Whole-pelvic irradiation with boost to involved nodes and prostate in node-positive prostate cancer-long-term data from the prospective PLATIN-2 trial.

PURPOSE: Node-positive prostate cancer is a potentially curable disease. Definitive radiotherapy to the prostate and lymphatic drainage is an effective treatment option but prospective long-term outcome data are scarce. Thus, the current study aimed to evaluate the toxicity and efficacy of definitive radiation therapy for men with prostate cancer and nodal metastases using modern irradiation techniques. METHODS: A total of 40 treatment-naïve men with node-positive prostate cancer were allocated to the trial. All patients received definitive radiation therapy at two German university hospitals between 2009 and 2018. Radiation was delivered as intensity-modulated radiation therapy (IMRT) with 51 Gy to the lymphatic drainage with simultaneous integrated boost (SIB) up to 61.2 Gy to involved nodes and 76.5 Gy to the prostate in 34 fractions. Feasibility and safety, overall and progression-free survival, toxicity, and quality of life measurements were analyzed. RESULTS: During a median follow-up of 79 months, median overall survival was 107 months and progression-free survival was 78 months. Based on imaging follow-up, no infield relapse was reported during the first 24 months of follow-up. There were 3 (8%) potentially treatment-related grade 3 toxicities. Common iliac node involvement was associated with a higher risk of progression (HR 15.8; 95% CI 2.1-119.8; p = 0.007). CONCLUSION: Definitive radiation to the lymphatic drainage with SIB to the involved nodes and prostate is a safe and effective treatment approach for patients with treatment-naïve, node-positive prostate cancer with excellent infield tumor control rates and tolerable toxicity. Location rather than number of involved nodes is a major risk factor for progression.

Primary immunosuppressive TNI-based conditioning regimens in pediatric patients treated with haploidentical hematopoietic cell transplantation.

PURPOSE: This retrospective analysis aims to address the toxicity and efficacy of a modified total nodal irradiation (TNI)-based conditioning regimen before haploidentical hematopoietic cell transplantation (HCT) in pediatric patients. MATERIALS AND METHODS: Patient data including long-term follow-up were evaluated of 7 pediatric patients with malignant (n = 2) and non-malignant diseases (n = 5) who were treated by a primary TNI-based conditioning regimen. TNI was performed using anterior/posterior opposing fields. All patients received 7 Gy single-dose TNI combined with systemic agents followed by an infusion of peripheral blood stem cells (n = 7). All children had haploidentical family donors. RESULTS: Engraftment was reached in 6/7 children after a median time of 9.5 days; 1 child had primary graft failure but was successfully reconditioned shortly thereafter. After an average follow-up time of 103.5 months (range 8.8-138.5 months), event-free (EFS) and overall survival (OS) rates were 71.4% and 85.7%, respectively. One child with a non-malignant disease died 8.8 months after transplantation due to a relapse and a multiple organ failure. Follow-up data was available for 5/6 long-term survivors with a median follow-up (FU) of 106.2 months (range 54.5-138.5 months). Hypothyroidism and deficiency of sexual hormones was present in 3/5 patients each. Mean forced expiratory volume in 1 s (FEV1) after TNI was 71%; mean vital capacity (VC) was 78%. Growth failure (< 10th percentile) occurred in 2/5 patients (height) and 1/5 patient (weight). No secondary malignancies were reported. CONCLUSION: In this group of patients, a primary single-dose 7 Gy TNI-based conditioning regimen before HCT in pediatric patients allowed sustained engraftment combined with a tolerable toxicity profile leading to long-term OS/EFS. Late toxicity after a median FU of over 9 years includes growth failure, manageable hormonal deficiencies, and acceptable decrease in lung function.

68Ga-PSMA-PET/CT-directed IGRT/SBRT for oligometastases of recurrent prostate cancer after initial surgery.

