Radiotherapy dose and survival outcomes in human papillomavirus positive oropharyngeal cancer.

OBJECTIVE: To evaluate the effect of definitive radiotherapy dose on survival in patients with human papillomavirus positive oropharyngeal carcinoma. METHODS: Human papillomavirus positive oropharyngeal carcinoma patients staged T1-3 and N0-2c, who received definitive radiotherapy (fraction sizes of 180 cGy to less than 220 cGy), were identified from the National Cancer Database 2010-2014 and stratified by radiation dose (50 Gy to less than 66 Gy, or 66 Gy or more). RESULTS: A total of 2173 patients were included, of whom 124 (6 per cent) received a radiation dose of 50 Gy to less than 66 Gy. With a median follow up of 33.8 months, patients had a 3-year overall survival rate of 88.6 per cent (95 per cent confidence interval = 87.1-90.1 per cent). On multivariate Cox analysis, a radiotherapy dose of 50 Gy to less than 66 Gy (hazard ratio = 0.95, 95 per cent confidence interval = 0.52-1.74, p = 0.86) was not a predictor of increased mortality risk. CONCLUSION: Human papillomavirus positive oropharyngeal carcinoma patients had excellent outcomes with definitive radiotherapy doses of 50 Gy to less than 66 Gy. These results further support patients enrolling into clinical trials for radiation dose de-escalation.

The accuracy of image-based safety analysis for robotic cochlear implantation.

PURPOSE: To evaluate the accuracy and reliability of image-based safety analysis for robotic cochlear implantation (RCI) in an ex vivo assessment. METHODS: The accuracy was evaluated in a study on 23 human temporal bones. For image analysis, a computer-assisted safety analysis based on intraoperative cone beam computed tomography was implemented. The method automatically segments the drill tunnel and predicts the distance between the tunnel and the facial nerve. In addition, the drilling error at the target is predicted. The predicted distances were compared with the actually drilled distances measured in postoperative high-resolution micro-computed tomography scans. The automatic method was compared to accuracies associated with a manual analysis of the image data. RESULTS: The presented computerized image-based analysis enabled the proximity of the facial nerve to the drill trajectory to be predicted with an accuracy of 0.22 ± 0.15 mm and drilling error at the target to be predicted with an accuracy of 0.11 mm ± 0.08 during N = 19 RCI procedures. The manual assessment of facial nerve proximity was performed with an accuracy of 0.34 ± 0.20 mm by a trained clinical expert. CONCLUSION: The assessment of intraoperative CT-based imaging presents multiple benefits over alternative safety mechanisms including early detection and applicability even in cases of malformation of the mastoid. This work presents a computer-assisted approach to image analysis that enables procedure safety measurements to be reliably performed with superior accuracy to other proposed safety methodologies, at a safe distance from the facial nerve. Its application must, however, be considered in relation to associated costs (time, cost, irradiation) and the dependence of the measure on a reliable preoperative segmentation.

Instrument flight to the inner ear.

Surgical robot systems can work beyond the limits of human perception, dexterity and scale making them inherently suitable for use in microsurgical procedures. However, despite extensive research, image-guided robotics applications for microsurgery have seen limited introduction into clinical care to date. Among others, challenges are geometric scale and haptic resolution at which the surgeon cannot sufficiently control a device outside the range of human faculties. Mechanisms are required to ascertain redundant control on process variables that ensure safety of the device, much like instrument-flight in avionics. Cochlear implantation surgery is a microsurgical procedure, in which specific tasks are at sub-millimetric scale and exceed reliable visuo-tactile feedback. Cochlear implantation is subject to intra- and inter-operative variations, leading to potentially inconsistent clinical and audiological outcomes for patients. The concept of robotic cochlear implantation aims to increase consistency of surgical outcomes such as preservation of residual hearing and reduce invasiveness of the procedure. We report successful image-guided, robotic CI in human. The robotic treatment model encompasses: computer-assisted surgery planning, precision stereotactic image-guidance, in-situ assessment of tissue properties and multipolar neuromonitoring (NM), all based on in vitro, in vivo and pilot data. The model is expandable to integrate additional robotic functionalities such as cochlear access and electrode insertion. Our results demonstrate the feasibility and possibilities of using robotic technology for microsurgery on the lateral skull base. It has the potential for benefit in other microsurgical domains for which there is no task-oriented, robotic technology available at present.

