Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies.

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.

Effects of altering the dose and timing of triptorelin when given as an intravaginal gel for advancing and synchronizing ovulation in weaned sows.

Previous studies have shown that triptorelin gel (TG) given intravaginally in gel form is effective for advancing the time of ovulation in weaned sows. Three experiments were performed to determine the effects of altering the dose and timing of administration of intravaginal TG for advancing and synchronizing ovulation in weaned sows. In all experiments, estrus was detected twice or three times daily and ultrasound was performed to determine ovulation at 8-hour intervals. In experiment 1, sows (n = 131) received intravaginal gel containing 0 (Placebo), 25, 100, or 200 µg of TG at 96 hours after weaning and sows were inseminated on each day of standing estrus. Wean-to-estrus interval and duration of estrus were correlated (P < 0.0001) with estrus duration longer in TG (P < 0.05) compared with Placebo. More sows ovulated (P < 0.001) by 48 hours after treatment with 200 (81%), 100 (64%), and 25 µg (63%) of TG compared with Placebo (42%). The farrowing rate and total pigs born did not differ (P > 0.10). In experiment 2, sows (n = 126) received 200 µg of TG at 72, 84, or 96 hours after weaning or were untreated (Control-96). Sows receiving TG were inseminated once 24 to 28 hours after treatment. Control-96 sows were inseminated on each day of standing estrus. Wean-to-estrus interval was not affected by treatment, but wean-to-ovulation interval was reduced (P < 0.05) by TG-72 and TG-84 compared with TG-96 and Control-96. More sows ovulated 40 hours after treatment (P < 0.001) with TG-72 (56.5%) and TG-84 (32.2%) compared with TG-96 and Control-96 (13%) and for all TG treatments 48 hours after treatment (64%) compared with Control-96 (34%, P < 0.05). The farrowing rate was lower (P < 0.05) for sows assigned to TG-72 and TG-84 compared with TG-96 and Control-96, whereas the number of liveborn pigs did not differ (P > 0.10). In experiment 3, sows (n = 113) were assigned to receive no treatment (Control), intravaginal gel alone (Placebo), or 200 µg of TG given intravaginally (OvuGel) at 96 hours after weaning. Wean-to-estrus interval did not differ, but the duration of estrus tended (P < 0.10) to be reduced with OvuGel compared with the other treatments. More sows ovulated (P < 0.001) by 48 hours after OvuGel treatment (79.1%) compared with Control (46.4%) and Placebo (37.9%) and by 56 hours (P < 0.05). The farrowing rate and the number of liveborn pigs did not differ among treatments. The results of these studies indicate that 200 µg of TG given intravaginally at 96 hours after weaning (OvuGel) synchronizes ovulation and results in fertility similar to Controls.

Impact of a novel nurse-led prechemotherapy education intervention (ChemoEd) on patient distress, symptom burden, and treatment-related information and support needs: results from a randomised, controlled trial.

BACKGROUND: High levels of distress and need for self-care information by patients commencing chemotherapy suggest that current prechemotherapy education is suboptimal. We conducted a randomised, controlled trial of a prechemotherapy education intervention (ChemoEd) to assess impact on patient distress, treatment-related concerns, and the prevalence and severity of and bother caused by six chemotherapy side-effects. PATIENTS AND METHODS: One hundred and ninety-two breast, gastrointestinal, and haematologic cancer patients were recruited before the trial closing prematurely (original target 352). ChemoEd patients received a DVD, question-prompt list, self-care information, an education consultation≥24 h before first treatment (intervention 1), telephone follow-up 48 h after first treatment (intervention 2), and a face-to-face review immediately before second treatment (intervention 3). Patient outcomes were measured at baseline (T1: pre-education) and immediately preceding treatment cycles 1 (T2) and 3 (T3). RESULTS: ChemoEd did not significantly reduce patient distress. However, a significant decrease in sensory/psychological (P=0.027) and procedural (P=0.03) concerns, as well as prevalence and severity of and bother due to vomiting (all P=0.001), were observed at T3. In addition, subgroup analysis of patients with elevated distress at T1 indicated a significant decrease (P=0.035) at T2 but not at T3 (P=0.055) in ChemoEd patients. CONCLUSIONS: ChemoEd holds promise to improve patient treatment-related concerns and some physical/psychological outcomes; however, further research is required on more diverse patient populations to ensure generalisability.