Background: We evaluated efficacy and toxicity of 68Ga-PSMA-Positron Emission Tomography/Computed Tomography (PET/CT)-directed stereotactic body radiotherapy and image-guided radiotherapy (SBRT/IGRT) for oligometastases of prostate cancer recurrences after previous surgery.Methods: Nineteen patients were analyzed within a prospective PET-registry study (064/2013BO1) and retrospectively analyzed (807/2017BO2) fulfilling the following inclusion criteria: biochemical recurrence after radical prostatectomy, ≤five 68Ga-PSMA-PET/CT positive lesions. Biochemical control was evaluated with EORTC (European Organization for Research and Treatment of Cancer)- and Phenix-definitions. Toxicity was scored according to CTCAE-criteria v. 4.03.Results: A total of 38 oligometastases (19 patients, 2 with re-treatment) were treated with SBRT/IGRT from October 2014 to July 2017. 68Ga-PSMA-PET/CT-positive lesions were detected on average 39 months (5-139) after prostatectomy (pT2b-3b pN0-1 cM0). Mean PSA (Prostate-specific antigen)-level at time of imaging reached 2.2 ng/mL (range 0.2-10.1). PET/CT-positive lesions were treated with different fractionation schedules reaching biological equivalent doses (BED) of 116.7-230.0 Gy. Concomitant androgen deprivation therapy (ADT) was given in seven patients. After a median follow-up of 17 months (4-42) all patients were alive. Estimated 1-year PSA- control (n = 19) reached 80.8% (Phenix) and 67.5% (EORTC). A PSA-decline (≥50%) was detected in 16/19 patients after radiotherapy. Higher graded G3+-acute toxicity did not occur. Temporary late G3-proctitis was detected in one patient.Conclusions: Reaching of nadir ≤0.1 or 0.2 ng/mL was associated by improved DMFS (distant metastases free survival) and could serve as a surrogate endpoint for RT of oligometastases after initial prostatectomy. Short term effects of 68Ga-PSMA-PET/CT-based ablative radiotherapy for oligometastases demonstrated an acceptable toxicity profile and favorable biochemical response.

Precision of T2 TSE MRI-CT-image fusions based on gold fiducials and repetitive T2 TSE MRI-MRI-fusions for adaptive IGRT of prostate cancer by using phantom and patient data.

INTRODUCTION: To increase precision of radiation treatment (RT) delivery in prostate cancer, MRI-based RT as well as the use of fiducials like gold markers (GMs) have shown promising results. Their combined use is currently under investigation in clinical trials. Here, we aimed to evaluate a workflow of image registration based on GMs between CT and MRI as well as weekly MRI-MRI adaption based on T2 TSE sequence. MATERIAL AND METHODS: A gel-phantom with two inserted GMs was scanned with CT and three different MR-scanners of 1.5 and 3 T (T2 TSE and T1 VIBE-Dixon, isotropic, voxel size 2 × 2 × 2 mm). After image fusion, deviations for fiducial and gel match were measured and artifacts were evaluated. Additionally, CT-MRI-match deviations and MRI-MRI-match deviations of 10 Patients from the M-basePro study using GMs were assessed. RESULTS: GMs were visible in all imaging modalities. The outer gel contours were matched with <1 mm deviation, contour volumes varied between 0 and 1%. The deviations of the GMs were less than 2 mm in any direction of MRI/CT. Shifts of peripherally or centrally located GMs were randomly distributed. The average MRI-CT-match precision of 10 patients with GMs was 1.9 mm (range 1.1-3.1 mm). CONCLUSIONS: Match inaccuracies for GMs between reference CT and voxel-isotropic T2-TSE sequences are small. Spatial deviations of CT- and MR-contoured fiducials were less than 2 mm, i.e., below SLT of the applied modalities. In patients, the average CT-MRI-match precision for GMs was 1.9 mm supporting their use in MR-guided high precision RT.

Activism on rifapentine pricing: removing cost barriers to improve the uptake of tuberculosis research innovations.

As recent advances have been made in developing tools to fight tuberculosis (TB), there is also a trend towards increasing advocacy by the civil society for TB research and access. One recent successful effort to increase access to treatment options for TB involved a collaborative effort to identify the need for and barriers to the use of rifapentine (RPT) use in the United States. Survey responses confirmed the under-utilization of RPT: 82% of survey respondents selected cost as a significant or potential barrier to use. Survey results provided data to support a year-long advocacy campaign urging the drug company Sanofi to lower the price of RPT. This campaign was based on a common evidence base built in part by the stakeholders themselves. After multiple engagements with communities and providers, Sanofi US announced on 12 December 2013 that they would drop the price of RPT to US$32 per blister pack of 32 tablets for US public health programs. While further work remains to secure access to RPT in the United States and worldwide, the lowering of the price of RPT reflects the positive impact that collaborative advocacy can accomplish, and sets an example for other drug companies to follow.

