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Purpose: To derive guidelines for the need to use positron emission tomography (PET) for delineation of the primary tumor (PT) according to its anatomical location in the lung. Methods and Materials: In 22 patients with non-small-cell lung cancer, thoracic X-ray computed tomography (CT) and PET were performed. Eleven radiation oncologists delineated the PT on the CT and on the CT-PET registered scans. The PTs were classified into two groups. In Group I patients, the PT was surrounded by lung or visceral pleura, without venous invasion, without extension to chest wall or the mediastinum over more than one quarter of its surface. In Group II patients, the PT invaded the hilar region, heart, great vessels, pericardium, mediastinum over more than one quarter of its surface and/or associated with atelectasis. A comparison of interobserver variability for each group was performed and expressed as a local standard deviation. Results: The comparison of delineations showed a good reproducibility for Group I, with an average SD of 0.4 cm on CT and an average SD of 0.3 cm on CT-PET (p = 0.1628). There was also a significant improvement with CT-PET for Group II, with an average SD of 1.3 cm on CT and SD of 0.4 cm on CT-PET (p = 0.0003). The improvement was mainly located at the atelectasis/tumor interface. At the tumor/lung and tumor/hilum interfaces, the observer variation was similar with both modalities. Conclusions: Using PET for PT delineation is mandatory to decrease interobserver variability in the hilar region, heart, great vessels, pericardium, mediastinum, and/or the region associated with atelectasis; however it is not essential for delineation of PT surrounded by lung or visceral pleura, without venous invasion or extension to the chest wall. [ABSTRACT FROM AUTHOR]

Patients with end-stage chronic kidney disease show higher systemic oxidative stress and exhale more hydrogen peroxide (H 2 O 2 ) than healthy controls. Kidney transplantation reduces oxidative stress and H 2 O 2 production by blood polymorphonuclear leukocytes (PMNs). Kidney transplant recipients (KTRs) may be predisposed to an impairment of lung diffusing capacity due to chronic inflammation. Lung function and H 2 O 2 concentration in the exhaled breath condensate (EBC) were compared in 20 KTRs with stable allograft function to 20 healthy matched controls. Serum interleukin eight (IL-8) and C-reactive protein (CRP), blood cell counts, and spirometry parameters did not differ between groups. However, KTRs showed lower total lung diffusing capacity for carbon monoxide, corrected for hemoglobin concentration (TLCO c ), in comparison to healthy controls (92.1 ± 11.5% vs. 102.3 ± 11.9% of predicted, p = 0.009), but similar EBC H 2 O 2 concentration (1.63 ± 0.52 vs. 1.77 ± 0.50 µmol/L, p = 0.30). The modality of pre-transplant renal replacement therapy had no effect on TLCO c and EBC H 2 O 2 . TLCO c did not correlate with time after transplantation. In this study, TLCO c was less reduced in KTRs in comparison to previous reports. We suggest this fact and the non-elevated H 2 O 2 exhalation exhibited by KTRs, may result perhaps from the evolution of the immunosuppressive therapy.

Carotenoids are organic, liposoluble pigments found in nature, which are responsible for the characteristic colors of ripe tomatoes, carrots, peppers, and crustaceans, among others. Palliative care provided to patients with an incurable disease is aimed at improving the patient's quality of life through appropriate treatment of symptoms accompanying the disease. Palliative care patients with burdensome symptoms related to advanced-stage cancers are especially interested in the use of natural dietary supplements and herbal remedies to reduce symptoms' intensity and ameliorate the quality of life. Carotenoids seem to be a group of natural compounds with particularly promising properties in relieving symptoms, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties. Moreover, carotenoids have been used in folk medicine to treat various diseases and alleviate the accompanying symptoms. In this narrative review, the authors decided to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms, such as neuropathic pain and cancer-related cachexia.

Hydroxyl radical ( • OH) scavenging and the regeneration of Fe 2+ may inhibit or enhance peroxidative damage induced by a Fenton system, respectively. Plant polyphenols reveal the afore-mentioned activities, and their cumulative net effect may determine anti- or pro-oxidant actions. We investigated the influence of 17 phenolics on ultra-weak photon emission (UPE) from a modified Fenton system (92.6 µmol/L Fe 2+ , 185.2 µmol/L EGTA (ethylene glycol-bis(β-aminoethyl-ether)-N,N,N',N,-tetraacetic acid) and 2.6 mmol/L H 2 O 2 pH = 7.4). A total of 8 compounds inhibited (antioxidant effect), and 5 enhanced (pro-oxidant effect) UPE at all studied concentrations (5 to 50 µmol/L). A total of 4 compounds altered their activity from pro- to antioxidant (or vice versa) along with increasing concentrations. A total of 3 the most active of those (ferulic acid, chlorogenic acid and cyanidin 3- O -glucoside; mean UPE enhancement by 63%, 5% and 445% at 5 µmol/L; mean UPE inhibition by 28%, 94% and 24% at 50 µmol/L, respectively) contained catechol or methoxyphenol structures that are associated with effective • OH scavenging and Fe 2+ regeneration. Most likely, these structures can determine the bidirectional, concentration-dependent activity of some phenolics under stable in vitro conditions. This is because the concentrations of the studied compounds are close to those occurring in human fluids, and this phenomenon should be considered in the case of dietary supplementation with isolated phenolics.

BACKGROUND COVID-19 can be complicated by kidney disease, including focal segmental glomerulosclerosis (FSGS), interstitial nephritis, and acute kidney injury (AKI). Almost all known cases of COVID-19-associated glomerulonephritis have been in patients of African descent, with G1 or G2 apolipoprotein L1 (APOL1) risk alleles, and they presented collapsing type of FSGS. CASE REPORT We report a case of biopsy-confirmed non-collapsing FSGS with secondary acute interstitial nephritis and AKI in a young White man with APOL1 low-risk genotype, who had COVID-19 pneumonia. His past history included arterial hypertension, anabolic steroids, and high-protein diet. He fully recovered from type 1 respiratory failure and AKI after transfusion of COVID-19 convalescent plasma and intravenous treatment with dexamethasone administered for 16 days in a dose reduced from 16 to 2 mg/day. Due to progressing severe nephrotic proteinuria (22.6 g/24 h), intravenous methylprednisolone was administered (1500 mg divided in 3 pulses over 3 days) immediately followed by oral prednisone (0.6 mg/kg body weight), with dose reduced 19 weeks later and switched to cyclosporine A (4 mg/kg body weight). Kidney re-biopsy, at that time, showed a decrease in proportion of glomeruli affected with podocytopathy, but progression of interstitial lesions. After 23 weeks of therapy, partial remission of FSGS was attained and proteinuria dropped to 3.6 g/24 h. After 43 weeks, proteinuria decreased to 0.4 g/24 h and the serum creatinine concentration remained steady. CONCLUSIONS High-dose glucocorticoid therapy was effective in the initial treatment of COVID-19-related non-collapsing FSGS, but had no effect on interstitial changes. Introduction of cyclosporine A to the therapy contributed to remission of disease.

Ascorbic acid (AA) has antioxidant properties. However, in the presence of Fe 2+ /Fe 3+ ions and H 2 O 2 , it may behave as a pro-oxidant by accelerating and enhancing the formation of hydroxyl radicals ( • OH). Therefore, in this study we evaluated the effect of AA at concentrations of 1 to 200 µmol/L on • OH-induced light emission (at a pH of 7.4 and temperature of 37 °C) from 92.6 µmol/L Fe 2+ -185.2 µmol/L EGTA (ethylene glycol-bis (β-aminoethyl ether)-N,N,N',N'-tetraacetic acid)-2.6 mmol/L H 2 O 2 , and 92.6 µmol/L Fe 3+ -185.2 µmol/L EGTA-2.6 mmol/L H 2 O 2 systems. Dehydroascorbic acid (DHAA) at the same range of concentrations served as the reference compound. Light emission was measured with multitube luminometer (AutoLumat Plus LB 953) for 120 s after automatic injection of H 2 O 2 . AA at concentrations of 1 to 50 µmol/L and of 1 to 75 µmol/L completely inhibited light emission from Fe 2+ -EGTA-H 2 O 2 and Fe 3+ -EGTA-H 2 O 2 , respectively. Concentrations of 100 and 200 µmol/L did not affect chemiluminescence of Fe 3+ -EGTA-H 2 O 2 but tended to increase light emission from Fe 2+ -EGTA-H 2 O 2 . DHAA at concentrations of 1 to 100 µmol/L had no effect on chemiluminescence of both systems. These results indicate that AA at physiological concentrations exhibits strong antioxidant activity in the presence of chelated iron and H 2 O 2 .