Poster - Thur Eve - 05: Safety systems and failure modes and effects analysis for a magnetic resonance image guided radiation therapy system.

INTRODUCTION: An online Magnetic Resonance guided Radiation Therapy (MRgRT) system is under development. The system is comprised of an MRI with the capability of travel between and into HDR brachytherapy and external beam radiation therapy vaults. The system will provide on-line MR images immediately prior to radiation therapy. The MR images will be registered to a planning image and used for image guidance. With the intention of system safety we have performed a failure modes and effects analysis. METHODS: A process tree of the facility function was developed. Using the process tree as well as an initial design of the facility as guidelines possible failure modes were identified, for each of these failure modes root causes were identified. For each possible failure the assignment of severity, detectability and occurrence scores was performed. Finally suggestions were developed to reduce the possibility of an event. RESULTS/DISCUSSION: The process tree consists of nine main inputs and each of these main inputs consisted of 5 - 10 sub inputs and tertiary inputs were also defined. The process tree ensures that the overall safety of the system has been considered. Several possible failure modes were identified and were relevant to the design, construction, commissioning and operating phases of the facility. The utility of the analysis can be seen in that it has spawned projects prior to installation and has lead to suggestions in the design of the facility.

SU-D-213CD-06: Workflow and Safety Systems of a Linac-MR Sim-Brachytherapy MRgRT™ Facility.

PURPOSE: To develop the operational workflow and safety systems of a magnetic resonance-guided radiotherapy system (MRgRT™), which comprises an MR scanner on rails that travels between a linac vault, MR simulation room and brachytherapy suite. METHODS: To develop a safe and streamlined clinical workflow, we conducted a comprehensive process review based on a layered approach to overall MRgRT safety that included i) facility design, (ii) workflow iii) system design and interlocks and iv) policies and procedures. We applied existing guidelines for MR and radiation safety, and employed system-level failure modes and effects analyses to design the MRgRT facility and clinical procedures. RESULTS: In the MRgRT system configuration, the MR and treatment systems are physically decoupled and used independently requiring novel administration of existing MR and radiation guidelines. A key element for the safe operation of the moving MR unit is the concept that all three rooms represent zone 4 areas (American College of Radiology guidelines). Using this concept, we applied MR guidelines to develop safe procedures for the overall suite, including screening of all persons entering the suite in zone 2 and control of ferromagnetic materials. We generated a clinical workflow that ensures expedient and safe transition between MR imaging and treatment delivery in both the linac and brachytherapy rooms. In addition, we designed emergency protocols for MRgRT, which helped drive requirements for the facility and system design, e.g., need for an accessible MR-safe stretcher. CONCLUSIONS: We designed the first comprehensive description of the MRgRT workflow, interlocking systems and safety procedures. With this layered approach to safety, we addressed critical aspects regarding safe operation and workflow for the system and provided multiple redundancies for key processes. Coupled with customized staff training, the proposed design ensures the safe operation of the MRgRT facility. This work has received research personnel support from IMRIS.

Improving superficial target delineation in radiation therapy with endoscopic tracking and registration.

