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Summary Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding Cancer Research UK.

Gamma Knife Icon™'s high-definition motion management (HDMM) system gates treatment delivery should intra-fraction displacement of a nose marker exceed some user-defined threshold. A method, previously-validated with a phantom, is used to relate intra-fractional displacements of the nose marker to displacements of patient targets. Additionally, novel analysis is performed to ascertain the relationship between nose marker displacement and displacement of a 3D grid of coordinates throughout stereotactic space. This spatial information is used to retrospectively review HDMM threshold levels based upon real target locations.For 41 targets from 22 patients, the mean(standard deviation) and maximum target-to-nose displacement ratio was 0.54(0.32) and 1.65, respectively. On average, displacements typically exceed those of the nose only for coordinates at the most extreme peripheral corner of the investigated 3D grid of points. Allowing target displacement of up to a maximum of 0.8mm, retrospective review indicated that at the locations of the 41 targets a median(range) HDMM threshold of 1.4(1.0-1.9) mm could have been adopted, compared to our standard threshold of 1.0mm.Intracranial targets typically displace by a magnitude around half that of the nose. Novel analysis to determine the spatial variation of target-to-nose displacement ratio suggests, for our 41 targets, HDMM threshold could have been increased from our standard. Cases for which HDMM threshold could be safely increased would minimise treatment gating events and expedite treatment delivery to offer patient comfort benefits.

ObjectA method for quantifying the efficiency of Gamma Knife treatment plans for metastases was previously implemented by the authors to retrospectively identify the least efficient plans and has provided insights into improved planning strategies. The aim of the current work was to ascertain whether those insights led to improved treatment plans.MethodsFollowing completion of the initial study, a 1-year audit of metastasis plans created at St. James's Institute of Oncology was carried out. Audited recent plans were compared with the earlier plans of the initial study, in terms of their efficiency and dosimetric quality. The statistical significance of any differences between relevant plan parameters was quantified by Mann-Whitney U-tests. Comparisons were made between all plans and repeated for a reduced set of plans from which the smallest lesions treated with a single 4-mm shot were excluded. The plan parameters compared were a plan efficiency index (PEI), the number of shots, Paddick conformity index (PCI), gradient index (GI), and percent coverage (of the lesion by the prescription isodose).ResultsA total of 157 metastatic lesions were included in the audit and were compared with 241 in the initial study. In a comparison of all cases, the audited plans achieved a higher median PEI score than did the earlier plans from the initial study (1.08 vs 1.02), indicating improved efficiency of the audited plans. When the smallest lesions (for which there was little scope for varying plan strategy) were discounted, the improvement in median PEI score was greater (1.23 vs 1.03, p < 0.001). This improvement in efficiency corresponds to an estimated mean (maximum) time saving of 15% (66%) per lesion (11 minutes [64 minutes] on the day of treatment). The modified planning strategy yielding these efficiency improvements did not rely on the use of significantly fewer shots (median 11 vs 11 shots, p = 0.924), nor did it result in significant detriment to dosimetric quality (median coverage 99% vs 99%, median PCI 0.84 vs 0.83, p = 0.449, and median GI 2.72 vs 2.67, p = 0.701, audited plans vs initial plans, respectively).ConclusionsChoice of planning strategy can substantially affect plan efficiency and thus strongly influence treatment time. Through increased emphasis on efficiency, resulting from the introduction of PEI combined with a modified planning strategy informed by previous work, it has been possible to reduce times for metastatic plans without compromising their dosimetric quality. Although the average time savings achieved per lesion are moderate, the potential benefits per patient are greater for those with multiple metastases. Reducing treatment times has clear benefits with regard to patient comfort and throughput. In addition, optimization of plan efficiency may potentially affect the biologically effective dose from Gamma Knife treatments and offers opportunity for further work.