Comme de récents progrès ont été réalisés dans l'élaboration d'outils de lutte contre la tuberculose (TB), on note également une tendance de la société civile à s'impliquer davantage dans la recherche et l'accès au traitement. Une activité récente couronnée de succès, visant à accroitre l'accès aux différentes options thérapeutiques de la TB, a impliqué un effort d'identification des besoins de rifapentine (RPT) aux Etats-Unis et des obstacles à son utilisation. Les réponses à l'enquête ont confirmé la sous-utilisation de la RPT : 82% des répondants ont estimé que son coût était un obstacle significatif ou potentiel à son utilisation. Ces résultats ont constitué des données permettant de soutenir une campagne de plaidoyer d'une année exhortant le fabricant, Sanofi, à réduire le prix de la RPT. Cette campagne a été basée sur un ensemble de preuves rassemblées en partie par les partenaires eux-mêmes. Après de multiples consultations avec les communautés et les fournisseurs, le 12 décembre 2013, Sanofi Etats-Unis a annoncé qu'ils allaient diminuer le prix de la RPT à US$32 par blister de 32 comprimés destinés aux programmes de santé publique américains. Même s'il reste du travail à faire pour sécuriser l'accès à la RPT aux Etats-Unis et dans le monde, la réduction du prix de la RPT témoigne de l'impact positif que le plaidoyer collaboratif peut avoir et constitue un exemple que les autres sociétés fabricant des médicaments devraient suivre.

Con el progreso reciente de los recursos destinados a combatir la tuberculosis (TB), se observa además una evolución en favor de la promoción de la causa de la investigación en TB y del acceso a sus resultados por parte de la sociedad civil. Una intervención reciente eficaz, encaminada a aumentar el acceso a las opciones de tratamiento antituberculoso, comportó un esfuerzo conjunto encaminado a reconocer la necesidad del uso de la rifapentina (RPT) en los Estados Unidos y los factores que obstaculizan su utilización. Las respuestas a una encuesta confirmaron la subutilización de la RPT; el 82% de quienes respondieron refirió el costo como un obstáculo importante o posible a su uso. Los datos de la encuesta respaldaron la utilidad de una campaña de promoción de la causa de un año de duración que instaba a la empresa Sanofi a disminuir el precio de la RPT. Esta campaña se basó en una serie de indicios aportados en parte por los mismos interesados directos. Después de celebrar múltiples compromisos con las comunidades y los profesionales de salud, Sanofi US anunció el 12 de diciembre del 2013 que disminuiría el precio de la RPT a US$32 por cada blíster de 32 comprimidos para los programas de salud pública en los Estados Unidos. Aunque todavía se precisan nuevas iniciativas que garanticen el acceso a la RPT en los Estados Unidos y en el mundo, la disminución del precio de este medicamento destaca el efecto positivo que puede lograr una promoción colectiva de la causa y constituye un ejemplo que deberían seguir otras empresas farmacéuticas.

p-Medicine: From data sharing and integration via VPH models to personalized medicine.

The Worldwide innovative Networking in personalized cancer medicine (WIN) initiated by the Institute Gustave Roussy (France) and The University of Texas MD Anderson Cancer Center (USA) has dedicated its 3rd symposium (Paris, 6-8 July 2011) to discussion on gateways to increase the efficacy of cancer diagnostics and therapeutics (http://www.winconsortium.org/symposium.html).Speakers ranged from clinical oncologist to researchers, industrial partners, and tools developers; a famous patient was present: Janelle Hail, a 30-year breast cancer survivor, founder and CEO of the National Breast Cancer Foundation, Inc. (NBCF).The p-medicine consortium found this venue a perfect occasion to present a poster about its activities that are in accordance with the take home message of the symposium.In this communication, we summarize what we presented with particular attention to the interaction between the symposium's topic and content and our project.

[Connection between hyponatriemia and local herpes in an old lady?]. / Die Hyponatriämie der Frau L.