PURPOSE: Target delineation within volumetric imaging is a critical step in the planning process of intensity modulated radiation therapy. In endoluminal cancers, endoscopy often reveals superficial areas of visible disease beyond what is seen on volumetric imaging. Quantitatively relating these findings to the volumetric imaging is prone to human error during the recall and contouring of the target. We have developed a method to improve target delineation in the radiation therapy planning process by quantitatively registering endoscopic findings contours traced on endoscopic images to volumetric imaging. METHODS: Using electromagnetic sensors embedded in an endoscope, 2D endoscopic images were registered to computed tomography (CT) volumetric images by tracking the position and orientation of the endoscope relative to a CT image set. Regions-of-interest (ROI) in the 2D endoscopic view were delineated. A mesh created within the boundary of the ROI was projected onto the 3D image data, registering the ROI with the volumetric image. This 3D ROI was exported to clinical radiation treatment planning software. The precision and accuracy of the procedure was tested on two solid phantoms with superficial markings visible on both endoscopy and CT images. The first phantom was T-shaped tube with X-marks etched on the interior. The second phantom was an anatomically correct skull phantom with a phantom superficial lesion placed on the pharyngeal surface. Markings were contoured on the endoscope images and compared with contours delineated in the treatment planning system based on the CT images. Clinical feasibility was tested on three patients with early stage glottic cancer. Image-based rendering using manually identified landmarks was used to improve the registration. RESULTS: Using the T-shaped phantom with X-markings, the 2D to 3D registration accuracy was 1.5-3.5 mm, depending on the endoscope position relative to the markings. Intraobserver standard variation was 0.5 mm. Rotational accuracy was within 2°. Using the skull phantom, registration accuracy was assessed by calculating the average surface minimum distance between the endoscopy and treatment planning contours. The average surface distance was 0.92 mm with 93% of all points in the 2D-endoscopy ROI within 1.5 mm of any point within the ROI contoured in the treatment planning software. This accuracy is limited by the CT imaging resolution and the electromagnetic (EM) sensor accuracy. The clinical testing demonstrated that endoscopic contouring is feasible. With registration based on em tracking only, accuracy was 5.6-8.4 mm. Image-based registration reduced this error to less than 3.5 mm and enabled endoscopic contouring in all cases. CONCLUSIONS: Registration of contours generated on 2D endoscopic images to 3D planning space is feasible, with accuracy smaller than typical set-up margins. Used in addition to standard 3D contouring methods in radiation planning, the technology may improve gross tumour volume (GTV) delineation for superficial tumors in luminal sites that are only visible in endoscopy.

Implementation and characterization of a 320-slice volumetric CT scanner for simulation in radiation oncology.

PURPOSE: Effective target definition and broad employment of treatment response assessment with dynamic contrast-enhanced CT in radiation oncology requires increased speed and coverage for use within a single bolus injection. To this end, a novel volumetric CT scanner (Aquilion One, Toshiba, Tochigi Pref., Japan) has been installed at the Princess Margaret Hospital for implementation into routine CT simulation. This technology offers great advantages for anatomical and functional imaging in both scan speed and coverage. The aim of this work is to investigate the system's imaging performance and quality as well as CT quantification accuracy which is important for radiotherapy dose calculations. METHODS: The 320-slice CT scanner uses a 160 mm wide-area (2D) solid-state detector design which provides the possibility to acquire a volumetric axial length of 160 mm without moving the CT couch. This is referred to as "volume" and can be scanned with a rotation speed of 0.35-3 s. The scanner can also be used as a 64-slice CT scanner and perform conventional (axial) and helical acquisitions with collimation ranges of 1-32 and 16-32 mm, respectively. Commissioning was performed according to AAPM Reports TG 66 and 39 for both helical and volumetric imaging. Defrise and other cone-beam image analysis tests were performed. RESULTS: Overall, the imaging spatial resolution and geometric efficiency (GE) were found to be very good (>10 lp/mm, <1 mm spatial integrity and GE160 mm=85%) and within the AAPM guidelines as well as IEC recommendations. Although there is evidence of some cone-beam artifacts when scanning the Defrise phantom, image quality was found to be good and sufficient for treatment planning (soft tissue noise <10 HU). Measurements of CT number stability and contrast-to-noise values across the volume indicate clinically acceptable scan accuracy even at the field edge. CONCLUSIONS: Initial experience with this exciting new technology confirms its accuracy for routine CT simulation within radiation oncology and allows for future investigations into specialized dynamic volumetric imaging applications.

Improving observer variability in target delineation for gastro-oesophageal cancer--the role of (18F)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography.

