Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Erratum: Formation of a Spin Texture in a Quantum Gas Coupled to a Cavity [Phys. Rev. Lett. 120, 223602 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.120.223602.

Worth a local treatment? - Analysis of modern radiotherapy concepts for oligometastatic prostate cancer.

BACKGROUND: Prostate cancer (PCA) is the most-prevalent non-skin cancer in men worldwide. Nevertheless, the treatment of oligometastatic, especially lymph-node (ln) recurrent, PCA remains elusive. The aim of our study was to provide insights in radiotherapy (RT)-treatment of recurrent PCA exhibiting ln- or osseous (oss)-oligometastases. METHODS: Between April 2012 and April 2017, 27 oligometastatic PCA patients (19 ln and 8 single oss) were treated with RT at our institution. RESULTS: The metastasis-free survival (MFS) was 24.8 m (22.0-36.0 m) and 25.4 m (23.9-28.1 m) for the ln- and oss-subgroup resulting in 1-year MFS of 75.4 and 100% and 2-year MFS of 58.7 and 83.3% for ln- and oss-metastatic patients, respectively. Of notice, none of the recurrences for ln-patients was in the RT-field, constituting a local control of 100%. Within the ln-group, pre-RT median-PSA was 2.6 ng/ml, median post-RT PSA was 0.3 ng/ml, which was significant (p = 0.003). Median biochemical-free survival (bfS) was 12.2 m. PCA that was initially confined to the prostate had a better bfS (p < 0.001) and MFS (p = 0.013). The oss-group had a median PSA of 4.9 ng/ml pre-treatment which dropped to a median value of 0.14 ng/ml (p = 0.004). Toxicities were moderate, with only 1 case of III° toxicity. There were no deaths in the ln-group, thus overall survial was 100% here. CONCLUSION: Our study points out the feasibility of RT as a treatment option in recurrent PCA and demonstrates an excellent local control with a low-toxicity profile.

Formation of a Spin Texture in a Quantum Gas Coupled to a Cavity.

We observe cavity mediated spin-dependent interactions in an off-resonantly driven multilevel atomic Bose-Einstein condensate that is strongly coupled to an optical cavity. Applying a driving field with adjustable polarization, we identify the roles of the scalar and the vectorial components of the atomic polarizability tensor for single and multicomponent condensates. Beyond a critical strength of the vectorial coupling, we infer the formation of a spin texture in a condensate of two internal states from the analysis of the cavity output field. Our work provides perspectives for global dynamical gauge fields and self-consistently spin-orbit coupled gases.

Acute outcome of chronic total occlusion (CTO) recanalizsation in the elderly.

OBJECTIVES: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. There is only insignificant knowledge reported in the literature about age differences in CTO recanalization. We analyzed in this study the issue of the impact of age on procedural characteristics, complications and short-term outcome. METHODS: Between 2012-2016 we included 440 patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. Continuous data are presented as the mean ± standard deviation; categorical data are presented as numbers and percentages unless otherwise specified. We used Twosamplet- t-test with equal variance to test the significant differences of the variables between the two cohorts. RESULTS: Procedural success proved independently of age. There was no significant interaction between age and procedural success (p=0.5). Complication rates were low in both groups (2.7% vs. 4%; p=0,4) with no difference in statistical significance. CONCLUSIONS: Our study suggests that in an aging society patients with severe coronary artery disease and chronical total occlusions an interventional therapy should be used more intensively. It can be performed safe and feasible.

Depth of the vadose zone controls aquifer biogeochemical conditions and extent of anthropogenic nitrogen removal.

We investigated biogeochemical conditions and watershed features controlling the extent of nitrate removal through microbial dinitrogen (N2) production within the surficial glacial aquifer located on the north and south shores of Long Island, NY, USA. The extent of N2 production differs within portions of the aquifer, with greatest N2 production observed at the south shore of Long Island where the vadose zone is thinnest, while limited N2 production occurred under the thick vadose zones on the north shore. In areas with a shallow water table and thin vadose zone, low oxygen concentrations and sufficient DOC concentrations are conducive to N2 production. Results support the hypothesis that in aquifers without a significant supply of sediment-bound reducing potential, vadose zone thickness exerts an important control of the extent of N2 production. Since quantification of excess N2 relies on knowledge of equilibrium N2 concentration at recharge, calculated based on temperature at recharge, we further identify several features, such as land use and cover, seasonality of recharge, and climate change that should be considered to refine estimation of recharge temperature, its deviation from mean annual air temperature, and resulting deviation from expected equilibrium gas concentrations.

Validity of the J-CTO Score and the CL-Score for predicting successful CTO recanalization.