In the United States, approximately 13% of the adult population is diagnosed with major depressive disorder in their lifetime (Hasin et al. 2005). Of particular concern, older adults may be at greater risk for depression than other age groups due to developmental, role expectation, and health-related changes (Teachman 2006). Declining physical health is often a primary trigger for depression (Yang 2006), and epidemiological data suggests that 75% of adults 65 and older have at least one, and almost 50% have two or more, chronic illnesses (National Center for Chronic Disease Prevention and Health Promotion 2000). The association between chronic medical conditions and depressive symptoms may be tempered, or exacerbated, by the degree and quality of an individual’s interpersonal relationships. The Interpersonal Theory of Depression proposes that difficulties in interpersonal relationships, perhaps due to recent changes in a major interpersonal role resulting from illness, are a robust contributing factor to the onset and maintenance of depressive symptoms (Davidson et al. 2004;Weissman 2010). Having a large, active social network and the receipt of emotional support may provide a buffer against health-related stressors (Penninx et al. 1998;Yang 2006), whereas loneliness, isolation, or negative social exchanges may exacerbate the effect of poor health on emotional functioning (Cacioppo et al. 2006). In the current study, we investigated the role of three types of social support as potential buffers of the association between illness, impairment and depressive symptoms, including: instrumental support (i.e., assistance with tasks of daily living); perceived support (i.e., subjective quality of and satisfaction with one’s social network); and, social interaction (i.e., the actual extent and availability of one’s social network) (George et al. 1989;Landerman et al. 1989). Of these, perceived social support is often more predictive of depressive symptoms than the objective forms of support (Antonucci et al. 1997). Not all interpersonal relationships are positive or helpful in nature. Concerns over close relationships, and negative social exchanges, are associated with elevated depressive symptoms (Krause et al. 1989). Importantly, dysfunctional familial relationships may impact well-being more than conflicts in peripheral relationships (Abbey et al. 1985), as they threaten enduring commitments. In the context of health dysfunction, family members may become critical, disapproving or rejecting of the health behaviors and decisions of an older adult (Seaburn et al. 2005), which may result in further functional decline, maladaptive health behaviors, increased negative affect, and depression (Bressi et al. 2007;Shields et al. 1992). As such, in the current study, we examined the role of family criticism, or the extent to which an individual perceives the receipt of critical comments from family members (Shields et al. 1994), as a potential exacerbating factor that might strengthen the association between illness or impairment and depressive symptoms. It is not clear from previous research, however, what type of social support, or negative social interaction, is most salient for illness versus impairment, if any differences exist. We hypothesized that both illness burden and functional impairment would be independently associated with greater levels of depressive symptoms. Further, we examined the potential independent and combined moderating effects of family criticism and social support, hypothesizing that family criticism would exacerbate the association between illness/impairment and depressive symptoms, whereas social support variables would buffer this relationship.

Background and purpose Standard treatment for rectal cancer which threatens the expected plane of resection on MRI imaging is long-course, pre-operative chemoradiotherapy (1.8–2 Gy, 25–28 fractions). Not all patients are suitable for this because of age, poor performance status or co-morbidities. We describe our experience of short-course (5 × 5 Gy) pre-operative radiotherapy with planned, delayed surgery (SCPRT-delay) in this patient group. Materials and methods Between April 2001 and October 2007, 43 patients were selected for SCPRT-delay. The clinical records were retrospectively evaluated. Results Median age was 82 (range 58–87). Forty-one patients had radiotherapy of which 26 (61%) were subsequently able to have surgery. Of these, R0, R1 and R2 resections were performed in 22, 2 and 2 patients, respectively. Treatment was well tolerated, although two patients required hospital admission for management of diarrhoea and one developed significant late small bowel toxicity, attributable to radiotherapy. In those undergoing R0 or R1 resection there have been no local recurrences (median follow-up 18 months). Median survival for the whole group was 23 months, although this was 44 months in those undergoing surgery. Conclusions SCPRT-delay appears to be a useful alternative to long-course pre-operative chemoradiotherapy in this high-risk group of patients.

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-alpha, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kappaB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

To report the results of patients with early-stage anal cancer treated using a low-dose, reduced-volume, involved-field chemoradiotherapy protocol.Between June 2000 and June 2006, 21 patients were treated with external beam radiotherapy (30 Gy in 15 fractions within 3 weeks) and concurrent chemotherapy (bolus mitomycin-C 12 mg/m(2) on Day 1 to a maximum of 20 mg followed by infusion 5-fluorouracil 1,000 mg/m(2)/24 h on Days 1-4). Of the 21 patients, 18 underwent small-volume, involved-field radiotherapy and 3 were treated with anteroposterior-posteroanterior parallel-opposed pelvic fields. Of the 21 patients, 17 had had lesions that were excised with close (1 mm) or involved margins, 1 had had microinvasive disease on biopsy, and 3 had had macroscopic tumor2 cm in diameter (T1). All were considered to have Stage N0 disease radiologically.After a median follow-up of 42 months, only 1 patient (4.7%) had experienced local recurrence and has remained disease free after local excision. No distant recurrences or deaths occurred. Only 1 patient could not complete treatment (because of Grade 3 gastrointestinal toxicity). Grade 3-4 hematologic toxicity occurred in only 2 patients (9.5%). No significant late toxicity was identified.The results of our study have shown that for patients with anal carcinoma who have residual microscopic or very-small-volume disease, a policy of low-dose, reduced-volume, involved-field chemoradiotherapy produces excellent local control and disease-free survival, with low rates of acute and late toxicity.