AIM: To evaluate the effect of the addition of fused positron emission tomography-computed tomography (PET-CT) imaging vs computed tomography alone in the identification of the gross tumour volume (GTV) in patients with gastro-oesophageal carcinoma. MATERIALS AND METHODS: Ten patients with gastro-oesophageal cancer referred for radiation therapy underwent both (18F)fluoro-2-deoxy-d-glucose-PET (FDG-PET) and computed tomography in the treatment position. Image sets were anonymised and co-registered. Six radiation oncologists independently defined the GTV, first using the computed tomography data alone supplemented by standardised clinical and diagnostic imaging information, and second, using co-registered computed tomography and FDG-PET data (PET-CT). The standard deviation for both GTV length and volume (excluding involved lymph nodes) was taken as a measurement of inter-observer and intra-observer variability. Computer software that calculates volume overlap between contours was also used to generate an observer agreement index to compare intra- and inter-observer variability. RESULTS: The addition of FDG-PET imaging decreased the median standard deviation for tumour length from 10 mm (range 8.1-33.3, mean 12.4 mm) for computed tomography alone to 8mm (range 4.4-18.1, mean 8.1 mm) for PET-CT (P = 0.02). Eight of the 10 patients showed an increase in volume of overlap between observers with the addition of FDG-PET imaging to the contouring process (P = 0.05). The average observer agreement index in PET-CT was 72.7% compared with 69.1% when using computed tomography alone. There was significantly less intra-observer variability in all measures when PET-CT was used. The median standard deviation in length improved from 5.3 to 1.8 mm, the median standard deviation in volume improved from 4.5 to 3 cm3 and the median observer agreement index improved from 76.2 to 78.7% when computed tomography alone was compared with PET-CT. The corresponding P values were 0.001, 0.033 and 0.022, respectively. CONCLUSIONS: The addition of FDG-PET to computed tomography-based planning for the identification of primary tumour GTV in patients with gastro-oesophageal carcinoma decreases both inter-observer and intra-observer variability.

A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

OBJECTIVES: To determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with selective serotonin reuptake inhibitors (SSRIs) plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. DESIGN: A pragmatic randomised controlled trial (RCT) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation. SETTING: Six English CAMHS participated in the study. PARTICIPANTS: A total of 208 patients aged between 11 and 17 years were recruited and randomised. INTERVENTIONS: All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT. MAIN OUTCOME MEASURES: The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS). RESULTS: Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on a severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at any time point. This lack of difference held when baseline and treatment characteristics where taken into account (age, sex, severity, co-morbid characteristics, quality and quantity of CBT treatment, number of clinic attendances). The SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group (p=0.057) and no more cost-effective. Over the trial period there was on average a decrease in suicidal thoughts and self-harm compared with levels recorded at baseline. There was no significant increase in disinhibition, irritability and violence compared with levels at baseline. Around 20% (n=40) of patients in the trial were non-responders. Of these, 17 (43%) showed no improvement by 28 weeks and 23 (57%) were considered minimally (n=10) or moderately to severely worse (n=13). CONCLUSIONS: For moderately to severely depressed adolescents who are non-responsive to a BII, the addition of CBT to fluoxetine plus routine clinical care does not improve outcome or confer protective effects against adverse events and is not cost-effective. SSRIs (mostly fluoxetine) are not likely to result in harmful adverse effects. The findings are broadly consistent with existing guidelines on the treatment of moderate to severe depression. Modification is advised for those presenting with moderate (6-8 symptoms) to severe depressions (>8 symptoms) and in those with either overt suicidal risk and/or high levels of personal impairment. In such cases, the time allowed for response to psychosocial interventions should be no more than 2-4 weeks, after which fluoxetine should be prescribed. Further research should focus on evaluating the efficacy of specific psychological treatments against brief psychological intervention, determining the characteristics of patients with severe depression who are non-responsive to fluoxetine, relapse prevention in severe depression and improving tools for determining treatment responders and non-responders.

Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behavioural therapy in adolescents with major depression.