BACKGROUND: Percutaneous coronary intervention (PCI) of total chronic coronary occlusion (CTO) still remains a major challenge in interventional cardiology. To predict the probability of a successful intervention different scoring systems are available. We analyzed in this study the validity of two scoring systems, the Japanese CTO score (J-CTO score) and the newly developed Clinical and Lesion-related score (CL Score). METHODS: Between 2012 and 2015 we included 379 consecutive patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. RESULTS: Patients undergoing CTO PCI were mainly men (84%). The overall procedural success rate was 84% (±0.4). The mean J-CTO score was 2.9 (±1.3) and the mean CL score was 4.3 (±1.7). The CL score predicted more precisely the interventional results than the J-CTO score. CONCLUSIONS: Our study suggests that the previously presented CL score is superior to the J-CTO score in identifying CTO lesions with a likelihood for successful recanalization. Generally it appears to be a helpful tool for selecting patients and identifying the appropriate operator.

[Prophylaxis of Recurrent Venous Leg Ulcer]. / Rezidivprophylaxe des Ulcus cruris venosum.

Venous leg ulcer (VLU) counts among the most common chronic wounds in Europe. Treatment is lengthy, cumbersome and costly, and there is a high rate of recurrence. This review shows the measures that should be offered to every patient with healed VLU to permanently prevent recurrence. To prevent VLU in case of varicose veins, the progression of chronic venous insufficiency (CVI) has to be stopped. There is convincing evidence that the effective treatment of varicose veins reduces the recurrence rate in patients with VLU. In patients with post-thrombotic syndrome (PTS), further thrombosis should be prevented through targeted prophylaxis of new thromboembolic events. The benefit of endovascular revascularization on the VLU recurrence rate in patients with post-thrombotic damage in the pelvic veins has not been proven in clinical studies. On the other hand, it has been clearly demonstrated in several studies that compression therapy is the basic procedure for the prevention of recurrent VLU in patients with varicose veins or PTS, regardless of whether other measures have been implemented or not. Good adherence in patients with compression therapy is more important than choosing the highest possible compression class. Future efforts for patients with VLU must aim to provide therapists with tools and treatment strategies to guide their patients and to increase patients' acceptance and understanding of the importance of self-management, in particular regarding compression therapy for the prevention of recurrent VLU.

[Options and Limitations in Endovascular Therapy for Acute and Chronic Mesenteric Arterial Occlusions]. / Endovaskuläre Möglichkeiten und Grenzen bei akuten und chronischen mesenterialen Verschlussprozessen.

BACKGROUND: The significance of endovascular therapy for mesenteric ischaemia (MI) is being debated. Despite initially lower mortality and morbidity, inconsistent early and late results led to questions concerning indications and technical applications of the procedure. METHODS: 91 patients with MI underwent endovascular treatment in a period of 11 years. In 78 (85.7 %) patients a stent was deployed and in 13 (14.3 %) an angioplasty was performed, principally of the superior mesenteric artery (n = 81/91, 89 %). Follow-up consisted of a clinical and an ultrasound examination in all cases. Mean follow-up was 4.2 years. Our results were compared to those in the literature. RESULTS: Endovascular treatment of the intestinal arteries accounted for 0.6 % of all vascular procedures. Seven of 91 patients (7.7 %) died after an initial PTA/stenting. The overall peri-interventional morbidity was 6.6 % (n = 6/91). Medium- to long-term complications were encountered in 20 patients (22 %), primarily during the first year (85 %). Six of 91 patients developed an in-stent stenosis (6.6 %) and 14/91 patients (15.4 %) stent occlusion. Additionally 2 dislocated stents (2.2 %) and an arterial perforation with bleeding into the mesentery (1.1 %) were seen. Although 3 of these 20 patients were successfully treated with an additional PTA or stenting (15.0 %; n = 3/91, 3.3 %), surgical conversion was necessary in 9 (n = 9/20, 45 %; n = 9/91, 9.9 %). The postoperative mortality was respectively 22.2 % (n = 2/9; n = 2/91, 2.2 %). In the case of acute MI, endovascular procedures are only indicated for patients without peritonitis. In chronic MI, the indication for endovascular treatment depends on the type of occlusion and the vascular anatomy. Despite favourable early results, the outcome of endovascular treatment deteriorates with time reaching a 1-year patency rate of 63 % in a multicentre analysis. This leads to secondary procedures in 30 %. A surgical conversion carries a high mortality. CONCLUSION: The endovascular treatment of intestinal artery disease cannot be considered the treatment of choice, it is rather an alternative method in patients with functional or local contraindications to surgery. Life-long follow-up is necessary to prevent stent complications with fatal consequences. A prospective randomised study concerning the evaluation of the advantages and disadvantages of surgical and endovascular therapy of intestinal artery occlusive disease is required.

[The future of vascular medicine]. / Die Zukunft der Gefäßmedizin.