SummaryObjective There are limited data concerning the evolution of radiation-induced hypopituitarism in adult-onset brain tumour (AO-BT) survivors, in part the consequence of the limited survival of many of these individuals. We aim to characterize the pituitary-related outcomes following cranial radiotherapy (cXRT) for adult-onset primary nonpituitary brain tumours. Design We retrospectively analysed longitudinal data of patients with AO-BT who received cXRT within a tertiary cancer referral centre. Patients A total of 107 adults (age 40·0 ± 13·1 years) followed for a median duration of 8 years following cXRT. Measurements Prevalence of radiotherapy-induced hypopituitarism. Results 94·4% received fractionated photon radiotherapy (median dose 54 Gy), while the remaining patients received proton beam or stereotactic radiotherapy. 88·8% of patients developed hypopituitarism during follow-up. The frequency of GH, gonadotrophin, ACTH and TSH deficiencies was 86·9% (severe GHD 64·5%, partial GHD 22·4%), 34·6%, 23·4% and 11·2%, respectively. ACTH deficiency was clinically significant, necessitating glucocorticoid replacement, in only 10·3% of cases. Hyperprolactinaemia developed in 15% of patients, which was persistent in only 50% of cases. Multiple pituitary hormone deficiencies were present in 47·7% of patients, encountered more frequently in patients with tumours in proximity to the sella. Longitudinal data analysis revealed accumulation of hormone deficits throughout the follow-up period, with incidence of all pituitary hormone deficiencies almost doubling between years 2 and 7 of follow-up. Conclusions Pituitary dysfunction in AO-BT survivors following cXRT is a common, evolving, time-dependent phenomenon. It is important that deficits are identified early and replacement therapies introduced to optimize quality of life in these individuals, where prognosis is often guarded.

There has been considerable effort over the last three decades to investigate the role of radiation in rectal cancer. Until the mid 1990’s randomised controlled trials included a standard arm of surgery alone. Today, however, there is unequivocal evidence that adjuvant radiation reduces the risk of local recurrence in resectable rectal cancer. Current controversy relates to the sequencing with respect to surgery, the choice of radiation schedule and the benefits of concurrent chemotherapy. At the same time there have also been important improvements in pelvic preoperative imaging, surgical technique, and histopathological analysis of the resected specimen that will require further randomised trials in order to refine the role of radiation in this new “era.”

Background Recognising that people are entering the last phase of illness isn’t always straightforward, and having conversations about treatment aims and planning for future care is not easy. In light of this a Senior Clinician Development Programme was established, comprising 7 consultants in different specialties and a GP to give a community perspective, facilitated by 2 palliative medicine consultants. This ran for 18 months from October 2011. The following audit specifically looked at oncology, assessing if there was improvement in communication between secondary and primary care. Method All letters to GPs of patients over 18 with a Leeds postcode previously under the care of an oncologist and who died in January 2010 (n=79) and January 2014(n=82) were included. Patients whose treatment was curative and more than 10 years before their death were excluded if they died of an unrelated cause. The improvement plan implemented between the two audits involved an oncology consultant participating in the development programme working alongside a GP in an Action Learning Set and spending time with District Nurses to understand their roles. He then worked with colleagues to highlight the importance of communication with GPs, patients and carers. Results There was a statistically significant improvement in all desired characteristics of the letters between 2010 and 2014. This was most marked in recommendation to add the patient to the palliative care register. There was also a major improvement in documenting discussions with patients about the palliative nature of the disease and emphasis on quality of life. Conclusion This audit shows that educational initiatives with system change can alter consultants’ behaviour. This was a sustained effect, as funding for the development programme finished 2 years before re-auditing. Whilst other factors may contribute, it does demonstrate that long term change in consultant behaviour is possible, particularly when initiated by their peers with insight into department specific issues.