BACKGROUND: Major depression is an important and costly problem among adolescents, yet evidence to support the provision of cost-effective treatments is lacking. AIMS: To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression. METHOD: Pragmatic randomised controlled trial in the UK. Outcomes and costs were assessed at baseline, 12 and 28 weeks. RESULTS: The trial comprised 208 adolescents, aged 11-17 years, with major or probable major depression who had not responded to a brief initial psychosocial intervention. There were no significant differences in outcome between the groups with and without CBT. Costs were higher in the group with CBT, although not significantly so (P=0.057). Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 30% probability that CBT plus SSRIs is more cost-effective than SSRIs alone. CONCLUSIONS: A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care.

Effect of altering dose of PG600 on reproductive performance responses in prepubertal gilts and weaned sows.

This study evaluated the effects of altering dose of PG600 on estrus and ovulation responses in prepubertal gilts and weaned sows. Experiment 1 tested the effects of one (1.0x, 400IU eCG+200IU hCG, n=74), one and a half (1.5x, n=82), or two (2.0x, n=71) doses of PG600 for prepubertal gilts. Estrus (58%) and ovulation (90%) were not affected (P>0.10) by dose. Higher doses increased (P<0.01) numbers of corpora lutea (17, 24, and 25), but not (P>0.10) the proportion of gilts with cysts (26, 36, and 46% for 1.0x, 1.5x, and 2.0x, respectively). Experiment 2 tested the effects of 0x (n=30), 0.5x (n=32), 1.0x (n=29), or 1.5x (n=30) doses of PG600 in weaned sows. Dose did not influence return to estrus (90%, P>0.10). There was an effect of dose (P<0.05) on incidence of cysts (3.4, 1.8, 6.4, and 29.8%, for 0x, 0.5x, 1.0x, and 1.5x doses, respectively). The 0.5x dose increased (P<0.01) farrowing rate (83.2%) compared to 0x (72.1%) and 1.5x (58.6%), but was not different from 1.0x (76.4%). Total pigs born (10.5+/-0.8) did not differ (P>0.10) among treatments. These data suggest that increasing dose of PG600 to 1.5x for gilts increases the number of corpora lutea but does not alter the proportion expressing estrus or ovulating. Reducing dose of PG600 for weaned sows did not alter estrus or ovulation, but the 0.5x dose increased farrowing rate compared to no PG600.

Effect of PG600 and adjusted mating times on reproductive performance in weaned sows.

The administration of PG600 to sows at weaning induces >90% of sows to return to estrus within a week, but farrowing rate and litter size are often not improved. This study evaluated the effects of adjusted artificial insemination (AI) times based on weaning to estrus interval (WEI) and estrus to ovulation interval (EOI) following PG600. All sows were given PG600 at weaning and allotted to adjusted (ADJ, n=47) or non-adjusted (NA, n=46) mating times after the onset of estrus. Adjusted mating involved: (1) 2-3 days WEI, AI at 36 h and 48 h; (2) 4 days WEI, AI at 24h and 36 h; (3) 5 days WEI, AI at 12h and 24h; and (4) 6-7 days WEI, AI at 0 h and 12h. Mating for NA occurred at 0 h and 24h after onset of estrus. There was no effect of treatment on return to estrus (92.9% versus 92.5%) or ovulation (92.7% versus 92.5% for ADJ and NA, respectively). The proportion of first AI occurring within 24h prior to ovulation was increased (83.8% versus 50.0%) and closer to ovulation for ADJ compared to NA treatment (19.4h versus 27.3h, P<0.05). Treatment did not influence (P>0.10) the proportion of second AI occurring within 24h of ovulation (72.8% versus 56.6%) but did influence (P<0.05) the interval from second AI to ovulation for ADJ compared to NA (10.6h versus 3.3h). The ADJ treatment increased (P<0.05) the proportion of sows that received an AI within 24h before ovulation (98.8% versus 87.0%). However, treatment did not influence pregnancy (87.4%) or farrowing (79.5%) rates but the NA treatment tended to increase (P<0.10) total number of pigs born (11.8 versus 8.9). In conclusion, while AI times for ADJ appeared to occur within optimal periods, farrowing rates were not improved and litter size decreased, suggesting that two AI at 12h intervals and closer to the time of ovulation may be detrimental. Overall, these data suggest that for sows injected with PG600 at weaning and receiving two AI, breeding at 0 h and 24h after onset of estrus is recommended.