Hemodialysis (HD) is the most common method of renal replacement therapy. Besides toxins, it eliminates nutrients from the circulation, such as ascorbic acid (AA). HD-patients present AA deficiency more often than representatives of the general population, also due to dietary restrictions. This condition aggravates oxidative stress and inflammation related to uremia and extracorporeal circulation and increases cardiovascular risk followed by mortality. Supplementation of AA seems to be a promising approach in the treatment of hemodialysis patients. Many successful interventions restored plasma AA concentration in HD patients by enteral or intravenous supplementation, concomitantly inhibiting oxidative stress and inflammation. A significant number of studies reported opposite, serious pro-oxidant effects of AA. In this narrative review, we present studies, commenting on their limitations; on AA plasma or serum concentration and the influence of its supplementation on protein and lipid peroxidation, DNA damage, reactive oxygen species generation, paraoxonase activity, advanced glycation endproducts, and C-reactive protein (CRP) concentration. Moreover, in terms of safety, the possible development of oxalosis in HD patients regarding the intravenous or enteral route of AA administration is discussed. Unequivocal clinical results of recent studies on hemodialysis patients are displayed.

High-dose intravenously administered vitamin C (IVC) is widely used in cancer patients by complementary and alternative medicine practitioners. The most frequent indications for IVC therapy result from the belief in its effectiveness as a potent anti-cancer agent which additionally enhances chemosensitivity of cancer cells and reduces chemotherapy-related toxicities and fatigue intensity. In this narrative review, we decided to deal with this issue, trying to answer the question whether there is any scientific evidence supporting the rationale for application of high-dose IVC therapy in advanced-stage cancer patients. Although results obtained from preclinical studies demonstrated that millimolar ascorbate plasma concentrations achievable only after IVC administration were cytotoxic to fast-growing malignant cells and inhibited tumor growth as well as prolonged the survival of laboratory animals, such positive effects were not found in human studies with advanced-stage cancer patients. We also have not found the rationale for the use of IVC to increase the effectiveness of chemotherapy and to reduce the chemotherapy-induced toxicity in the above mentioned group. Nevertheless, in palliative care, high-dose IVC might be considered as a therapy improving the quality of life and reducing cancer-related symptoms, such as fatigue and bone pain. However, because of the absence of placebo-controlled randomized trials on IVC efficacy in advanced-stage cancer patients, the placebo effect cannot be excluded.

Oxidative reactions can result in the formation of electronically excited species that undergo radiative decay depending on electronic transition from the excited state to the ground state with subsequent ultra-weak photon emission (UPE). We investigated the UPE from the Fe 2+ -EDTA (ethylenediaminetetraacetic acid)-AA (ascorbic acid)-H 2 O 2 (hydrogen peroxide) system with a multitube luminometer (Peltier-cooled photon counter, spectral range 380-630 nm). The UPE, of 92.6 μmol/L Fe 2+ , 185.2 μmol/L EDTA, 472 μmol/L AA, 2.6 mmol/L H 2 O 2 , reached 1217 ± 118 relative light units during 2 min measurement and was about two times higher (P < 0.001) than the UPE of incomplete systems (Fe 2+ -AA-H 2 O 2 , Fe 2+ -EDTA-H 2 O 2 , AA-H 2 O 2 ) and medium alone. Substitution of Fe 2+ with Cr 2+ , Co 2+ , Mn 2+ or Cu 2+ as well as of EDTA with EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid) or citrate powerfully inhibited UPE. Experiments with scavengers of reactive oxygen species (dimethyl sulfoxide, mannitol, sodium azide, superoxide dismutase) revealed the dependence of UPE only on hydroxyl radicals. Dimethyl sulfoxide at the concentration of 0.74 mmol/L inhibited UPE by 79 ± 4%. Plant phenolics (ferulic, chlorogenic and caffec acids) at the concentration of 870 μmol/L strongly enhanced UPE by 5-, 13.9- and 46.8-times (P < 0.001), respectively. It is suggested that augmentation of UPE from Fe 2+ -EDTA-AA-H 2 O 2 system can be applied for detection of these phytochemicals., (© 2019 John Wiley & Sons, Ltd.)

Oxidative reactions can result in the formation of electronically excited species that undergo radiative decay depending on electronic transition from the excited state to the ground state with subsequent ultra-weak photon emission (UPE). We investigated the UPE from the Fe 2+ -EGTA (ethylene glycol-bis(β-aminoethyl ether)- N , N , N ', N '-tetraacetic acid)-H₂O₂ system with a multitube luminometer (Peltier-cooled photon counter, spectral range 380 to 630 nm). The UPE of 92.6 µmol/L Fe 2+ -185.2 µmol/L EGTA-2.6 mmol/L H₂O₂ reached 4319 ± 755 relative light units during 2 min measurement and was about seven times higher ( p < 0.001) than the UPE of incomplete systems (Fe 2+ -H₂O₂, EGTA-H₂O₂) and medium alone. Substitution of Fe 2+ with Cr 2+ , Co 2+ , Mn 2+ or Cu 2+ as well as of EGTA with EDTA (ethylenediaminetetraacetic acid) or citrate completely abolished UPE. Experiments with ROS scavengers revealed the dependence of UPE on hydroxyl radicals suggesting occurrence of oxidative attack and cleavage of the ether bond in EGTA backbone structure and formation of triplet excited carbonyl groups with subsequent light emission. Plant phenolics (ferulic, chlorogenic and caffec acids) at concentration 87 µmol/L and ascorbate at 0.46 mmol/L inhibited UPE by 90 ± 4%, 90 ± 5%, 97 ± 2% and 92 ± 1%, respectively. Quenching of UPE from Fe 2+ -EGTA-H₂O₂ system can be used for evaluation of antioxidant activity of phytochemicals., Competing Interests: The authors declare no conflict of interest. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Plant phenols may accumulate in end-stage kidney disease. The effect of hemodialysis on their plasma concentration remains poorly determined. Contingent on concentration, health-promoting or noxious effects occur; therefore, we assessed plasma concentration in hemodialyzed patients. In total, 21 maintenance hemodialyzed patients with diuresis < 500 mL per day (with oliguria), nine hemodialyzed patients with diuresis ≥ 500 mL per day (without oliguria) and 31 healthy volunteers were included. Nine phenolic acids were identified with high-performance liquid chromatography and total polyphenol concentration was determined with the Folin-Ciocalteu method in pre- or post-hemodialysis plasma and pre- or intra-hemodialysis dialysate. The concentration of total polyphenols was 27% higher in pre-hemodialysis plasma than in that of controls (0.95 ± 0.18 mmol/L [P < 0.0001]). The concentration of total polyphenols was higher in patients with oliguria (1.01 ± 0.17) than in those without (0.84 ± 0.13 mmol/L), despite the former having more intense hemodialysis (Kt/V 1.29 ± 0.31 and 0.77 ± 0.25, respectively). Pre-hemodialysis phenolic acid concentration in patients undergoing dialysis exceeded reference values by 3 to 34 times (3-hydroxyphenylacetic acid and vanillic acid, respectively), from 0.69 (dihydrocaffeic acid) to 169.3 μmol/L (hippuric acid). The concentration of six phenolic acids (3-hydroxyhippuric, caffeic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid) was 1.1 (homovanillic) to 11.3 (3-hydroxyhippuric) times higher in patients with oliguria than in those without. 4-hydroxyhippuric acid occurred more in the plasma of patients with oliguria than in those without oliguria. A single hemodialysis session decreased total polyphenol concentration by 16% and phenolic acids from 30% (caffeic) to 58% (vanillic and 3-hydroxyphenylacetic acid) and these compounds appeared in the dialysate. The percentage decrease (Δ%) of creatinine concentration correlated with the Δ% of total polyphenols and five phenolic acids (3-hydroxyphenylacetic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid). Urea Δ% and Kt/V correlated only with the Δ% of homovanilic acid. The results demonstrate that phenols accumulate variably in hemodialyzed patients and are differently eliminated during hemodialysis. Residual renal function ensures a lower concentration of plasma phenols., (© 2017 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Objectives: Reactive oxygen species, which are implicated in the process of carcinogenesis, are also responsible for cell death during chemotherapy (CHT). Therefore, the aim of the study was to evaluate exhaled H 2 O 2 levels in non-small cell lung cancer (NSCLC) patients before and after CHT., Methods: Thirty patients (age 61.3 ± 9.3 years) with advanced NSCLC (stage IIIB-IV) and 15 age-matched healthy cigarette smokers were enrolled into the study. Patients received four cycles of cisplatin or carboplatin with vinorelbine every three weeks. Before and after the first, second, and fourth cycle, the concentration of H 2 O 2 in exhaled breath condensate was measured with respect to treatment response., Results: At the baseline, NSCLC patients exhaled 3.8 times more H 2 O 2 than the control group (0.49 ± 0.14 vs. 0.13 ± 0.03 µmol/L, P < 0.05); this difference persisted throughout the study. CHT had no noticeable effect on exhaled H 2 O 2 levels independent of the treatment response (partial remission vs. progressive disease). Pre- and post-CHT cycles of H 2 O 2 levels generally correlated positively., Discussion: The study demonstrated the occurrence of oxidative stress in the airways of advanced NSCLC patients. Exhaled H 2 O 2 level was not affected by CHT and independent of treatment results and changes in the number of circulating neutrophils.