A method for quantifying the efficiency of Gamma Knife treatment plans for metastases was previously implemented by the authors to retrospectively identify the least efficient plans and has provided insights into improved planning strategies. The aim of the current work was to ascertain whether those insights led to improved treatment plans.Following completion of the initial study, a 1-year audit of metastasis plans created at St. James's Institute of Oncology was carried out. Audited recent plans were compared with the earlier plans of the initial study, in terms of their efficiency and dosimetric quality. The statistical significance of any differences between relevant plan parameters was quantified by Mann-Whitney U-tests. Comparisons were made between all plans and repeated for a reduced set of plans from which the smallest lesions treated with a single 4-mm shot were excluded. The plan parameters compared were a plan efficiency index (PEI), the number of shots, Paddick conformity index (PCI), gradient index (GI), and percent coverage (of the lesion by the prescription isodose).A total of 157 metastatic lesions were included in the audit and were compared with 241 in the initial study. In a comparison of all cases, the audited plans achieved a higher median PEI score than did the earlier plans from the initial study (1.08 vs 1.02), indicating improved efficiency of the audited plans. When the smallest lesions (for which there was little scope for varying plan strategy) were discounted, the improvement in median PEI score was greater (1.23 vs 1.03, p0.001). This improvement in efficiency corresponds to an estimated mean (maximum) time saving of 15% (66%) per lesion (11 minutes [64 minutes] on the day of treatment). The modified planning strategy yielding these efficiency improvements did not rely on the use of significantly fewer shots (median 11 vs 11 shots, p = 0.924), nor did it result in significant detriment to dosimetric quality (median coverage 99% vs 99%, median PCI 0.84 vs 0.83, p = 0.449, and median GI 2.72 vs 2.67, p = 0.701, audited plans vs initial plans, respectively).Choice of planning strategy can substantially affect plan efficiency and thus strongly influence treatment time. Through increased emphasis on efficiency, resulting from the introduction of PEI combined with a modified planning strategy informed by previous work, it has been possible to reduce times for metastatic plans without compromising their dosimetric quality. Although the average time savings achieved per lesion are moderate, the potential benefits per patient are greater for those with multiple metastases. Reducing treatment times has clear benefits with regard to patient comfort and throughput. In addition, optimization of plan efficiency may potentially affect the biologically effective dose from Gamma Knife treatments and offers opportunity for further work.

Stereotactic radiosurgery (SRS) for brain metastases has been carried out at the Leeds Gamma Knife Centre since March 2009. The aim of this study was to examine the outcomes and toxicity in our initial cohort of patients. The medical records of patients with brain metastases referred to the Leeds Gamma Knife Centre between March 2009 and July 2010 were retrospectively reviewed. Data on survival, primary tumour, Karnofsky performance status, time from diagnosis to identification of brain metastases, previous treatment for brain metastases and results of staging prior to SRS were recorded. Patients were followed up with regular magnetic resonance imaging of the brain for a minimum of 6 months and data on toxicity and oral steroid dose were recorded. Statistical analysis was carried out using SPSS v14.0. Survival curves were compared using the Log Rank test. Fifty eight patients (19 male) had a median survival of 50.4 weeks (95% CI, 32.6-68.2 weeks). Lung (36%) and breast (27%) were the most common primary tumours. Patients with a total volume of metastases treated5000 mm(3) (p = 0.007) or between 5000 mm(3) and 10,000 mm(3) (p = 0.01) had significantly improved survival compared with patients with a total treated volume10,000 mm(3). In addition, largest treated lesion5000 mm(3) was a positive prognostic factor. Patients with a single metastasis did not survive significantly longer than those with multiple metastases. Steroid dose dropped significantly after SRS (p0.01) and was the same or less in 91% of patients. There were only three cases of grade 3 toxicity. Our study reports survival comparable with other series on radiosurgery and demonstrates a significant decrease in steroid dose following treatment. It also shows that the size of the largest treated metastasis and total volume of metastatic disease seemed a better predictor of outcome than number of metastases treated.

MRI is the preferred staging modality for rectal carcinoma patients. This work assesses the CT-MRI co-registration accuracy of four commercial rigid-body techniques for external beam radiotherapy treatment planning for patients treated in the prone position without fiducial markers.17 patients with biopsy-proven rectal carcinoma were scanned with CT and MRI in the prone position without the use of fiducial markers. A reference co-registration was performed by consensus of a radiologist and two physicists. This was compared with two automated and two manual techniques on two separate treatment planning systems. Accuracy and reproducibility were analysed using a measure of target registration error (TRE) that was based on the average distance of the mis-registration between vertices of the clinically relevant gross tumour volume as delineated on the CT image.An automated technique achieved the greatest accuracy, with a TRE of 2.3 mm. Both automated techniques demonstrated perfect reproducibility and were significantly faster than their manual counterparts. There was a significant difference in TRE between registrations performed on the two planning systems, but there were no significant differences between the manual and automated techniques.For patients with rectal cancer, MRI acquired in the prone treatment position without fiducial markers can be accurately registered with planning CT. An automated registration technique offered a fast and accurate solution with associated uncertainties within acceptable treatment planning limits.