We report the case of a 84 year old patient who developed a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with severe hyponatremia in the context of a localized herpes zoster L1/2. This is a rare but known complication of localized varizella zoster infection. Under water restriction and salt administration the hyponatremia was corrected slowly. One month after hospital discharge the patient showed a normal sodium value without diet.

The influence of guiding equipment and stents on the beta dose distribution in the brachytherapy of in-stent restenosis.

BACKGROUND: Intracoronary devices such as stents or guide wires may disturb the dose distribution of beta sources in cardiovascular brachytherapy. As clinical observations indicate that underdosage increases the risk of restenosis, accurate measurements are mandatory to investigate these effects. METHODS AND RESULTS: Dose perturbation effects of different interventional equipment were systematically determined. Dose distributions of 90Sr-beta line sources were measured by means of a special set-up employing plastic scintillator dosimeters in a water phantom. Shielding effects were found to be 2-5% for single stents and 5-10% for graft stents, stent-in-stent geometries, and guiding catheters. Guide wires close to the source reduced the dose by 25-30%. CONCLUSIONS: Beta dose perturbation effects of typical stent types are almost negligible and can be corrected by an increased source dwell time if necessary. Guide wires produce effects which are clinically much more important and should therefore be retracted from the irradiation area.

Race and ethnicity and the identification of special needs children.

Increasingly, Medicaid and Title XXI Programs are using survey-based approaches to identify children with special health care needs (CSHCN) for quality assurance monitoring and program referrals. However, little work has been done examining how well instruments, like the Questionnaire for Identifying Children with Chronic Conditions and the CSHCN Screener, identify CSHCN among black and Hispanic families. Differences in item interpretation and in response styles could influence the identification of CSHCN from these groups. Our results suggest that children who are black or Hispanic with special health care needs may be underidentified relative to white or non-Hispanic children using currently available survey tools.

Directed evolution of a (beta alpha)8-barrel enzyme to catalyze related reactions in two different metabolic pathways.

Enzymes participating in different metabolic pathways often have similar catalytic mechanisms and structures, suggesting their evolution from a common ancestral precursor enzyme. We sought to create a precursor-like enzyme for N'-[(5'-phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (ProFAR) isomerase (HisA; EC ) and phosphoribosylanthranilate (PRA) isomerase (TrpF; EC ), which catalyze similar reactions in the biosynthesis of the amino acids histidine and tryptophan and have a similar (betaalpha)(8)-barrel structure. Using random mutagenesis and selection, we generated several HisA variants that catalyze the TrpF reaction both in vivo and in vitro, and one of these variants retained significant HisA activity. A more detailed analysis revealed that a single amino acid exchange could establish TrpF activity on the HisA scaffold. These findings suggest that HisA and TrpF may have evolved from an ancestral enzyme of broader substrate specificity and underscore that (betaalpha)(8)-barrel enzymes are very suitable for the design of new catalytic activities.

A high-precision, high-resolution and fast dosimetry system for beta sources applied in cardiovascular brachytherapy.

A fast dosimetry system based on plastic scintillator detectors has been developed which allows three-dimensional measurement of the radiation field in water of beta-sources appropriate for application in cardiovascular brachytherapy. This system fulfills the AAPM Task Group 60 recommendations for dosimetry of cardiovascular brachytherapy sources. To demonstrate the use of the system, measurements have been performed with an 90Y-wire source. The dose distribution was determined with a spatial resolution of better than 0.2 mm, with only a few minutes needed per scan. The scintillator dosemeter was absolutely calibrated in terms of absorbed dose to water with a precision of +/-7.5%. The relative precision achievable is +/-2.5%. The response of the system is linear within +/-2% for dose rates from 0.5 mGy s(-1) to 500 mGy s(-1).

Beyond valence in the perception of likelihood: the role of emotion specificity.

Positive and negative moods have been shown to increase likelihood estimates of future events matching these states in valence (e.g., E. J. Johnson & A. Tversky, 1983). In the present article, 4 studies provide evidence that this congruency bias (a) is not limited to valence but functions in an emotion-specific manner, (b) derives from the informational value of emotions, and (c) is not the inevitable outcome of likelihood assessment under heightened emotion. Specifically, Study 1 demonstrates that sadness and anger, 2 distinct, negative emotions, differentially bias likelihood estimates of sad and angering events. Studies 2 and 3 replicate this finding in addition to supporting an emotion-as-information (cf. N. Schwarz & G. L. Clore, 1983), as opposed to a memory-based, mediating process for the bias. Finally, Study 4 shows that when the source of the emotion is salient, a reversal of the bias can occur given greater cognitive effort aimed at accuracy.

