid)=-0.003±0.060) training cohorts yielded mean values near zero and small with respect to the standard deviations, indicating that the average models are capturing the essential behavior of the training cohorts. The predictive abilities of the average rectum and bladder models were statistically indistinguishable between the training and validation sets, with SR(rectum)=0.002±0.044 and SR(bladder)=-0.018±0.058 for the validation set. The refined models' ability to detect outliers and predict achievable OAR DVHs was demonstrated by a strong correlation between predicted gains (RSR) and realized gains after replanning with sample correlation coefficients of r = 0.92 for the rectum, r = 0.88 for the bladder, and r = 0.84 for the parotid glands. CONCLUSIONS: The results demonstrate that our mathematical framework and modest training cohorts successfully predict achievable OAR DVHs based on individual patient anatomy. The models correctly identified suboptimal plans that demonstrated further OAR sparing after replanning. This modeling technique requires no manual intervention except for appropriate selection of a training set with identical evaluation criteria. Clinical implementation is in progress to evaluate impact on real-time IMRT QC.

Predictive models for pulmonary function changes after radiotherapy for breast cancer and lymphoma.

PURPOSE: To propose multivariate predictive models for changes in pulmonary function tests (ΔPFTs) with respect to preradiotherapy (pre-RT) values in patients undergoing RT for breast cancer and lymphoma. METHODS AND MATERIALS: A prospective study was designed to measure ΔPFTs of patients undergoing RT. Sixty-six patients were included. Spirometry, lung capacity (measured by helium dilution), and diffusing capacity of carbon monoxide tests were used to measure lung function. Two lung definitions were considered: paired lung vs. irradiated lung (IL). Correlation analysis of dosimetric parameters (mean lung dose and the percentage of lung volume receiving more than a threshold dose) and ΔPFTs was carried out to find the best dosimetric predictor. Chemotherapy, age, smoking, and the selected dose-volume parameter were considered as single and interaction terms in a multivariate analysis. Stability of results was checked by bootstrapping. RESULTS: Both lung definitions proved to be similar. Modeling was carried out for IL. Acute and late damage showed the highest correlations with volumes irradiated above ~20 Gy (maximum R(2) = 0.28) and ~40 Gy (maximum R(2) = 0.21), respectively. RT alone induced a minor and transitory restrictive defect (p = 0.013). Doxorubicin-cyclophosphamide-paclitaxel (Taxol), when administered pre-RT, induced a late, large restrictive effect, independent of RT (p = 0.031). Bootstrap values confirmed the results. CONCLUSIONS: None of the dose-volume parameters was a perfect predictor of outcome. Thus, different predictor models for ΔPFTs were derived for the IL, which incorporated other nondosimetric parameters mainly through interaction terms. Late ΔPFTs seem to behave more serially than early ones. Large restrictive defects were demonstrated in patients pretreated with doxorubicin-cyclophosphamide-paclitaxel.

Renal safety of Non Steroidal Anti Inflammatory Drugs (NSAIDs) in the pharmacologic treatment of patent ductus arteriosus.

Patent ductus arteriosus (PDA) often complicates the clinical course of neonates born prematurely and increases their short- and long-term morbidity. Treatment of PDA remains an ongoing debate among neonatologists for various issues such as the timing, the criteria and the methods for its closure. Non steroidal anti inflammatory drugs have been used as the standard pharmacological treatment for PDA. Indomethacin was the first one to be used. Its use though, waned due recognition of renal cerebral and gastrointestinal complications associated with the administration of this drug. Ibuprofen has emerged in clinical practice, as it has been reported to have lower nephrotoxicity. This review will examine existing data in the literature on the early- and long-term nephrotoxicity associated with the two drugs and will discuss present and future directions the management and prevention of this condition.

[The prophylaxis and treatment of renal dysfunction by pancreatogenic endotoxicosis].

The treatment of 386 patients with the acute pancreatitis of various etiology was analyzed. Renal dysfunction was revealed in 243 (63%) of them. The prognostic factors of renal dysfunction were carried out. The timely application of the treatment scheme, including early extracorporal detoxification, permit the significant improvement of the treatment results of the acute pancreatitis.

Papel de la MAPA en el manejo de la hipertensión arterial resistente / Role of ambulatory blood pressure monitoring in the management of resistant hypertension

La hipertensión arterial (HTA) se define como refractaria o resistente al tratamiento antihipertensivo cuando no se obtiene un adecuado control de la presión arterial (PA) por debajo de 140/90 mmHg o cifras inferiores (< 130/80 mmHg) en determinadas situaciones, como la diabetes mellitus o la enfermedad renal crónica, mediante un tratamiento antihipertensivo con 3 o más fármacos, incluido un diurético, a dosis plenas. Es importante descartar la falta de cumplimiento de la medicación antihipertensiva y las principales causas de HTA secundaria. La importancia de la monitorización ambulatoria de la presión arterial (MAPA) en el manejo de la HTA arterial refractaria se resume básicamente en 3 puntos: a) la confirmación de la HTA refractaria clínica mediante la MAPA permite descartar un 25-30% de los casos que presentan HTA seudorrefractaria, por lo que estos pacientes no precisan añadir nuevos fármacos antihipertensivos ni estudios complejos para descartar HTA secundaria; b) como en otros tipos de HTA, el pronóstico de los sujetos con HTA refractaria se relaciona más estrechamente con los valores de PA obtenidos durante la MAPA, como se ha confirmado en varios estudios prospectivos, y c) el patrón circadiano no reductor de la PA durante la noche se asocia a un peor pronóstico (AU)

Hypertension is considered to be resistant when blood pressure goals (<140/90 mmHg in general, <130/80 mmHg in hypertensive patients with diabetes or renal disease) are not achieved by means of a triple-drug combination including a diuretic at full doses. In this situation, lack of therapeutic adherence, and causes of secondary hypertension must be excluded. The importance of ambulatory blood pressure monitoring (ABPM) in the management of resistant hypertension can be summarized in three points: a) ABPM-confirmation of true resistant hypertension allows false (“white-coat”) resistant hypertension (25-30% of cases with apparent resistant hypertension) to be excluded and consequently these patients do not required new antihypertensive agents to be added or complex complementary investigations to exclude secondary hypertension; b) as in other types of hypertension, the prognosis of patients with resistant hypertension is closely related to ambulatory blood pressure levels, as confirmed by several prospective studies, and c) a non-dipper pattern of nocturnal blood pressure confers a worse outcome profile (AU)