Dendritic cells (DC) are under intense preclinical and early clinical evaluation for the immunotherapy of cancer. However, the optimal culture conditions and route of delivery for DC vaccination have not been established. Here we describe the first human application of DC matured with the bacterial agent OK432 (OK-DC), using a short-term serum-free culture protocol, which generates mature DC from CD14+ precursors after 5 days. These cells were prepared within the framework of a National Blood Service facility, demonstrating that DC represent a product which is potentially deliverable alongside current standardized cell therapies within the UK National Health Service. In vitro analysis confirmed that OK-DC were mature, secreted tumor necrosis factor-alpha, interleukin-6, and interleukin-12, and stimulated both T cell and natural killer cell function. To explore effective delivery of OK-DC to lymph nodes, we performed an initial clinical tracking study of radioactively labeled, unpulsed OK-DC after intralymphatic injection into the dorsum of the foot. We showed that injected DC rapidly localized to ipsilateral pelvic lymph nodes, but did not disseminate to more distant nodes over a 48-hour period. There was no significant toxicity associated with OK-DC delivery. These results show that OK-DC are suitable for clinical use, and that intralymphatic delivery is feasible for localizing cells to sites where optimal priming of innate and adaptive antitumor immunity is likely to occur.

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3–50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.

PURPOSE: Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination. EXPERIMENTAL DESIGN: Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects. RESULTS: Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion. CONCLUSIONS: FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.

Understanding the visuospatial aspects of anatomic structures is one of the most important goals of gross anatomy. Creation of realistic three-dimensional structures of human anatomy has thus been a goal of medical doctors and computer scientists. In this paper, we describe a PC/NT based system in which a user can easily select anatomical structures to be created, along with the chosen connected structures. The system then constructs a three-dimensional volumetric model, a virtual body structure, slice-by-slide. Once the virtual structure is assembled it is possible to "walk" through the volume with coronal, sagittal, and transverse views, or at any angle. The dynamic nature of the system is unique in that it allows for real time choice of volumetric body structures to be created, their rapid generation, and the ability to manipulate the resulting visualization.

Major efforts are being made to improve the teaching of human anatomy to foster cognition of visuospatial relationships. The Visible Human Project of the National Library of Medicine makes it possible to create virtual reality-based applications for teaching anatomy. Integration of traditional cadaver and illustration-based methods with Internet-based simulations brings us closer to this goal. Web-based three-dimensional Virtual Body Structures (W3D-VBS) is a next-generation immersive anatomical training system for teaching human anatomy over the Internet. It uses Visible Human data to dynamically explore, select, extract, visualize, manipulate, and stereoscopically palpate realistic virtual body structures with a haptic device. Tracking user's progress through evaluation tools helps customize lesson plans. A self-guided “virtual tour” of the whole body allows investigation of labeled virtual dissections repetitively, at any time and place a user requires it.

Purpose: In Gamma Knife radiosurgery, an efficient plan is one that achieves dosimetric quality while minimizing treatment time. Although minimization of treatment time to improve throughput and benefit patient comfort is a common and important goal of radiosurgery planning, to date no studies have attempted to specifically quantify efficiency. The aim of this study was to define simple index to score efficiency, and by quantifying time savings achieved by replanning those cases identified as least efficient, so demonstrate the efficacy of the index. Methods: To quantify efficiency, it is necessary to determine treatment times expected for specified lesions. However, because of numerous case-specifics, efficiency cannot be quantified in terms of treatment times alone. This study defines a new quantity, the attenuation-corrected normalized treatment time-dose rate product,nTRPcorr, to account for differing dose rates, prescriptions, and attenuation. A plan efficiency index (PEI) is then defined for lesions of similar volume and shape in terms of expected and planned nTRPcorr. nTRPcorr was retrospectively calculated for metastatic lesions of comparable shape. A curve fitted to data describing how nTRPcorr typically varied with volume for these lesions was then used to determine expected nTRPcorr. For each lesion, PEI was calculated as the ratio of expected-to-planned nTRPcorr. Plans with the lowest PEI were replanned, with the aim of maintaining dosimetric quality while minimizing treatment time. Dosimetric quality was defined in terms of coverage, conformity, and gradient index. Statistical significance of differences between original and replans was quantified via paired t-tests. Results: The mean(standard deviation) PEI of all reviewed lesions was 1.08(0.28). The 14 least efficient plans across the range of investigated volumes (45–19 800 mm3) had a mean PEI of 0.64, versus 1.18 when replanned (p 0.05) change in dosimetric quality. Conclusions: The PEI is a viable metric for identifying those plans that benefit from a more efficient planning strategy.