Fluorescence 125I eye applicator.

A new approach to optimize curative eye plaque brachytherapy is presented. The application of ophthalmic plaques is a common therapy modality for small and medium sized intraocular tumors. At Essen University Hospital eye applicators with photon emitting 125I seeds are used for the treatment of tumors with a thickness from 5 to 10 mm. Our clinical experiences indicate that the dose distributions of these applicators-used so far worldwide-are not optimal. A steeper dose falloff would meet the radiobiological requirements better, to provide the eradication of all tumor cells as well as sufficient occlusion of tumor supplying blood vessels. Our investigations for eye plaque optimization are based both on measurements and Monte Carlo simulation. For fast dosimetric measurements we have built a computer controlled device which allows reading out, directly and simultaneously, 16 1 mm3 scintillators. For the numerical simulations of the dose distribution of 125I eye plaques we have adapted a Monte Carlo program originally developed to calculate the synchrotron radiation in particle physics. We have investigated the influence of geometrical as well as physical eye plaque parameters on the dose distribution: Shielding of the primary radiation, penumbra modification, and energy conversion by exploiting fluorescence x-radiation have been considered. New types of fluorescence eye applicators have been designed which are more suitable for the prevention of radiopathic effects on structures at risk.

Crowd out: evidence from the Florida Healthy Kids Program.

OBJECTIVE: To determine the percentage of children who had insurance coverage in the 12 months preceding enrollment in a state-subsidized program; the percentage of parents who had access to employer-based family coverage; and the cost of the families' share of the premium per month. METHODS: We randomly selected 930 families whose children were enrolled in the Florida Healthy Kids Program for a period of between 1 and 3 months and conducted telephone interviews with them in 1998 about their children's insurance coverage before program entry and their access to employer-based family coverage. There were 653 families in the final sample. RESULTS: Only 5% of the children had employer-based coverage before program enrollment. However, 26% had access to family coverage through their employers with the family share of the premiums representing on average 13% of their incomes. Access to employer-based coverage varied significantly by family income. CONCLUSIONS: Throughout the development of the State Children's Health Insurance Program legislation, policy analysts expressed concern that families may crowd out or substitute a subsidized state plan for employer-based coverage. This substitution could result in fewer improvements in access to care and health status than were anticipated, because families are simply moving to a different form of health insurance. There is some degree of crowd out in the Healthy Kids Program. The economic burden to near-poor families to purchase employer-based coverage is significant. Some degree of substitution may need to be tolerated to ensure that children receive needed health insurance.

Children's health care use in the Healthy Kids Program.

BACKGROUND: In 1990, the Florida Legislature established the Florida Healthy Kids Corporation to implement the concept of school enrollment-based health insurance coverage for children. The county school districts are used as a grouping mechanism to negotiate health insurance policies. The Florida Healthy Kids Corporation negotiates contracts with health maintenance organizations (HMOs) to assume financial risk and to provide health care services at each program site. In 1994, there were five sites with four different participating HMOs. Assessing quality of care is particularly important when contracting with HMOs because of the perception that financial and utilization review arrangements may restrict the enrollees' access to needed health care. One essential component of health care quality is the extent to which health care services are used in a manner consistent with the expected pattern of use for the population of enrolled children. The purpose of this study is to compare children's health care use across five different Florida Healthy Kids Program sites. Specifically, we compare the enrollees' actual health care use across HMO settings and program sites to the expected health care use based on the enrollees' case-mix. METHODS: Each HMO provided child-specific health care use data including Physician's Current Procedural Terminology codes and International Classification of Diseases, 9th Revision codes. We used the Ambulatory Care Groups (ACGs) software to compare the children's actual health care use to the expected health care use at each site adjusted for case-mix. Several steps were then taken to determine if the children were receiving the anticipated number of health care visits based on their diagnoses. First, we divided the average number of encounters at each site by the group average across all of the sites, without adjusting for the case-mix of the enrollees. We then divided the average number of visits at each site by the expected number of visits based on the case-mix adjustment. A value of 1.00 means that the actual use and the expected use are identical. Values below 1 indicate underuse and values over 1 indicate overuse of health care services. Statistical comparisons of the actual versus expected average health care use across the five sites were performed by deriving the appropriate chi2 statistics. RESULTS: A census of all children (N = 14 688) enrolled in the Florida Healthy Kids Program at each of the sites for 6 months or longer were included in the analysis. The average number of health care encounters across all sites for a 12-month time period was 2.98 +/- 4.6 visits. After adjusting for the case-mix of the enrollees in each site using the ACG software, several of the five sites differed from one in a statistically significant way. However, these statistical assessments must be tempered with assessing the practical magnitude of the observed differences. CONCLUSIONS: The number of public and private efforts to insure children who are not eligible for Medicaid and whose parents cannot purchase private insurance has grown dramatically. These programs are vital for ensuring financial access to care for uninsured children. However, it is essential that such programs are not viewed as merely cost containment efforts. Assessing the degree to which children receive the health care services they need across multiple delivery settings is an essential yet challenging component of quality assurance. Generally, our analysis indicates that children in the Florida Healthy Kids Program are receiving the amount of health care expected based on their health care needs; which is one component of a high-quality health care program.