Patient's experience with subcutaneous and oral methotrexate for the treatment of rheumatoid arthritis.

BACKGROUND: Despite the prominent position of methotrexate (MTX) in Rheumatoid Arthiris (RA) therapeutics, its real-world effectiveness may be influenced by a relative lack of tolerability or other side effects that physicians may not be aware of but that are bothersome to patients. The aim of this study is to identify suboptimal patient experience with MTX and to raise awareness for clinicians to identify opportunities to mitigate bothersome symptoms and side effects and optimize response to MTX. METHODS: We conducted a prospective, cross-sectional, online survey among RA patients who were members of Creakyjoints, a large arthritis patient community. Eligible participants must have recently initiated a new biologic, subcutaneous (SQ) MTX, or oral MTX in the last 12 months and were uniquely assigned to one of these 3 groups. Descriptive statistics were used to compare patient-reported side effects and tolerability related to MTX use in the 3 medication groups (SQ MTX, oral MTX, and biologic). RESULTS: A total of 382 (85 %) of 448 eligible patients completed the survey and were grouped as: biologic (n = 218), SQ MTX (n = 49), and oral MTX (n = 115). Demographics were mean standard deviation (SD) age 48 (10) years, 92 % white, 91 % women. Symptoms significantly more prevalent in the SQ and oral MTX groups included diarrhea, fatigue, malaise, and hair loss. Injection related pain was lower with SQ MTX compared to SQ biologics. Out of a total of 8 potential symptoms and side effects examined, higher dose MTX (> = 20 mg/week) was associated with a 2.26 (1.25-4.09) greater likelihood of more side effects referent to < =10 mg/week. CONCLUSION: Results from this real-world RA patient cohort suggest that MTX is accompanied by many patient-reported side effects and tolerability problems that may be under-recognized by physicians. These may impact both treatment satisfaction and medication adherence.

[12 years of Computer-Aided Surgery around the Head : Developments in surgical planning and simulation from a Bern perspective]. / 12 Jahre Computer-Aided Surgery around the Head : Entwicklungen in der chirurgischen Planung und Simulation aus Berner Perspektive.

Over the past years, the multidisciplinary character of the international Computer-Aided Surgery around the Head (CAS-H) symposium has advanced many medical technologies, which were often adopted by industry. In Bern, the synergetic effects of the CAS-H symposium have enabled many experiences and developments in the area of computer-aided surgery. Planning and simulation methods in the areas of craniomaxillofacial surgery and otorhinolaryngology were developed and tested in clinical settings. In the future, further CAS-H symposia should follow, in order to promote the possibilities and applications of computer-assisted surgery around the head.

Recent developments and current concepts in medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies.

Outcomes of induction chemotherapy followed by chemoradiation using intensity-modulated radiation therapy for esophageal adenocarcinoma.

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.

Bone involvement in atypical teratoid/rhabdoid tumors of the CNS.

SUMMARY: Destruction of the bony structures of the skull is rare in primary tumors of the CNS. In low-grade gliomas, modeling of the skull is caused by slow growth and chronic pressure. Bony destruction is exceptional even in highly malignant gliomas. Atypical teratoid/rhabdoid tumors of the CNS are highly malignant neoplasms diagnosed with an increasing frequency, mainly in young children. On imaging, these tumors exhibit distinct though not specific morphologic features including peripheral cysts, bleeding residues, and a distinct bandlike, wavy pattern of enhancement. A combination of these single characteristics together with a predilection for young age is suggestive of an atypical teratoid/rhabdoid tumor. We present 5 children with an atypical teratoid/rhabdoid tumor affecting the adjacent bone. These 5 patients were collected in our imaging data base for childhood atypical teratoid/rhabdoid tumor consisting of 91 children at the time of this evaluation and thus representing 6.6%. The mean age of children with bone involvement (4.8 years) was above the average age (2 years) of all children in the data base. We add this rare feature to the list of typical features in MR imaging and CT morphology of atypical teratoid/rhabdoid tumor.

Quality of life in cirrhosis.