Effect of age and physical or fence-line boar exposure on estrus and ovulation response in prepubertal gilts administered PG600.

Boar exposure has been used for estrus induction of prepubertal gilts, but has limited effect on estrus synchronization within 7 d of introduction. In contrast, PG600 (400 IU of PMSG and 200 IU of hCG; Intervet, Millsboro, DE) is effective for induction of synchronized estrus, but the response is often variable. It is unknown whether boar exposure before PG600 administration might improve the efficiency of estrus induction of prepubertal gilts. In Exp. 1, physical or fence-line boar contact for 19 d was evaluated for inducing puberty in gilts before administration of i.m. PG600. Exp. 2 investigated whether 4-d boar exposure and gilt age influenced response to PG600. In Exp. 1, 150-d-old prepubertal gilts were randomly allotted to receive fence-line (n = 27, FBE) or physical (n = 29, PBE) boar exposure. Gilts were provided exposure to a mature boar for 30 min daily. All gilts received PG600 at 169 d of age. Estrous detection continued for 20 d after injection. In Exp. 2, prepubertal gilts were allotted by age group (160 or 180 d) to receive no boar exposure (NBE) or 4 d of fence-line boar exposure (BE) for 30 min daily before receiving PG600 either i.m. or s.c. Following PG600 administration, detection for estrus occurred twice-daily using fence-line boar exposure for 7 d. Results of Exp. 1 indicated no differences between FBE and PBE on estrus (77%), age at puberty (170 d), interval from PG600 to estrus (4 d), gilts ovulating (67%), or ovulation rate (12 corpora lutea, CL). Results from Exp. 2 indicated no effect of age group on estrus (55%) and days from PG600 to estrus (4 d). A greater (P < 0.05) proportion of BE gilts expressed estrus (65 vs. 47%), had a shorter (P < 0.05) interval from PG600 to estrus (3.6 vs. 4.3 d), and had decreased (P < 0.05) age at estrus (174 vs. 189 d) compared with NBE. Ovulation rate was greater (P < 0.05) in the BE group for the 180-d-old gilts (12.7 vs. 11.9 CL) compared with the NBE group. However, age group had no effect on ovulation (77%) or ovulation rate (12 CL). Collectively, these results indicate that physical boar contact may not be necessary when used in conjunction with PG600 to induce early puberty. The administration of PG600 to 180-d-old gilts in conjunction with 4 d prior fence-line boar exposure may improve induction of estrus, ovulation, and decrease age at puberty.

Effect of housing system and boar exposure on estrus expression in weaned sows.

Reproductive efficiency depends on detection of estrus, which may be influenced by housing and boar exposure. This experiment investigated the effects of housing system and boar contact on measures of estrus in weaned sows. Mixed-parity sows were randomly assigned to be weaned into gestation crates away from boars (AWC, n = 45), into pens away from boars (AWP, n = 42), or into pens adjacent to a mature boar (ADJ, n = 46). Estrus detection was initiated at approximately 0700 (0 h) and again at 0.25-, 0.5-, 1-, 2-, 4-, and 8-h intervals beginning on d 4 and continuing through d 7 following weaning. Estrus detection involved observation of the standing response after application of nose-to-nose boar exposure, backpressure, and side rubbing. For the AWC sows, a mature boar was moved to the front of the crates for a 10-min period and then removed. Sows housed in AWP were moved approximately 15 m to an empty pen adjacent to a mature boar for a 10-min period, and then returned to their pen. Sows housed ADJ were not moved and estrus detection was performed in their home pen for a 10-min period. The proportion of sows expressing estrus within 7 d from weaning was lowest for ADJ (80%, 37/46) compared with AWP (98%, 41/42) and AWC (96%, 43/45; P < 0.05). There was an effect of interval from weaning to estrus on the percentage of sows expressing estrus, but there was no interaction with treatment. Sows in AWC and AWP (4.7 d) had decreased (P = 0.01) intervals from weaning to estrus compared with ADJ (5.2 d). The duration of estrus was also shorter (P < 0.001) for ADJ (45 h) compared with AWC (58 h) or AWP (62 h). There was a treatment x interval x day of estrus effect for the percentage of sows expressing estrus. After detection of the first standing response on the first day of estrus, only 62 to 82% of sows were detected standing over the next 2 h for all treatments. However, at 4 to 8 h, this increased to 85 to 98% for the AWC and AWP sows, but <73% of the ADJ sows were detected during this period. On the second day of estrus, estrus expression was not influenced by interval for the AWC and AWP sows and was between 90 to 100% during the 8-h period, whereas ADJ sow detection rates were between 68 to 88%. These data suggest that housing sows adjacent to boars negatively affects estrus expression and detection. In addition, refractory behavior occurs in approximately 30 to 40% of sows and is influenced by housing relative to the boar, day of estrus, and interval from last boar exposure.