Background and Purpose: To study the impact of coronal and sagittal views (CSV) on the gross tumor volume (GTV) delineation on CT and matched PET/CT scans in non-small cell lung cancer., Material and Methods: GTV delineations were performed by 11 experienced radiation oncologists on CT and PET/CT in 22 patients. Two tumor groups were defined: Group I: Primary tumors surrounded by lung or visceral pleura, without venous invasion, and without large extensions to the chest wall or the mediastinum. Group II: Tumors invading the hilar region, heart, large vessels, pericardium, and the mediastinum and/or associated with atelectasis. Tumor volumes and inter-observers variations (SD) were calculated and compared according to the use of axial view only (AW), axial/coronal/sagittal views (ACSW) and ACSW/PET (ACSWP)., Results: CSV were not frequently used (57.4% out of 242 delineations on CT). For group I, ACSW didn't improve significantly mean GTVs. SDs were small on CT and on PET (SD=0.3cm). For group II, ACSW had 27-46% smaller observer variation (mean SD=0.7cm) than AW (mean SD=1.1cm). The smaller observer variation of ACSW users was associated with, on average, a 40% smaller delineated volume (p=0.038). Mean GTV of ACSWP was 21% larger than mean GTV of ACSW on CT., Conclusions: For smaller lung tumors surrounded by healthy lung tissue the effect of multiple axis delineation is limited. However, application of coronal and sagittal windows is highly beneficial for delineation of more complex tumors, with atelectasis and/or pathological lymph nodes even if PET is used., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objective: Strawberries can improve oxidants-antioxidants balance and reduce some cardiovascular risk factors in obese subjects. Paraoxonase-1 (PON-1) is a high-density lipoprotein-associated enzyme with antioxidant properties that can protect from coronary artery disease in humans. We examined the effect of strawberry consumption on plasma PON-1 activity and lipid profile in healthy nonobese subjects., Methods: Thirty-one subjects (body mass index [BMI] 24.4 ± 4.0 kg/m(2)) on their usual diet consumed 500 g of strawberry pulp daily for 30 days (first course) and after a 10-day washout the cycle was repeated (second course). Fasting blood and spot morning urine samples were collected before, during, and after each strawberry course (8 time points) for determination of paraoxonase and arylesterase PON-1 activities and lipid profile. Twenty subjects served as controls with respect to cholesterol and PON-1 activities changes over the study period., Results: Strawberries decreased mean plasma paraoxonase PON-1 activity and this effect was more evident after the second course (by 11.6%, p < 0.05) than after the first course (5.4%, p = 0.06), whereas arylesterase activity was constant. Strawberries altered total cholesterol levels (p < 0.05) with a tendency to transiently decrease it (by 5.1%) only after 15 days of the first course. Triglycerides and high- and low-density lipoprotein cholesterol did not change in response to fruit consumption. No changes in PON-1 activities and lipid profile were noted in controls. Paraoxonase correlated with arylesterase activity (ƿ from 0.33 to 0.46 at the first 7 time points, p < 0.05). This association disappeared at the end of study (ƿ = 0.07) when the strongest inhibition of paraoxonase was noted., Conclusions: Supplementation of the usual diet with strawberries decreased paraoxonase PON-1 activity and did not improve lipid profiles in healthy nonobese subjects. Further studies are necessary to establish the clinical significance of paraoxonase suppression and to define a group of healthy subjects who can benefit from strawberry consumption with respect to cholesterol levels.

HERV-W is a multi-locus family of human endogenous retroviruses (HERVs) that has been found to play an important role in human physiology and pathology. Two particular members of HERV-W family are of special interests: ERVWE1 (coding syncytin-1, which is a glycoprotein essential in the formation of the placenta) and MSRV (multiple sclerosis-associated retrovirus that is thought to play a significant role in human pathology as a result of its increased expression in the brain tissue and blood cells derived from patients with multiple sclerosis (MS)). Both ERVWE1 and MSRV mRNA share high level of similarity and hence a method that allows to exclusively quantify the MSRV expression in clinical samples would be desirable. We developed a quantitative polymerase chain reaction (QPCR) technique for the detection and quantification of the multiple sclerosis-associated retrovirus. The assay utilises fluorescently labelled oligonucleotide probe, which is complementary to the conservative fragment of MSRV env gene and a peptide nucleic acid (PNA) probe, fully complementary to the ERVWE1 sequence fragment that efficiently blocks the polymerase action on ERVWE1 templates. The PNA molecule, if used parallel with hydrolysis probe in QPCR analysis, greatly facilitates the detection efficiency of MSRV even if ERVWE1 is present abundantly in respect to MSRV in the analysed sample. We achieved a wide and measurable range from 1 × 10 e(2) to 1 × 10 e(8) copies/reaction; the linearity of the technique was maintained even at the low MSRV level of 1% in respect to ERVWE1. Using our newly developed method we confirmed that the expression of MSRV takes place in normal human astrocytes and in human umbilical vein endothelial cells in vitro. We also found that the stimulation of human monocytes did not influence the specific expression of MSRV but it caused changes in mRNA level of distinct HERV-W templates.

Context: Polymorphonuclear leukocytes (PMNs) produce oxidants, contributing to systemic oxidative stress. Diets rich in plant polyphenols seem to decrease the risk of oxidative stress-induced disorders including cardiovascular disease., Objective: The objective of this study was to examine the in vitro effect of each of the 14 polyphenols on PMNs chemotaxis, intracellular calcium response, oxidants production., Materials and Methods: Blood samples and PMNs suspensions were obtained from 60 healthy non-smoking donors and incubated with a selected polyphenol (0.5-10 µM) or a control solvent. We assessed resting and fMLP-dependent changes of intracellular calcium concentration ([Ca(2+)]i) in PMNs with the Fura-2AM method and measured fMLP-induced luminol enhanced whole blood chemiluminescence (fMLP-LBCL). Polyphenol chemoattractant activity for PMNs was tested with Boyden chambers., Results: Polyphenols had no effect on resting [Ca(2+)]i. Unaffected by other compounds, fMLP-dependent increase of [Ca(2+)]i was inhibited by quercetin and catechol (5 µM) by 32 ± 14 and 12 ± 10% (p < 0.04), respectively. Seven of the 14 tested substances (5 µM) influenced fMLP-LBCL by decreasing it. Catechol, quercetin, and gallic acid acted most potently reducing fMLP-LBCL by 49 ± 5, 42 ± 15, and 28 ± 18% (p < 0.05), respectively. 3,4-Dihydroxyhydrocinnamic, 3,4-dihydroxyphenylacetic, 4-hydroxybenzoic acid, and catechin (5 µM) revealed distinct (p < 0.02) chemoattractant activity with a chemotactic index of 1.9 ± 0.8, 1.8 ± 0.7, 1.6 ± 0.6, 1.4 ± 0.2, respectively., Conclusion and Discussion: Catechol, quercetin, and gallic acid at concentrations commensurate in human plasma strongly suppressed the oxidative response of PMNs. Regarding quercetin and catechol, this could result from an inhibition of [Ca(2+)]i response.