In the future vascular medicine will still have a great impact on health of people. It should be noted that the aging of the population does not lead to a dramatic increase in patient numbers, but will be associated with a changing spectrum of co-morbidities. In addition, vascular medical research has to include the intensive care special features of vascular patients, the involvement of vascular medicine in a holistic concept of fast-track surgery, a geriatric-oriented intensive monitoring and early geriatric rehabilitation. For the future acceptance of vascular medicine as a separate subject area under delimitation of cardiology and radiology is important. On the other hand, the subject is so complex and will become more complex in future specialisations that mixing of surgery and angiology is desirable, with the aim to preserve the vascular surgical knowledge and skills on par with the medical and interventional measures and further develop them. Only large, interdisciplinary guided vascular centres will be able to provide timely diagnosis and therapy, to deal with the growing multi-morbidity of the patient, to perform complex therapies even in an acute emergency and due to sufficient number of cases to present with well-trained and experienced teams. These requirements are mandatory to decrease patients' mortality step by step.

Perceptions of Door-to-Door HIV Counselling and Testing in Botswana

Prevalence of HIV infection in Botswana is among the highest in the world; at 23.9 of 15 - 49-year-olds. Most HIV testing is conducted in voluntary counselling and testing centres or medical settings. Improved access to testing is urgently needed. This qualitative study assessed and documented community perceptions about the concept of door-to-door HIV counselling and rapid testing in two of the highest-prevalence districts of Botswana. Community members associated many positive benefits with home-based; door-to-door HIV testing; including convenience; confidentiality; capacity to increase the number of people tested; and opportunities to increase knowledge of HIV transmission; prevention and care through provision of correct information to households. Community members also saw the intervention as increasing opportunities to engage and influence family members and to role model positive behaviours. Participants also perceived social risks and dangers associated with home-based testing including the potential for conflict; coercion; stigma; and psychological distress within households. Community members emphasised the need for individual and community preparation; including procedures to protect confidentiality; provisions for psychological and social support; and links to appropriate services for HIV-positive persons

A parent training model for toilet training children with autism.

BACKGROUND: Azrin & Foxx pioneered an intensive toilet training protocol for individuals with intellectual disability living in a residential setting. Since the development of the Rapid Toilet Training (RTT) protocol, many have replicated the efficacy, most notably in educational and outpatient treatment settings, but often training over longer periods of time. This study presents data from a parent training model that replicates Azrin and Foxx's results and training time. METHOD: This multiple baseline across subjects design study employs an ABA design where two boys diagnosed with autism were toilet trained using a modified Azrin & Foxx intensive teaching protocol. The first subject, a 4-year-old boy, did not have a history of attempted toilet training. The second subject, a 6-year-old boy, demonstrated a history of failed toilet training attempts in both the home and school settings. The trainings were conducted in the home setting where a novel parent-training approach was implemented. RESULTS: Participant 1 was continent at the end of the second day of training, and completely toilet trained (including initiation and communication) by day 10 of the intervention. Participant 2 was continent after day 1 and completely toilet trained by day 5 of the intervention. CONCLUSIONS: Long-term follow-up demonstrates maintenance of skills 3 years post training. Social validity via parent satisfaction was assessed. Limitations to the current study and recommendations for future research were discussed.

Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma.

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.

Herpes simplex virus type 1 thymidine kinase sequence fused to the lacz gene increases levels of {beta}-galactosidase activity per genome of high-capacity but not first-generation adenoviral vectors in vitro and in vivo.

Increased transgene expression per vector genome is an important goal in the optimization of viral vectors for gene therapy. Herein we demonstrate that herpes simplex virus type 1 (HSV1) thymidine kinase (TK) gene sequences (1,131 bp) fused to the 3' end of lacZ increase transgene expression from high-capacity adenoviral vectors (HCAd), but not from first-generation (Ad) vectors. The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), in contrast, increased transgene expression levels from Ad but not HCAd vectors. The differential activity of the HSV1 TK gene and WPRE sequences was detected both in vitro and in vivo and suggests potentially different mechanisms of action or the interaction of these elements with vector genomic sequences.

Randomized comparison of effects of suture-based and collagen-based vascular closure devices on post-procedural leg perfusion.