A comparison of conventional, conformal and intensity-modulated coplanar radiotherapy plans for posterior fossa treatment.

Radiotherapy of the posterior fossa for medulloblastoma treatment can induce ototoxicity, especially when combined with cisplatin chemotherapy. Sensorineural hearing loss can be severe enough to cause permanent disability, which may compromise cognitive development in paediatric patients. This study evaluates the sparing of the cochlea in conventional radiotherapy, three-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT). CT scans of three patients were used to plan posterior fossa radiotherapy using coplanar beam arrangements. The posterior fossa and the cochlea were contoured as well as other organs-at-risk (non-posterior fossa brain, lenses, optic nerves, pituitary and cervical spinal cord). Three treatment plans were compared: conventional two-dimensional treatment (parallel-opposed lateral pair); 3D-CRT (two wedged posterior oblique fields); and a four-field coplanar IMRT plan. 3D-CRT and IMRT reduced cochlear doses to less than 70% of the mean target dose. These plans also reduced dose to the non-posterior fossa brain and cervical spinal cord. IMRT showed no advantage over 3D-CRT in sparing the optic nerves and lenses, compared with 3D-CRT. Normal tissue doses were higher in both conformal techniques than in the IMRT plans. Conformal techniques reduced the dose to the cochlea, non-posterior fossa brain and cervical spinal cord. The small size and proximity to the planning target volume (PTV) of the cochlea limited the effectiveness of the IMRT plan. Coplanar 3D-CRT was judged superior to coplanar IMRT, particularly in children, because it achieved adequate sparing of the cochlea and anterior cranial structures, such as the lenses and optic nerves, without compromising the dose to the posterior fossa.

Cardiac and respiratory activity at arousal from sleep under controlled ventilation conditions.

Arousal from sleep is associated with elevated cardiac and respiratory activity. It is unclear whether this occurs because of homeostatic mechanisms or a reflex activation response associated with arousal. Cardiorespiratory activity was measured during spontaneous arousals from sleep in subjects breathing passively on a ventilator. Under such conditions, homeostatic mechanisms are eliminated. Ventilation, end-tidal PCO2, mask pressure, diaphragmatic electromyograph, heart rate, and blood pressure were measured in four normal subjects under two conditions: assisted ventilation and a normal ventilation control condition. In the control condition, there was a normal, sleep-related fall in ventilation and rise in end-tidal PCO2. Subsequently, at an arousal, there was an increase in respiratory and cardiac activity. In the ventilator condition, a vigorous cardiorespiratory response to a spontaneous arousal from sleep remained. These results indicate that sleep-related respiratory stimuli are not necessary for the occurrence of elevated cardiorespiratory activity at an arousal from sleep and are consistent with the hypothesis that such activity is at least in part due to a reflex activation response.

Autonomic activity during human sleep as a function of time and sleep stage.