Purpose: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival., Methods and Materials: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for ≤3 months, ≥2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis., Results: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively., Conclusions: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To determine local control, late toxicity and metastatic free survival (MFS) of patients treated with fractionated stereotactic radiation therapy (fSRT) for uveal melanoma (UM)., Methods and Materials: Between 1999 and 2007, 102 UM patients were included in a prospective study of a single institution (median follow-up (FU) 32 months; median tumor thickness 6 mm); five fractions of 10 Gy were given. Primary endpoints were local tumor control and late toxicity (including visual outcome and eye preservation). Secondary endpoint was MFS., Results: Local tumor control was achieved in 96% of the patients. Fifteen enucleations were performed, 2-85 months after radiation. Four eyes were enucleated because of local tumor progression. Nine patients developed grade 3 or 4 neovascular glaucoma (NVG), 19 developed severe retinopathy, 13 developed opticoneuropathy grade 3 or 4, 10 developed cataract grade 3, and 10 patients suffered from keratitis sicca. Best corrected visual acuity (BCVA) decreased from a mean of 0.26 at diagnosis to 0.16, 3 months after radiation and it gradually declined to 0.03, 4 years after therapy. The 5-year actuarial MFS was 75% (95% CIs: 62-84%)., Conclusions: fSRT is an effective treatment modality for uveal melanoma with a good local control. With that, fSRT is a serious eye sparing treatment modality. However, our FU is relatively short. Also, the number of secondary enucleations is substantial, mainly caused by NVG., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare pathology macroscopic tumor dimensions with magnetic resonance imaging (MRI) measurements and to establish the microscopic tumor extension of colorectal liver metastases., Methods and Materials: In a prospective pilot study we included patients with colorectal liver metastases planned for surgery and eligible for MRI. A liver MRI was performed within 48 hours before surgery. Directly after surgery, an MRI of the specimen was acquired to measure the degree of tumor shrinkage. The specimen was fixed in formalin for 48 hours, and another MRI was performed to assess the specimen/tumor shrinkage. All MRI sequences were imported into our radiotherapy treatment planning system, where the tumor and the specimen were delineated. For the macroscopic pathology analyses, photographs of the sliced specimens were used to delineate and reconstruct the tumor and the specimen volumes. Microscopic pathology analyses were conducted to assess the infiltration depth of tumor cell nests., Results: Between February 2009 and January 2010 we included 13 patients for analysis with 21 colorectal liver metastases. Specimen and tumor shrinkage after resection and fixation was negligible. The best tumor volume correlations between MRI and pathology were found for T1-weighted (w) echo gradient sequence (r(s) = 0.99, slope = 1.06), and the T2-w fast spin echo (FSE) single-shot sequence (r(s) = 0.99, slope = 1.08), followed by the T2-w FSE fat saturation sequence (r(s) = 0.99, slope = 1.23), and the T1-w gadolinium-enhanced sequence (r(s) = 0.98, slope = 1.24). We observed 39 tumor cell nests beyond the tumor border in 12 metastases. Microscopic extension was found between 0.2 and 10 mm from the main tumor, with 90% of the cases within 6 mm., Conclusions: MRI tumor dimensions showed a good agreement with the macroscopic pathology suggesting that MRI can be used for accurate tumor delineation. However, microscopic extensions found beyond the tumor border indicate that caution is needed in selecting appropriate tumor margins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To develop a delineation tool that refines physician-drawn contours of the gross tumor volume (GTV) in nasopharynx cancer, using combined pixel value information from x-ray computed tomography (CT) and magnetic resonance imaging (MRI) during delineation., Methods: Operator-guided delineation assisted by a so-called "snake" algorithm was applied on weighted CT-MRI registered images. The physician delineates a rough tumor contour that is continuously adjusted by the snake algorithm using the underlying image characteristics. The algorithm was evaluated on five nasopharyngeal cancer patients. Different linear weightings CT and MRI were tested as input for the snake algorithm and compared according to contrast and tumor to noise ratio (TNR). The semi-automatic delineation was compared with manual contouring by seven experienced radiation oncologists., Results: A good compromise for TNR and contrast was obtained by weighing CT twice as strong as MRI. The new algorithm did not notably reduce interobserver variability, it did however, reduce the average delineation time by 6 min per case., Conclusions: The authors developed a user-driven tool for delineation and correction based a snake algorithm and registered weighted CT image and MRI. The algorithm adds morphological information from CT during the delineation on MRI and accelerates the delineation task.

The aim of the present study is to determine and compare initial treatment costs of microsurgery, linear accelerator (LINAC) radiosurgery, and gamma knife radiosurgery in meningioma patients. Additionally, the follow-up costs in the first year after initial treatment were assessed. Cost analyses were performed at two neurosurgical departments in The Netherlands from the healthcare providers' perspective. A total of 59 patients were included, of whom 18 underwent microsurgery, 15 underwent LINAC radiosurgery, and 26 underwent gamma knife radiosurgery. A standardized microcosting methodology was employed to ensure that the identified cost differences would reflect only actual cost differences. Initial treatment costs, using equipment costs per fraction, were 12,288 for microsurgery, 1,547 for LINAC radiosurgery, and 2,412 for gamma knife radiosurgery. Higher initial treatment costs for microsurgery were predominantly due to inpatient stay (5,321) and indirect costs (4,350). LINAC and gamma knife radiosurgery were equally expensive when equipment was valued per treatment (2,198 and 2,412, respectively). Follow-up costs were slightly, but not significantly, higher for microsurgery compared with LINAC and gamma knife radiosurgery. Even though initial treatment costs were over five times higher for microsurgery compared with both radiosurgical treatments, our study gives indications that the relative cost difference may decrease when follow-up costs occurring during the first year after initial treatment are incorporated. This reinforces the need to consider follow-up costs after initial treatment when examining the relative costs of alternative treatments.

BACKGROUND/AIMS To report the outcome of primary radiotherapy in patients with progressive optic nerve sheath meningioma (ONSM). METHODS The clinical records of all patients were reviewed in a retrospective, observational, multicentre study. RESULTS Thirty-four consecutive patients were included. Twenty-six women and eight men received conventional or stereotactic fractionated radiotherapy, and were followed for a median 58 (range 51-156) months. Fourteen eyes (41%) showed improved visual acuity of at least two lines on the Snellen chart. In 17 (50%) eyes, the vision stabilised, while deterioration was noted in three eyes (9%). The visual outcome was not associated with age at the time of radiotherapy (p=0.83), sex (p=0.43), visual acuity at the time of presentation (p=0.22) or type of radiotherapy (p=0.35). Optic disc swelling was associated with improved visual acuity (p<0.01) and 4/11 patients with optic atrophy also showed improvement. Long-term complications were dry eyes in five patients, cataracts in three, and mild radiation retinopathy in four. CONCLUSION Primary radiotherapy for patients with ONSM is associated with long-term improvement of visual acuity and few adverse effects.

Purpose: To determine the variation in target delineation of nasopharyngeal carcinoma and the impact of measures to minimize this variation., Materials and Methods: For ten nasopharyngeal cancer patients, ten observers each delineated the Clinical Target Volume (CTV) and the CTV elective. After 3D analysis of the delineated volumes, a second delineation was performed. This implied improved delineation instructions, a combined delineation on CT and co-registered MRI, forced use of sagittal reconstructions, and an on-line anatomical atlas., Results: Both for the CTV and the CTV elective delineations, the 3D SD decreased from Phase 1 to Phase 2, from 4.4 to 3.3 mm for the CTV and from 5.9 to 4.9 mm for the elective. There was an increase agreement, where the observers intended to delineate the same structure, from 36 to 64 surface % (p = 0.003) for the CTV and from 17 to 59% (p = 0.004) for the elective. The largest variations were at the caudal border of the delineations but these were smaller when an observer utilized the sagittal window. Hence, the use of sagittal side windows was enforced in the second phase and resulted in a decreased standard deviation for this area from 7.7 to 3.3 mm (p = 0.001) for the CTV and 7.9 to 5.6 mm (p = 0.03) for the CTV elective., Discussion: Attempts to decrease the variation need to be tailored to the specific causes of the variation. Use of delineation instructions multimodality imaging, the use of sagittal windows and an on-line atlas result in a higher agreement on the intended target.

Purpose: To assess day-to-day differences between planned and delivered target volume (TV) and organ-at-risk (OAR) dose distributions in liver stereotactic body radiation therapy (SBRT), and to investigate the dosimetric impact of setup corrections., Methods and Materials: For 14 patients previously treated with SBRT, the planning CT scan and three treatment scans (one for each fraction) were included in this study. For each treatment scan, two dose distributions were calculated: one using the planned setup for the body frame (no correction), and one using the clinically applied (corrected) setup derived from measured tumor displacements. Per scan, the two dose distributions were mutually compared, and the clinically delivered distribution was compared with planning. Doses were recalculated in equivalent 2-Gy fraction doses. Statistical analysis was performed with the linear mixed model., Results: With setup corrections, the mean loss in TV coverage relative to planning was 1.7%, compared with 6.8% without corrections. For calculated equivalent uniform doses, these figures were 2.3% and 15.5%, respectively. As for the TV, mean deviations of delivered OAR doses from planning were small (between -0.4 and +0.3 Gy), but the spread was much larger for the OARs. In contrast to the TV, the mean impact of setup corrections on realized OAR doses was close to zero, with large positive and negative exceptions., Conclusions: Daily correction of the treatment setup is required to obtain adequate TV coverage. Because of day-to-day patient anatomy changes, large deviations in OAR doses from planning did occur. On average, setup corrections had no impact on these doses. Development of new procedures for image guidance and adaptive protocols is warranted.