Quality of life is a construct that reflects the positive and negative aspects of one's life, and is expanded upon by health-related quality of life (HRQL), which specifically address the impact of health on patients' well-being. Cirrhosis is the culmination of various pathways that leads into development of advanced hepatic fibrosis with its complications. This paper addresses the impact of cirrhosis on individuals HRQL. In addition, we will define what disease specific and general HRQL instruments aim to measure. We discuss the liver disease specific scales [Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life 1.0 (LDQOL)] and the most commonly used generic health profile [Short Form 36 Profile (SF-36)]. Furthermore, we examine recent literature which describes how to measure and what is known about quality of life of patients with cirrhosis. This information gives insight to health care providers concerning the impact of disease on patients if treatments are not only to improve health but also function and unexpected treatment outcomes.

Development of an auditory implant manipulator for minimally invasive surgical insertion of implantable hearing devices.

OBJECTIVE: To present the auditory implant manipulator, a navigation-controlled mechanical and electronic system which enables minimally invasive ('keyhole') transmastoid access to the tympanic cavity. MATERIALS AND METHODS: The auditory implant manipulator is a miniaturised robotic system with five axes of movement and an integrated drill. It can be mounted on the operating table. We evaluated the surgical work field provided by the system, and the work sequence involved, using an anatomical whole head specimen. RESULTS: The work field provided by the auditory implant manipulator is considerably greater than required for conventional mastoidectomy. The work sequence for a keyhole procedure included pre-operative planning, arrangement of equipment, the procedure itself and post-operative analysis. CONCLUSION: Although system improvements are necessary, our preliminary results indicate that the auditory implant manipulator has the potential to perform keyhole insertion of implantable hearing devices.

Surveillance for avian influenza virus subtypes H5 and H7 in chickens and turkeys farmed commercially in New Zealand.

AIM: To determine the status of avian influenza (AI) virus sub-types H5 and H7 of New Zealand's commercial chicken and turkey farms. METHODS: A cross-sectional serological survey, stratified by production sector, used a sample frame defined by those farms registered with the Poultry Industry Association of New Zealand (PIANZ) or the Egg Producers Federation of New Zealand (EPF). Sectors included were chicken broiler, caged/barn layer, free-range layer, pullet rearer and turkey broiler. The survey used a between- and within-farm design prevalence of 5% (95% confidence for chickens, 99% confidence for turkeys) and 30% (95% confidence), respectively, of AI virus subtypes H5 and H7. The epidemiological unit was the farm for the free-range layer sector, and the individual shed/barn for the other sectors. Serum samples were screened using a commercial generic influenza A indirect ELISA; positive samples were subjected to haemagglutination-inhibition (HI) testing for AI virus subtypes H5 and H7. A comprehensive investigation, that included widespread serological and antigenic screening, was carried out on all farms identified with serum reactors to either the H5 or H7 virus subtype. RESULTS: A total of 4,180 blood samples from 167 chicken and 10 turkey farms were collected and tested using ELISA. Positive ELISA results were returned from 26 farms, comprising 10 caged/barn layer, 14 free-range layer and two turkey (shed-raised) broiler farms. HI testing of ELISA-positive sera for the H7 subtype virus identified no positive sera in any sector. Reactors to the H5 subtype virus were limited to three free-range layer chicken farms; each farm returned a single serum reactor. Follow-up investigations on these free-range farms identified evidence of historic exposure to the H5 subtype virus on one farm, and concluded that the serum reactors identified in the initial sampling round on the other two farms were non-specific (false-positive) reactions. CONCLUSIONS: The survey found no evidence of active infection with notifiable AI viruses, and provided evidence of absence of exposure to AI virus subtypes H5 and H7 in the chicken broiler, caged/barn layer, turkey broiler and pullet-rearer sectors at a between- and within-farm prevalence of 5% and 30%, respectively, with 95% confidence. The results established commercial free-range layer farms as a risk sector for exposure to notifiable AI virus.

Using rapid prototyping molds to create patient specific polymethylmethacrylate implants in cranioplasty.

Cranioplasty is a commonly performed procedure. Outcomes can be improved by the use of patient specific implants, however, high costs limit their accessibility. This paper presents a low cost alternative technique to create patient specific polymethylmethacrylate (PMMA) implants using rapid prototyped mold template. We used available patient's CT-scans, one dataset without craniotomy and one with craniotomy, for computer-assisted design of a 3D mold template, which itself can be brought into the operating room and be used for fast and easy building of a PMMA implant. We applied our solution to three patients with positive outcomes and no complications.