While there is a developing understanding of the influence of sleep on cardiovascular autonomic activity in humans, there remain unresolved issues. In particular, the effect of time within the sleep period, independent of sleep stage, has not been investigated. Further, the influence of sleep on central sympathetic nervous system (SNS) activity is uncertain because results using the major method applicable to humans, the low frequency (LF) component of heart rate variability (HRV), have been contradictory, and because the method itself is open to criticism. Sleep and cardiac activity were measured in 14 young healthy subjects on three nights. Data was analysed in 2-min epochs. All epochs meeting specified criteria were identified, beginning 2 h before, until 7 h after, sleep onset. Epoch values were allocated to 30-min bins and during sleep were also classified into stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. The measures of cardiac activity were heart rate (HR), blood pressure (BP), high frequency (HF) and LF components of HRV and pre-ejection period (PEP). During non-rapid eye movement (NREM) sleep autonomic balance shifted from sympathetic to parasympathetic dominance, although this appeared to be more because of a shift in parasympathetic nervous system (PNS) activity. Autonomic balance during REM was in general similar to wakefulness. For BP and the HF and LF components the change occurred abruptly at sleep onset and was then constant over time within each stage of sleep, indicating that any change in autonomic balance over the sleep period is a consequence of the changing distribution of sleep stages. Two variables, HR and PEP, did show time effects reflecting a circadian influence over HR and perhaps time asleep affecting PEP. While both the LF component and PEP showed changes consistent with reduced sympathetic tone during sleep, their pattern of change over time differed.

Oral zolmitriptan is effective in the acute treatment of cluster headache.

OBJECTIVE: To evaluate the efficacy and tolerability of oral zolmitriptan 5 mg and 10 mg and placebo in cluster headache. METHODS: A multicenter, double-blind, randomized, three-period, crossover, outpatient study. Adult patients received placebo and zolmitriptan 5 mg and 10 mg orally for the acute treatment of episodic or chronic cluster headache. Headache intensity was rated by a five-point scale: none, mild, moderate, severe, or very severe. Patients only treated moderate to very severe headaches. The primary efficacy measure was headache response (two-point or greater reduction from baseline in the cluster headache rating scale) at 30 minutes. Secondary efficacy measures included proportion of patients with initial headache relief within 15 and 30 minutes, mild or no pain at 30 minutes, meaningful headache relief, and use of escape medication. RESULTS: A total of 124 patients took at least one dose of study medication, with 73% having episodic and 27% chronic cluster headache. For the primary endpoint, there was a treatment-by-cluster-headache-type interaction (p = 0.0453). Therefore, results are presented separately for chronic and episodic cluster headache. In patients with episodic cluster headache, the difference between zolmitriptan 10 mg and placebo at 30 minutes reached significance (47% versus 29%; p = 0.02). Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% patients treated with zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo (both p

Cavity theory applied to the dosimetry of systemic radiotherapy of bone metastases.

A two-component model of an osteoblastic metastatic lesion has been developed to determine the absorbed dose delivered to soft tissue during systemic radiotherapy of osseous metastases. Doses to soft tissue from radioisotopes distributed in bone were calculated using Burlin's general cavity theory. A correction term was used to account for the absence of charged particle equilibrium within the metastatic lesion. Radiation doses for 153Sm, 186Re, 89Sr and 32P were calculated for several physiologically realistic lesion structures. Burlin's cavity weighting factor was greatest for higher energy isotopes and it decreased as the soft tissue cavity size increased. The correction for the absence of charged particle equilibrium also decreased with soft tissue pathlength, but increased with average bone pathlengths. Doses to soft tissue cavities ranged from 0.1 to 0.2 Gy MBq(-1) d(-1) for 153Sm to 0.5 to 0.6 Gy MBq(-1) d(-1) for 32P. Using the factors calculated in this work, the dose to soft tissue cavities within bone metastases can be calculated when the dose to adjacent bone has been determined, perhaps by autoradiography or electron paramagnetic resonance dosimetry. The doses calculated with this more accurate model of bone metastases demonstrate errors of 20% to 50% in previous calculations of the average dose to homogeneous metastatic lesions.