Purpose: To find a dose-volume effect for inhomogeneous irradiated lacrimal glands., Methods and Materials: Between 1999 and 2006, 72 patients (42 men and 30 women) were treated with fractionated stereotactic radiotherapy in a prospective, nonrandomized clinical trial (median follow-up, 32 months). A total dose of 50 Gy was given on 5 consecutive days. The mean of all Schirmer test results obtained > or =6 months after treatment was correlated with the radiation dose delivered to the lacrimal gland. Also, the appearance of dry eye syndrome (DES) was related to the lacrimal gland dose distribution., Results: Of the 72 patients, 17 developed a late Schirmer value <10 mm; 9 patients developed DES. A statistically significant relationship was found between the received median dose in the lacrimal gland vs. reduced tear production (p = 0.000) and vs. the appearance of DES (p = 0.003), respectively. A median dose of 7 Gy/fraction to the lacrimal gland caused a 50% risk of low Schirmer results. A median dose of 10 Gy resulted in a 50% probability of DES., Conclusion: We found a clear dose-volume relationship for irradiated lacrimal glands with regard to reduced tear production and the appearance of DES.

Agricultural nonpoint source pollution remains a persistent environmental problem, despite the large amount of money that has been spent on its abatement. At local scales, agricultural best management practices (BMPs) have been shown to be effective at reducing nutrient and sediment inputs to surface waters. However, these effects have rarely been found to act in concert to produce measurable, broad-scale improvements in water quality. We investigated potential causes for this failure through an effort to develop recommendations for the use of riparian buffers in addressing nonpoint source pollution in Wisconsin. We used frequency distributions of phosphorus pollution at two spatial scales (watershed and field), along with typical stream phosphorus (P) concentration variability, to simulate benefit/cost curves for four approaches to geographically allocating conservation effort. The approaches differ in two ways: (1) whether effort is aggregated within certain watersheds or distributed without regard to watershed boundaries (dispersed), and (2) whether effort is targeted toward the most highly P-polluting fields or is distributed randomly with regard to field-scale P pollution levels. In realistic implementation scenarios, the aggregated and targeted approach most efficiently improves water quality. For example, with effort on only 10% of a model landscape, 26% of the total P load is retained and 25% of watersheds significantly improve. Our results indicate that agricultural conservation can be more efficient if it accounts for the uneven spatial distribution of potential pollution sources and the cumulative aspects of environmental benefits.

Purpose: Stereotactic body radiation therapy (SBRT) provides a high local control rate for primary and metastatic liver tumors. The aim of this study is to assess the impact of this treatment on the patient's quality of life. This is the first report of quality of life associated with liver SBRT., Methods and Materials: From October 2002 to March 2007, a total of 28 patients not suitable for other local treatments and with Karnofsky performance status of at least 80% were entered in a Phase I-II study of SBRT for liver tumors. Quality of life was a secondary end point. Two generic quality of life instruments were investigated, EuroQol-5D (EQ-5D) and EuroQoL-Visual Analogue Scale (EQ-5D VAS), in addition to a disease-specific questionnaire, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C-30). Points of measurement were directly before and 1, 3, and 6 months after treatment. Mean scores and SDs were calculated. Statistical analysis was performed using paired-samples t-test and Student t-test., Results: The calculated EQ-5D index, EQ-5D VAS and QLQ C-30 global health status showed that mean quality of life of the patient group was not significantly influenced by treatment with SBRT; if anything, a tendency toward improvement was found., Conclusions: Stereotactic body radiation therapy combines a high local control rate, by delivering a high dose per fraction, with no significant change in quality of life. Multicenter studies including larger numbers of patients are recommended and under development.

Purpose: To evaluate the image quality of retrospectively attenuation corrected Positron Emission Tomography (PET) scans used for gross tumor volume (GTV) delineation in lung cancer patients., Materials and Methods: Data of 13 lymph node positive lung cancer patients were acquired on separate CT and PET scanners under free breathing conditions (for radiotherapy planning). First we determined a protocol for CT/PET registration. Second, we compared the image quality of attenuation-corrected PET images using positron transmission images and CT images, in terms of signal-to-noise ratio (SNR) and lesion-to-background ratio (contrast)., Results: The largest differences between manual and automatic CT/PET registration were found in the anterior-posterior direction with a mean of 1.8 mm (SD 1.0 mm). Differences in rotations were always smaller than 1.0 degrees . The attenuation-corrected images using CT showed a larger SNR (mean 30%, SD 17%) and larger contrast (mean 14.0%, SD 8.5%) compared to attenuation-corrected images using positron transmission. For lymph nodes, the mean contrast was 16% (SD 6.4%) larger., Conclusions: This study demonstrated that attenuation correction based on CT provides a better image quality for GTV delineation than when using positron transmission for attenuation correction. Retrospective attenuation correction of PET scans based on registered CT is a good alternative for a dedicated PET/CT scanner if a free-breathing CT is available, e.g., for radiotherapy planning, and allows the use of CT with diagnostic quality for attenuation correction.

Purpose: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only., Methods and Materials: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called "Big Brother.", Results: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p<0.001) and mean number of corrections (25 vs. 39, p<0.001) were reduced in the second phase compared with the first phase., Conclusion: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion).

Background and Purpose: To evaluate the process of target volume delineation in lung cancer for optimization of imaging, delineation protocol and delineation software., Patients and Methods: Eleven radiation oncologists (observers) from five different institutions delineated the Gross Tumor Volume (GTV) including positive lymph nodes of 22 lung cancer patients (stages I-IIIB) on CT only. All radiation oncologist-computer interactions were recorded with a tool called 'Big Brother'. For each radiation oncologist and patient the following issues were analyzed: delineation time, number of delineated points and corrections, zoom levels, level and window (L/W) settings, CT slice changes, use of side windows (coronal and sagittal) and software button use., Results: The mean delineation time per GTV was 16 min (SD 10 min). The mean delineation time for lymph node positive patients was on average 3 min larger (P = 0.02) than for lymph node negative patients. Many corrections (55%) were due to L/W change (e.g. delineating in mediastinum L/W and then correcting in lung L/W). For the lymph node region, a relatively large number of corrections was found (3.7 corr/cm2), indicating that it was difficult to delineate lymph nodes. For the tumor-atelectasis region, a relative small number of corrections was found (1.0 corr/cm2), indicating that including or excluding atelectasis into the GTV was a clinical decision. Inappropriate use of L/W settings was frequently found (e.g. 46% of all delineated points in the tumor-lung region were delineated in mediastinum L/W settings). Despite a large observer variation in cranial and caudal direction of 0.72 cm (1 SD), the coronal and sagittal side windows were not used in 45 and 60% of the cases, respectively. For the more difficult cases, observer variation was smaller when the coronal and sagittal side windows were used., Conclusions: With the 'Big Brother' tool a method was developed to trace the delineation process. The differences between observers concerning the delineation style were large. This study led to recommendations on how to improve delineation accuracy by adapting the delineation protocol (guidelines for L/W use) and delineation software (double window with lung and mediastinum L/W settings at the same time, enforced use of coronal and sagittal views) and including FDG-PET information (lymph nodes and atelectasis).

Background: Aggressive fibromatosis (AF) is a soft tissue tumor and is rare in childhood, with high potential for local invasiveness and recurrence. General recommendations for the clinical management of pediatric patients with AF remain undetermined., Methods: The authors retrospectively analyzed 13 children with AF who were diagnosed from 1987 until 2004 in the Erasmus MC-Sophia Children's Hospital, and a review of the pediatric literature was conducted., Results: Two patients received preoperative chemotherapy with combined vincristine, actinomycin-D, and cyclophosphamide (VAC). All 13 patients underwent surgery. Three of six patients who underwent incomplete resection received adjuvant treatment, two patients received radiotherapy, and one patient received chemotherapy (VAC). The median follow-up was 3.9 years (range, 0.6-14.0 years). Three patients developed recurrent AF, including two recurrences after patients underwent incomplete resection without adjuvant treatment. Secondary resection was performed, which was incomplete in one patient who subsequently received chemotherapy (VAC). At the time of the current report, all 13 patients were in complete remission. Ten pediatric AF studies, including the current study, with a total of 187 patients were reviewed. Incomplete resection was the most important determinant for disease recurrence; in the authors' opinion, the role of adjuvant therapy needs to be studied further., Conclusions: Primary surgery with negative surgical margins was found to be the most successful primary treatment modality for children with AF. Positive margins after surgery indicated a high risk for disease recurrence. Multicenter, prospective (randomized) trials will be necessary to clarify the role of adjuvant treatment for patients with pediatric AF.

Purpose: To study the effectiveness and acute side effects of fractionated stereotactic radiation therapy (fSRT) for uveal melanoma., Methods and Materials: Between 1999 and 2003, 38 patients (21 male, 17 female) were included in a prospective, nonrandomized clinical trial (mean follow-up of 25 months). A total dose of 50 Gy was given in 5 consecutive days. A blinking light and a camera (to monitor the position of the diseased eye) were fixed to a noninvasive relocatable stereotactic frame. Primary end points were local control, best corrected visual acuity, and toxicity at 3, 6, 12, and 24 months, respectively., Results: After 3 months (38 patients), the local control was 100%; after 12 months (32 patients) and 24 months (15 patients), no recurrences were seen. The best corrected visual acuity declined from a mean of 0.21 at diagnosis to 0.06 2 years after therapy. The acute side effects after 3 months were as follows: conjunctival symptoms (10), loss of lashes or hair (6), visual symptoms (5), fatigue (5), dry eye (1), cataract (1), and pain (4). One eye was enucleated at 2 months after fSRT., Conclusions: Preliminary results demonstrate that fSRT is an effective and safe treatment modality for uveal melanoma with an excellent local control and mild acute side effects. The follow-up should be prolonged to study both long-term local control and late toxicity.