Patterns of contact within the New Zealand poultry industry.

Members of the Poultry Industry Association and the Egg Producers Federation of New Zealand (n=420) were sent a questionnaire asking them to describe the type and frequency of on- and off-enterprise movements relating to feed, live birds and hatching eggs, table eggs and poultry product, and manure and waste litter. Social network analyses were used to describe patterns of contact among poultry enterprises and their associates for these four movement types. The response rate to the survey was 58% (244 out of 420). Network structures for enterprise-to-enterprise movements of feed, live birds and hatching eggs, and table egg and poultry product were characterised by 'hub and spoke' type structures with small-world characteristics. Small worlds were created by network hubs (e.g. feed suppliers and hatcheries) providing goods and services to larger numbers of client farms. In addition to hubs acting as the predominant source of material moving onto farms we identified enterprises acting as bridges between identified small worlds. The presence of these bridges is a concern, since their presence has the potential to facilitate the spread of hazards (e.g. feed contaminants, infectious agents carried within feed) more readily throughout the population. An ability to predict enterprises with these network characteristics on the basis of factors such as shed capacity, enterprise type, geographic location would be useful for developing risk-based approaches to disease prevention, surveillance, detection, response and control activities.

The influence of cooking and fat trimming on the actual nutrient intake from meat.

The effects of cooking and trimming of visible fatty tissue on the content of fat, fatty acids, minerals and vitamins was studied in six meat cuts (beef rib-eye and brisket, pork neck steak and belly, veal chop and rolled breast) in order to improve the estimates of the actual nutrient intake from meat. Cooking decreased the absolute fat content by about 17.9-44.4% and therefore concomitantly influenced the content of different fatty acids. The trimming of visible fatty tissue additionally decreased the fat content by about 23.8-59.1%. Calcium, sodium, potassium, magnesium and phosphorus decreased during cooking in all cuts and cooking processes, while iron and zinc were found to increase in beef. All vitamins decreased during cooking, with thiamine showing the highest losses, from 73% up to 100%. In conclusion, the cooking and trimming of meat cuts considerably affected the nutrients in various ways and to different degrees, which should be taken into account when the nutrient intakes of meat are estimated.

Variability of selected trace elements of different meat cuts determined by ICP-MS and DRC-ICPMS.

The aim of this study was to determine the levels of cadmium, lead, iron, zinc, selenium, manganese, copper and molybdenum in different cuts of beef, pork, lamb, chicken and foal collected from supermarkets and butcheries in Switzerland. The concentrations of manganese, copper, molybdenum, zinc, iron, selenium, cadmium and lead were determined by inductively coupled plasma mass spectrometry (ICP-MS) after microwave digestion. Mean values and their respective coefficients of variation were calculated from the measured concentrations. The concentrations found for cadmium and lead ranged from 0.6 to 3.9 µg/100 g and 1.0 to 2.1 µg/100 g, respectively. Concentrations ranged between 0.5 and 3.3 mg/100 g for iron, 0.7 and 5.1 mg/100 g for zinc, 9 and 44 µg/100 g for selenium, 3.1 and 16.7 µg/100 g for manganese, 0.3 and 132 µg/100 g for copper and 0.9 and 3.2 µg/100 g for molybdenum. Differences found for the concentrations in meat from different species as well as between the individual meat cuts were notable for iron, zinc, selenium and copper. Manganese concentrations were found to vary unsystematically within muscles and species. Molybdenum concentrations were higher in chicken meat in comparison with the mammalian meats. The highest coefficients of variation were found for manganese (13% to 142%) and copper (13% to 224%), while the lowest was found for zinc (4% to 45%). In conclusion, in order to provide an accurate overview and to be able to calculate reliable dietary intakes, it is important to include the variability in food composition data.

Outcome in children with brain tumours diagnosed in the first year of life: long-term complications and quality of life.