BACKGROUND: Vascular closure devices (VCD) are well established to facilitate hemostasis after cardiac catheterization procedures. However, impairment of flow due to the reduction of femoral artery diameter remains a major concern. The present study aims to evaluate leg perfusion before and after application of collagen- and suture-based vascular closure devices. METHODS: A total of 366 patients (age: 64.3 years+/-10.7, male: 71.3%) were randomized to receive femoral access site closure with either a collagen-based closure device (group A) (n=214) or a suture-mediated device (group B) (n=152), immediately following coronary catheterization procedures. In all patients, the ankle-brachial-index (ABI) was measured before and the day after closure device application. RESULTS: In group A, mean ABI at baseline was 1.09+/-0.2, in group B 1.11+/-0.2. In both groups, there was a significant, albeit clinically not relevant, reduction in post-procedural ABI (group A: 1.04+/-0.2, p<0.01 vs baseline, group B: 1.06+/-0.2, p<0.01 vs baseline). DeltaABI was not different between both VCD groups (p=0.55). In patients with peripheral vascular disease (PVD), neither the Angioseal device (mean ABI at baseline 0.76+/-0.1) nor the Perclose-device (mean ABI at baseline 0.79+/-0.1) induced a remarkable impairment of leg perfusion (Angioseal: 0.77+/-0.1, p=0.9 vs baseline, Perclose: 0.78+/-0.1, p=1.0 vs baseline). Clinically, no aggravation of claudication was observed in the PVD patient group. CONCLUSION: Both vascular closure devices are not associated with clinically relevant reduction in ABI. There was no difference between the two groups with respect to the level of flow impairment. Both devices may be safely used in patients with reduced ABI.

A comparison of two group-delivered social skills programs for young children with autism.

A social skills group intervention was developed and evaluated for young children with autism. Twenty-five 4- to 6-year-old (diagnosed) children were assigned to one of two kinds of social skills groups: the direct teaching group or the play activities group. The direct teaching group used a video-modeling format to teach play and social skills over the course of the intervention, while the play activities group engaged in unstructured play during the sessions. Groups met for 5 weeks, three times per week, 1 h each time. Data were derived and coded from videotapes of pre- and post-treatment unstructured play sessions. Findings indicated that while members of both groups increased prosocial behaviors, the direct teaching group made more gains in social skills.

[Simultaneous manifestation of blue-rubber-bleb-nevus-syndrome and malignant melanoma]. / Gemeinsame Manifestation von Blue-Rubber-Bleb-Naevus-Syndrom und malignem Melanom.

Blue rubber bleb nevi (BRBN) are rare vascular malformations of the integument and mucous membranes. Little is known about coherence between these nevi and malignant diseases. We report on a young man with progressive BRBN syndrome representing a thitherto unknown malignant melanoma.

Quantification of high-capacity helper-dependent adenoviral vector genomes in vitro and in vivo, using quantitative TaqMan real-time polymerase chain reaction.

First-generation adenoviral (Ad) and high-capacity adenoviral (HC-Ad) vectors are efficient delivery vehicles for transferring therapeutic transgenes in vivo into tissues/organs. The initial successes reported with adenoviral vectors in preclinical trials have been limited by immune-related adverse side effects. This has been, in part, attributed to the use of poorly characterized preparations of adenoviral vectors and also to the untoward immune adverse side effects elicited when high doses of these vectors were used. HC-Ads have several advantages over Ads, including the lack of viral coding sequences, which after infection and uncoating, makes them invisible to the host's immune system. Another advantage is their large cloning capacity (up to approximately 35 kb). However, accurate characterization of HC-Ad vectors, and of contaminating replication-competent adenovirus (RCA) or helper virus, is necessary before these preparations can be used safely in clinical trials. Consequently, the development of accurate, simple, and reproducible methods to standardize and validate adenoviral preparations for the presence of contaminant genomes is required. By using a molecular method that allows accurate, reproducible, and simultaneous determination of HC-Ad, contaminating helper virus, and RCA genome copy numbers based on real-time quantitative PCR, we demonstrate accurate detection of these three genomic entities, within CsCl-purified vector stocks, total DNA isolated from cells transduced in vitro, and from brain tissue infected in vivo. This approach will allow accurate assessment of the levels and biodistribution of HC-Ad and improve the safety and efficacy of clinical trials.

A language programme to increase the verbal production of a child dually diagnosed with Down syndrome and autism.

BACKGROUND: The incidence of children dually diagnosed with Down syndrome and autism is estimated to be as high as 11%. There is a paucity of research investigating linguistic treatment interventions for such children. This single-subject experiment examined a programme designed to increase the language production and verbal behaviour of a 9-year-old dually diagnosed boy who had been receiving a 15-h/week home-based applied behaviour analysis (ABA) programme. METHODS: Training principles were derived from previously empirically validated research in discrete trail learning and natural environment teaching, as well as modified incidental teaching procedures. The crux of the language programme involved withholding reinforcement until a spoken request was made. RESULTS: Language production noticeably increased for each target area after the introduction of the language programme and was maintained at a 9-month follow-up session. CONCLUSIONS: A combined treatment approach incorporating direct instruction, natural environment teaching and incidental teaching can be effective in increasing and maintaining responsive and spontaneous speech in a child with Down syndrome diagnosed with autism. Replication studies are needed with such multiple dually diagnosed children to further evaluate the effectiveness and generalizability of this combined language programme.