Purpose: We used four-dimensional multislice spiral computed tomography (MSCT) to determine respiratory lung-tumor motion and compared this strategy to common clinical practice in conformal radiotherapy treatment-planning imaging., Methods and Materials: The entire lung volume of 10 consecutive patients with 14 lung metastases were scanned by a 16-slice MSCT. During the scans, patients were instructed to breathe through a spirometer that was connected to a laptop computer. For each patient, 10 stacks of 1.5-mm slices, equally distributed throughout the respiratory cycle, were reconstructed from the acquired MSCT data. The lung tumors were manually contoured in each data set. For each patient, the tumor-volume contours of all data sets were copied to 1 data set, which allowed determination of the volume that encompassed all 10 lung-tumor positions (i.e., the tumor-traversed volume [TTV]) during the respiratory cycle. The TTV was compared with the 10 tumor volumes contoured for each patient, to which an empiric respiratory-motion margin was added. The latter target volumes were designated internal-motion included tumor volume (IMITV)., Results: The TTV measurements were significantly smaller than the reference IMITV measurements (5.2 +/- 10.2 cm(3) and 10.1 +/- 13.7 cm(3), respectively). All 10 IMITVs for 2 of the 4 tumors in 1 subject completely encompassed the TTV. All 10 IMITVs for 3 tumors in 2 patients did not show overlap with up to 35% of the corresponding TTV. The 10 IMITVs for the remaining tumors either completely encompassed the corresponding TTV or did not show overlap with up to 26% of the corresponding TTV., Conclusions: We found that individualized determination of respiratory lung-tumor motion by four-dimensional respiratory-gated MSCT represents a better and simple strategy to incorporate periodic physiologic motion compared with a generalized approach. The former strategy can, therefore, improve common and state-of-the-art clinical practice in conformal radiotherapy.

Purpose: The prostate is known to translate and rotate under influence of rectal filling changes and many studies have addressed the magnitude of these motions. However, prostate shape variations also have been reported. For image-guided radiotherapy, it is essential to know the relative magnitude of translations, rotations, and shape variation so that the most appropriate correction strategy can be chosen. However, no quantitative analysis of shape variation has been performed. It is, therefore, the purpose of this article to develop a method to determine shape variation of complex organs and apply it to determine shape variation during external beam radiotherapy of a GTV (gross tumor volume) consisting of prostate and seminal vesicles., Methods and Materials: For this study, the data of 19 patients with prostate cancer were used. Each patient received a planning computed tomography (CT) scan and 8-12 (11 on average) repeat CT scans that were made during the course of conformal radiotherapy. One observer delineated the GTV in all scans, and volume variations were measured. After matching the GTVs for each patient for translation and rotation, a coverage probability matrix was constructed and the 50% isosurface was taken to determine the average GTV surface. Perpendicular distances between the average GTV and the individual GTVs were calculated for each point of the average GTV, and their variation was expressed in terms of local standard deviation (SD). The local SDs of the shape variation of all 19 patients were mapped onto a reference case by matching and morphing of the individual average GTVs. Repeated delineation of the GTV was done for 6 patients to determine intraobserver variation. Finally, the measured shape variation was corrected for intraobserver variation to estimate the "real" shape variation., Results: No significant variations in GTV volume were observed. The measured shape variation (including delineation variation) was largest at the tip of the vesicles (SD = 2.0 mm), smallest at the left and right side of the prostate (SD = 1.0 mm), and average elsewhere (SD = 1.5 mm). At the left, right, and cranial sides of the prostate, the intraobserver variation was of the same order of magnitude as the measured shape variation; elsewhere it was smaller. However, the accuracy of the estimated SD for intraobserver variation was about half of the accuracy of the estimated SD for the measured shape variation, giving an overall uncertainty of maximum 0.6 mm SD in the estimate of the "real" shape variation. The "real" shape variation was small at the left, right, and cranial side of the prostate (SD <0.5 mm) and between 0.5 mm and 1.6 mm elsewhere., Conclusions: We developed a method to quantify shape variation of organs with a complex shape and applied it to a GTV consisting of prostate and seminal vesicles. Deformation of prostate and seminal vesicles during the course of radiotherapy is small (relative to organ motion). Therefore, it is a valid approximation in image-guided radiotherapy of prostate cancer, in first order, to correct only for setup errors and organ motion. Prostate and seminal vesicles deformation can be considered as a second-order effect.

Purpose: To evaluate the impact of different tabletops with or without a knee support on the position of the rectum, prostate, and bulb of the penis; and to evaluate the effect of these patient-positioning devices on treatment planning., Methods and Materials: For 10 male volunteers, five MRI scans were made in four different positions: on a flat tabletop with knee support, on a flat tabletop without knee support, on a rounded tabletop with knee support, and on a rounded tabletop without knee support. The fifth scan was in the same position as the first. With image registration, the position differences of the rectum, prostate, and bulb of the penis were measured at several points in a sagittal plane through the central axis of the prostate. A planning target volume was generated from the delineated prostates with a margin of 10 mm in three dimensions. A three-field treatment plan with a prescribed dose of 78 Gy to the International Commission on Radiation Units and Measurements point was automatically generated from each planning target volume. Dose-volume histograms were calculated for all rectal walls., Results: The shape of the tabletop did not affect the rectum and prostate position. Addition of a knee support shifted the anterior and posterior rectal walls dorsally. For the anterior rectal wall, the maximum dorsal shift was 9.9 mm (standard error of the mean [SEM] 1.7 mm) at the top of the prostate. For the posterior rectal wall, the maximum dorsal shift was 10.2 mm (SEM 1.5 mm) at the middle of the prostate. Therefore, the rectal filling was pushed caudally when a knee support was added. The knee support caused a rotation of the prostate around the left-right axis at the apex (i.e., a dorsal rotation) by 5.6 degrees (SEM 0.8 degrees ) and shifts in the caudal and dorsal directions of 2.6 mm (SEM 0.4 cm) and 1.4 mm (SEM 0.6 mm), respectively. The position of the bulb of the penis was not influenced by the use of a knee support or rounded tabletop. The volume of the rectal wall receiving the same dose range (e.g., 40-75 Gy) was reduced by 3.5% (SEM 0.9%) when a knee support was added. No significant differences were observed between the first and fifth scan (flat tabletop with knee support) for all measured points, thereby excluding time trends., Conclusions: The rectum and prostate were significantly shifted dorsally by the use of a knee support. The rectum shifted more than the prostate, resulting in a dose benefit compared with irradiation without knee support. The shape of the tabletop did not influence the rectum or prostate position.

Stereotactic arc treatment of small intracranial tumors is usually performed with arcs collimated by circular cones, resulting in treatment volumes which are basically spherical. For nonspherical lesions this results in a suboptimal dose distribution. Multiple isocenters may improve the dose conformity for these lesions, at the cost of large overdosages in the target volume. To achieve improved dose conformity as well as dose homogeneity, the linac jaws (with a minimum distance of 1.0 cm to the central beam axis) can routinely be used to block part of the circular beams. The purpose of this study was to investigate the feasibility of blocking cones with diameters as small as 1.0 cm and a minimum distance between the jaw and the central beam axis of 0.3 cm. First, the reproducibility in jaw positioning and resulting dose delivery on the treatment unit were assessed. Second, the accuracy of the TPS dose calculation for these small fields was established. Finally, clinically applied treatment plans using nonblocked cones were compared with plans using the partially blocked cones for several treatment sites. The reproducibility in dose delivery on our Varian Clinac 2300 C/D machines on the central beam axis is 0.8% (1 SD). The accuracy of the treatment planning system dose calculation algorithm is critically dependent on the used fits for the penumbra and the phantom scatter. The average deviation of calculated from measured dose on the central beam axis is -1.0%+/-1.4% (1 SD), which is clinically acceptable. Partial cone blocking results in improved dose distributions for elongated tumors, such as vestibular schwannoma and uveal melanoma. Multiple isocenters may be avoided. The technique is easy to implement and requires no additional workload.