Attitudes and attitude change.

We review empirical and conceptual developments over the past four years (1992-1995) on attitudes and persuasion. A voluminous amount of material was produced concerning attitude structure, attitude change, and the consequences of holding attitudes. In the structure area, particular attention is paid to work on attitude accessibility, ambivalence, and the affective versus cognitive bases of attitudes. In persuasion, our review examines research that has focused on high effort cognitive processes (central route), low effort processes (peripheral route), and the multiple roles by which variables can have an impact on attitudes. Special emphasis is given to work on cognitive dissonance and other biases in message processing, and on the multiple processes by which mood influences evaluations. Work on the consequences of attitudes focuses on the impact of attitudes on behavior and social judgments.

Characterization of two class II chitinase genes from peanut and expression studies in transgenic tobacco plants.

Two different genes encoding class II chitinases from peanut (Arachis hypogaea L. cv. NC4), A.h.Chi2;1 and A.h.Chi2;2, have been cloned. In peanut cell suspension cultures, mRNA levels of A.h.Chi2;2 increased after ethylene or salicylate treatment and in the presence of conidia from Botrytis cinerea. The second gene, A.h.Chi2;1, was only expressed after treatment with the fungal spores. Transgenic tobacco plants containing the complete peanut A.h.Chi2;1 gene exhibited essentially the same expression pattern in leaves as observed in peanut cell cultures. Expression characteristics of transgenic tobacco carrying a promoter-GUS fusion of A.h.Chi2;1 are described.

Positive mood can increase or decrease message scrutiny: the hedonic contingency view of mood and message processing.

Currently dominant explanations of mood effects on persuasive message processing (i.e., cognitive capacity and feelings as information) predict that happy moods lead to less message scrutiny than neutral or sad moods. The hedonic contingency view (D. T. Wegener & R. E. Petty, 1994) predicts that happy moods can sometimes be associated with greater message processing activity because people in a happy mood are more attentive than neutral or sad people to the hedonic consequences of their actions. Consistent with this view, Experiment 1 finds that a happy mood can lead to greater message scrutiny than a neutral mood when the message is not mood threatening. Experiment 2 finds that a happy mood leads to greater message scrutiny than a sad mood when an uplifting message is encountered, but to less message scrutiny when a depressing message is encountered.

Flexible correction processes in social judgment: the role of naive theories in corrections for perceived bias.

Unlike many models of bias correction, our flexible correction model posits that corrections occur when judges are motivated and able to adjust assessments of targets according to their naive theories of how the context affects judgments of the target(s). In the current research, people flexibly correct assessments of different targets within the same context according to the differing theories associated with the context-target pairs. In Study 1, shared theories of assimilation and contrast bias are identified. Corrections consistent with those theories are obtained in Studies 2 and 3. Study 4 shows that idiographic measures of theories of bias predict the direction and magnitude of corrections. Implications of this work for corrections of attributions and bias removal in general are discussed.