OBJECTIVE: To study the outcome in children with brain tumours diagnosed in the first year of life, we followed up 27 consecutive children who were diagnosed between 1980 and 2005 in a single institution. METHODS: Tumour control and neurological, endocrine and cognitive complications and their impact on behavioural and emotional adjustment and health-related quality of life (HRQoL) were comprehensively assessed in 11 survivors (mean follow-up time 12.3 years). RESULTS: Persistent neurological complications occurred in 9/11 patients, endocrine and growth complications in 4/11, and cognitive deficits leading to school problems/impaired choice of occupation in 8/10. Behavioural and psychological adjustment problems were reported by 4/6 patients and 7/10 parents. HRQoL as rated by patients and their parents was considerably lower than that of healthy controls. In comparison with healthy controls, social functioning was rated by the patients and the parents as the QoL dimension most affected. HRQoL was lowest for patients with high-grade tumour histology and more intense therapy. CONCLUSION: Long-term survivors of brain tumours diagnosed in the first year of life are not only at great risk of neurological and cognitive complications, but also of social isolation thereby substantially decreasing self-rated HRQoL.

Quantification of risperidone and 9-hydroxyrisperidone in plasma and saliva from adult and pediatric patients by liquid chromatography-mass spectrometry.

A robust and validated LC-MS-MS quantitative method, using column switching and mutiple reaction monitoring was developed for the analysis of risperidone (RIS) and 9-hydroxyrisperidone in human plasma and saliva. The analytical range was 1-100 ng/ml. The method used 25 microl of sample precipitated with 75 microl of acetonitrile containing internal standard (R068808). Analyses were conducted on a PE Sciex API-III + triple quadrupole mass spectrometer fitted with a Turbo IonSpray source. The method was validated for human plasma using EDTA as the anticoagulant and cross-validated to heparinized human plasma and saliva. The recoveries of risperidone and 9-hydroxyrisperidone were 90-93 and 89-93%, respectively. The validated method was applied to clinical samples to study risperidone and 9-hydroxyrisperidone concentrations in plasma and saliva. Risperidone and 9-hydroxyrisperidone appear in the saliva of patients treated with risperidone. Their detection/quantification in saliva provides evidence for recent adherence with therapy.

Role of conformational changes in the heme-dependent regulation of human soluble guanylate cyclase.

Soluble guanylate cyclase (sGC) is a receptor for endogenous and exogenous nitric oxide (NO) and is activated many fold upon its binding, making it a core enzyme in the nitric oxide signal transduction pathway. Much effort has been made to understand the link between binding of NO at the sGC heme and activation of the cyclase activity. We report here the first direct evidence for the role of conformational changes in transmitting the signal between the heme and cyclase domains. Using both circular dichroism (CD) and fluorescence spectroscopies, we have probed the effect that the sGC activators NO and 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl-indazole (YC-1) and the inhibitor 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ) have on the structure of the protein. Surprisingly, binding of either ODQ or YC-1 to NO-bound sGC cause virtually identical changes in the far-UV CD spectra of sGC, reflecting a perturbation in the secondary structure of the enzyme. This change is absent upon binding of NO, YC-1 or ODQ alone. Using this and previous data, we propose a working model for the mechanism of activation of sGC by NO and YC-1 and inhibition by ODQ.

Human soluble guanylate cyclase: functional expression, purification and structural characterization.

Soluble guanylate cyclase is an enzyme that catalyzes formation of cGMP from GTP and is a member of the nucleotide cyclase family of enzymes. sGC is a receptor for endogenous and exogenous nitric oxide and is activated several-fold upon its binding, constituting a core enzyme in the nitric oxide signal transduction pathway. cGMP generated by sGC is an important second messenger that regulates activity of several enzymes triggering such important physiologic reactions as vasodilation, smooth muscle relaxation and platelet aggregation. We report here the functional expression of the human isoform of soluble guanylate cyclase in HighFive insect cells using a baculovirus expression system. Highly active recombinant protein was obtained without heme reconstitution or supplementation of the cell growth medium and the level of protein expression was found to be heavily affected by the composition of the growth medium. We have successfully purified highly active sGC (sp act up to 940 nmol/min/mg) from adherent cultures using a three-column, 1-day procedure. The UV-Vis spectrum of the isolated protein shows a Soret band at 431 nm, consistent with a histidine-ligated, 5-coordinate heme as previously reported. Far UV CD spectroscopy, intrinsic tryptophan fluorescence, fluorescence of the hydrophobic dye bis-ANS, size-exclusion chromatography, and small angle X-ray scattering (SAXS) were used to characterize the structural properties of the purified sGC. We used two hierarchical neural network methods to predict the secondary structure of sGC and found it to be consistent with the observed CD spectrum of sGC.