Purpose: High-precision external beam radiotherapy (EBRT) has been suggested as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis. The purpose of our study was to investigate and compare different options to define a smallest feasible target volume., Methods and Materials: The cardiac motion of 17 coronary artery stents in 17 patients was studied by use of biplane conventional angiography, recorded during breath-hold. Each stent was reconstructed in three dimensions by use of biplane sets of frames covering an entire cardiac cycle. The volume traversed by the stent during the entire or part of the cardiac cycle was determined. Four options to define the stent-traversed volume (STV) as a target for high-precision EBRT were investigated., Results: The mean STV during the entire cardiac cycle was 3.5 cm3; the STV represented less than 1% of the heart volume in all patients. The STV during the diastolic and systolic phase resulted in a mean reduction of 26.6% and 29.1%, respectively, compared with the STV during the entire cardiac cycle. The smallest STV, measured during a 160-ms interval within the cardiac cycle, resulted in a mean maximal reduction of 75.9% compared with the STV during the entire cardiac cycle., Conclusions: The STV during the entire cardiac cycle represents a small potential target volume for high-precision EBRT. A significant reduction of this target volume is possible in case of definition during a selected interval within the cardiac cycle.

Purpose: To describe a reliable, patient-friendly relocatable stereotactic frame for irradiation of eye melanoma and to evaluate the repositioning accuracy of the stereotactic treatment., Methods and Materials: An extra construction with a blinking light and a camera is attached to a noninvasive relocatable Gill-Thomas-Cosman stereotactic frame. The position of the blinking light is in front of the unaffected eye and can be adjusted to achieve an optimal position for irradiation. The position of the diseased eye is monitored with a small camera. A planning CT scan is performed with the affected eye in treatment position and is matched with an MR scan to improve the accuracy of the delineation of the tumor. Both the translation and rotation of the affected eye are calculated by comparing the planning CT scan with a control CT scan, performed after the radiation therapy is completed., Results: Nineteen irradiated eye melanoma patients were analyzed. All patients received 5 fractions of 10 Gy within 5 days. The depth-confirmation helmet measurements of the day-to-day treatment position of the skull within the Gill-Thomas-Cosman frame were analyzed in the anteroposterior, lateral, and vertical directions and were 0.1 +/- 0.3, 0.0 +/- 0.2, and 0.2 +/- 0.2 mm (mean +/- SD), respectively. The average translations of the eye on the planning and control CT scan were 0.1 +/- 0.3 mm, 0.1 +/- 0.4, and 0.1 +/- 0.5 mm, respectively. The median rotation of the diseased eye was 8.3 degrees., Conclusions: The described Rotterdam eye fixation system turned out to be a feasible, reliable, and patient-friendly system.

Purpose: The prostate volume delineated on MRI is smaller than on CT. The purpose of this study was to determine the influence of MRI- vs. CT-based prostate delineation using multiple observers on the dose to the target and organs at risk during external beam radiotherapy., Materials and Methods: CT and MRI scans of the pelvic region were made of 18 patients and matched three-dimensionally on the bony anatomy. Three observers delineated the prostate using both modalities. A fourth observer delineated the rectal wall and the bulb of the penis. The planning treatment volume (PTV) was generated from the delineated prostates with a margin of 10 mm in three-dimensions. A three-field treatment plan with a prescribed dose of 78 Gy to the International Commission on Radiation Units and Measurements point was automatically generated from each PTV. Dose-volume histograms were calculated of all PTVs, rectal walls, and penile bulbs. The equivalent uniform dose was calculated for the rectal wall using a volume exponent (n = 0.12)., Results: The equivalent uniform dose of the CT rectal wall in plans based on the CT-delineated prostate was, on average, 5.1 Gy (SEM 0.5) greater than in the plans based on the MRI-delineated prostate. For the MRI rectal wall, this difference was 3.6 Gy (SEM 0.4). Allowing for the same equivalent uniform dose to the CT rectal wall, the prescribed dose to the PTV could be raised from 78 to 85 Gy when using the MRI-delineated prostate for treatment planning. The mean dose to the bulb of the penis was 11.6 Gy (SEM 1.8) lower for plans based on the MRI-delineated prostate. The mean coverage (volume of the PTV receiving > or =95% of the prescribed dose) was 99.9% for both modalities. The interobserver coverage (coverage of the PTV by a treatment plan designed for the PTV delineated by another observer in the same modality) was 97% for both modalities. The MRI rectum was significantly more ventrally localized than the CT rectum, probably because of the rounded tabletop and no knee support on the MRI scanner., Conclusions: The dose delivered to the rectal wall and bulb of the penis is significantly reduced with treatment plans based on the MRI-delineated prostate compared with the CT-delineated prostate, allowing a dose escalation of 2.0-7.0 Gy for the same rectal wall dose. The interobserver coverage was the same for CT and MRI delineation of the prostate. A statistically significant difference in position between the CT- and MRI-delineated rectum was observed, probably owing to a different tabletop and use of knee support.

Purpose: Prevention of damage to critical normal tissues is of paramount importance for the quality of life of patients irradiated for cancers in the head and neck. The purpose of this paper was to evaluate the parotid gland sparing 3D conformal radiation therapy technique (3DCRT) in a prospective study in node negative cancer of the larynx., Materials and Methods: Twenty-six patients with node negative squamous cell cancer of the larynx were irradiated by a 3DCRT technique (class solution) to both sides of the neck (elective dose 46 Gy to levels II, III and IV) and primary tumour (70 Gy). Dose distributions of the major salivary glands were correlated with objective (stimulated whole saliva flow, WS) and subjective (questionnaire; visual analogue scale, VAS) salivary gland function. Apart from the clinically used 3DCRT technique, in order to optimise 3DCRT dose distributions, intensity modulated (IMRT) treatment plans were generated for the same patient population. Dose-volume histograms of 3DCRT and IMRT treatment plans were analysed and compared., Results: For the 26 patients irradiated with the 3DCRT class solution technique: VAS scores and questionnaires reached their nadir 3 months post-radiotherapy; WS reached its nadir 6 months post-radiotherapy. WS flow rates improved significantly, but never normalised; 2 years post-treatment WS measurements were 48% of the pre-treatment values. VAS scores deteriorated during ERT from 0 pre-treatment to 6.1 immediately post-treatment. Compared to pre-treatment, questionnaires were answered affirmative by increasing numbers of patients. For all patients, IMRT treatment plans resulted in a significant reduction of the dose delivered to the parotid glands compared to the 3DCRT-treatment technique., Conclusions: The class solution for the 3DCRT salivary gland sparing technique is inadequate for fully preserving salivary gland function, given the dose distributions (DVHs) as well as the subjective- and objective salivary gland function assessments. The results can be optimised in the future, that is a further reduction of xerostomia can be achieved, by using IMRT techniques focused at sparing major and minor salivary glands.

Purpose: Several drawbacks of endovascular brachytherapy for the treatment of coronary artery in-stent restenosis may be addressed by high-precision external beam radiotherapy (EBRT). The dosimetric characteristics of both treatment techniques were compared., Methods and Materials: The traversed volume of 10 coronary artery stents during the cardiac cycle was determined by electrocardiographically gated multislice spiral CT in 10 patients. By use of this traversed volume, high-precision EBRT treatment plans were generated for stents in the left circumflex (LCx), left anterior descending (LAD), and right coronary artery (RCA). The maximum dose to the nontargeted major coronary arteries was determined and compared to similar data calculated for endovascular brachytherapy., Results: High-precision EBRT targeted at LCx stents contributed a mean maximum dose (D(max)) of 83.5% (range: 71.6-95.3%) and 16.3% to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D(max) of 39.3% (range: 14.5-94.8%) and 5.2% (range: 0-13.4%) to the LCx and RCA, respectively. Targeted RCA stents contributed a mean D(max) of 6.2% (range: 0-12.4%) and 5.8% (range: 0-11.5%) to the LCx and LAD, respectively. Endovascular brachytherapy targeted at LCx stents contributed a mean D(max) of 1.7% (range: 0.7-2.7%) and 1.0% (range: 0.6-1.4%) to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D(max) of 5.2% (range: 0.5-11.4%) and 0.7% (range: 0.4-1.1%) to the LCx and RCA, respectively; targeted RCA stents contributed a mean D(max) of 0.3% (range: 0.2-0.5%) and 0.2% (range: 0.1-0.3%) to the LCx and LAD, respectively., Conclusions: Although the doses distributed throughout the heart were higher for high-precision EBRT compared to endovascular brachytherapy, they are expected to be clinically irrelevant when nontargeted major coronary arteries are not closely situated to the targeted vessel segment. These encouraging results warrant further investigation of high-precision EBRT as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis.

Pulmonary blastoma (PB) is a rare malignant tumor of the lung. Treatment is primarily surgical, although, combination chemotherapy has been reported to result in objective responses in inoperable tumors or after incomplete resections. To our knowledge, this is the first report of a very radiosensitive PB, which showed major tumor reduction after several fractions of radiotherapy without further tumor regression after additional chemotherapy with cisplatin and etoposide. The literature on the treatment of PB is reviewed.

Three-dimensional reconstructions of 19 coronary artery stents from biplane angiograms were used for measurement of the volume through which the stents traversed during the cardiac cycle. This volume, less than 0.8% of the whole heart volume in all patients, represents a target volume for high-precision radiotherapy to treat coronary artery in-stent restenosis.

Purpose: The aim of the study is to define the role and type of high-dose, high-precision radiation therapy for boosting early staged T1,2a, but in particular locally advanced, T2b-4, nasopharyngeal cancer (NPC)., Materials and Methods: Ninety-one patients with primary stage I-IVB NPC, were treated between 1991 and 2000 with 60-70Gy external beam radiation therapy (ERT) followed by 11-18Gy endocavitary brachytherapy (ECBT) boost. In 1996, for stage III-IVB disease, cisplatinum (CDDP)-based neoadjuvant chemotherapy (CHT) was introduced per protocol. Patients were analyzed for local control and overall survival. For a subset of 18 patients, a magnetic resonance imaging (MRI) scan at 46Gy was obtained. After matching with pre-treatment computed tomogram, patients (response) were graded into four categories; i.e. LD (T1,2a, with limited disease, i.e. disease confined to nasopharynx), LRD (T2b, with limited residual disease), ERD (T2b, with extensive residual disease), or patients initially diagnosed with T3,4 tumors. Dose distributions for ECBT (Plato-BPS v. 13.3, Nucletron) were compared to parallel-opposed three-dimensional conformal radiation therapy (Cadplan, Varian Dosetek v. 3.1), intensity modulated radiation therapy (IMRT) (Helios, Varian) and stereotactic radiotherapy (SRT) (X-plan, Radionics v. 2.02)., Results: For stage T1,2N0,1 tumors, at 2 years local control of 96% and overall survival of 80% were observed. For the poorest subset of patients, well/moderate/poorly differentiated T3,4 tumors, local control and overall survival at 2 years with CHT were 67 and 67%, respectively, vs. local control of 20% and overall survival of 12% without CHT. For LD and LRD, conformal target coverage and optimal sparing can be obtained with brachytherapy. For T2b-ERD and T3,4 tumors, these planning goals are better achieved with SRT and/or IMRT., Conclusions: The dosimetric findings, ease of application of the brachytherapy procedure, and the clinical results in early staged NPC, necessitates ERT combined with brachytherapy boost to be the therapy of preference for LD and LRD. For locally advanced T3,4 tumors, our current protocol indicates neoadjuvant chemotherapy in conjunction with high cumulative doses of radiotherapy (81Gy); IMRT and/or SRT to be the preferred technique for boosting the primary tumor.

Purpose: We previously reported our preliminary experience with nasopharyngeal cancer boosted after 60-70 Gy external beam radiotherapy (EBRT) by fractionated endocavitary brachytherapy (ECBT) to cumulative doses of 78-82 Gy. As for Stage III-IVB disease, cisplatin (CDDP)-based neoadjuvant chemotherapy (CHT) was given. The aim of the present study was to define the role of ECBT more accurately., Methods and Materials: Ninety-one patients with primary nasopharyngeal cancer, staged according to the 1997 UICC/AJCC classification system, were treated between 1991 and 2000 with 60-70 Gy external beam radiotherapy and 11-18 Gy ECBT. Of the 91 patients, 21 were treated in conjunction with CHT and 70 without CHT. Tumors were subdivided into undifferentiated (UD) and well, moderately, and poorly differentiated (WMP-D) subtypes. Treatment results were analyzed for local control (LC), disease-free survival (DFS), freedom from distant metastasis, and overall survival (OS)., Results: A univariate and multivariate Cox regression analysis found stage, treatment period, age, and grade significant for LC, DFS, and OS. At 2 years, for Stage I-IIB (1st period, 1991-1996), the LC, DFS, and OS were 96%, 88%, and 80%, respectively, vs. 65%, 46%, and 52% for Stage III-IVB. For the 2nd treatment period (1996-2000; CHT for Stage III-IVB), the LC, DFS, and OS at 2 years was 100%, 90%, and 61% (Stage I-IIB), respectively, vs. 86%, 74%, and 66% (Stage III-IVB). Three prognostic groups (PGs) were constructed. For the 1991-1996 period, at 2 years, patients in the good PG (UD Stage I-IIB disease) had 100% LC and 92% OS; those in the intermediate PG (UD Stage III-IVB or WMP-D Stage I-IIB), had 94% LC and 71% OS; and those in the poor PG (WMP-D Stage III-IVB) had 47% LC and 40% OS. For the 1996-2000 period, at 2 years, the good PG had 100% LC and 88% OS; the intermediate PG had 100% LC and 64% OS; and the poor PG had 71% LC and 60% OS., Conclusion: For Stage I-IIB disease treated between 1991 and 2000, at 3 years, the LC and OS was 97% and 67%, respectively. The results with 77-81 Gy without CHT warrant EBRT combined with ECBT to remain our standard of care for Stage I-IIB disease. For N2-3 and/or T3-4 tumors, in addition to high doses of RT, neoadjuvant CHT was administered as of 1996. For the 1991-2000 period, at 3 years, the LC was 86% and the OS was 72% with CHT, with little extra morbidity; they were 68% and 35% without CHT. Because of better target coverage and sparing, T3-4 tumors are currently boosted by stereotactic RT to 81.2 Gy.

Purpose: To measure the effect of cardiac motion on coronary artery stent position during the cardiac cycle as a first step toward exploring the feasibility of stereotactic external beam radiation therapy targeted at restenotic stented coronary arteries., Methods and Materials: The three-dimensional (3D) position of eight coronary artery stents in 8 patients immobilized in a stereotactic body frame was studied noninvasively by single-breathhold ECG-gated multislice spiral computed tomography (MSCT) during 10 retrospectively selected phases, equally distributed throughout the R-R interval of consecutive cardiac cycles. The volume encompassing all measured 3D positions of the stent was measured., Results: Stent volumes measured by MSCT closely agreed with measurements by quantitative coronary angiography (r > 0.99). The mean of the maximum 3D stent center of mass displacement between any two phases during the cardiac cycle for all eight coronary arteries was 7.5 mm (range 3.3-20.5 mm) in the lateral direction, 8.6 mm (range 2.7-21.6 mm) in the ventrodorsal direction, and 8.2 mm (range 2.5-19.7 mm) in the craniocaudal direction. As was anticipated, the volume encompassing all measured 3D positions of the stent represented only a fraction of the whole heart volume in all patients, i.e., less than 0.6%., Conclusions: ECG-gated MSCT allowed the measurement of the volume encompassing multiphase 3D positions of coronary artery stents during the cardiac cycle. This volume, a measure of the cardiac motion effect on coronary artery stent position during the cardiac cycle, represents a moving gross target for stereotactic external beam radiation therapy.

Meningioma was diagnosed in four women, aged 40, 24, 41 and almost 75 years, respectively. The first of these patients was treated with surgery, the second and third patients underwent surgery followed by conventional radiotherapy because of a tumour residue or dural tail, and the last patient was treated with stereotactic radiosurgery. They recovered well and were followed by means of regular outpatient check-ups. Twenty percent of all primary brain tumours are meningiomas, over 90% of which are benign. Nevertheless, a large hospital-based population study showed a 5-year survival rate of only 70%. Microsurgery is usually the treatment of first choice. However, in about 25% of cases, excision is incomplete and tumour growth almost always continues. Further surgery influences prognosis unfavourably. New sophisticated radiation techniques help to control tumour progression in about 80-90% of cases. This success, however, may be associated with new cranial nerve deficits or panhypopituitarism. Prospective, comparative studies are not available.

Purpose: Different methods have been described to define a target volume for the treatment of restenotic (stented) coronary arteries by external beam radiation therapy (EBRT). The purpose of this study was to explore two methods to define a target for such therapy, and to compare these with previously investigated methods., Materials and Methods: The 3-D position of a stent throughout the cardiac cycle in the three major epicardial coronary arteries was measured in three patients by single-breathhold multislice spiral CT and breathhold biplane conventional X-ray angiography, both indexed in time with the ECG. The volume through which the stent traversed (STV) during the cardiac cycle was determined by use of displacement measurements., Results: For multislice CT and biplane angiography, respectively, the mean STV was 1.23 cm(3) (range 0.65-2.22 cm(3)) and 2.81 cm(3) (range 1.60-4.99 cm(3)). The STV represented only a fraction of the whole heart volume in all patients, that is, equal to or less than 0.4%., Conclusions: Multislice CT and biplane angiography allowed the measurement of a relatively small potential target, that is the STV, for EBRT of restenotic stented coronary arteries. Both studied imaging modalities are instrumental for targeting the STV by highly conformal radiation therapy in case of restenotic stented coronary arteries.