Hypothalamic-pituitary axis irradiation dose thresholds for the development of hypopituitarism in adult-onset gliomas.

BACKGROUND: Childhood brain tumour survivors who receive cranial radiotherapy undergo regular surveillance for the development ofhypothalamic-pituitary (HP) axis dysfunction. Much less attention has been given to radiation-induced hypopituitarism in patients with malignant brain tumours of adult onset. DESIGN: Retrospective cohort study. PATIENTS/MEASUREMENTS: We assessed the effects of cranial radiotherapy (cXRT) on pituitary function in 58 adults (32 male) with gliomas distant to the HP axis. The XRT dose exposure at the HP axis was correlated with individual axis dysfunction to establish dose thresholds. RESULTS: Mean age at cXRT was 41.2 ± 10.9 years and duration of endocrine follow-up 8.2 ± 5.2 years. Mean XRT dose to the HP axis was 35.9 ± 15.5 Gy. Overall prevalence of radiation-induced hypopituitarism was 84.5%. GH, LH/FSH, ACTH and TSH deficiency were present in 82.8%, 20.7%, 19% and 6.9% of patients, respectively. Hyperprolactinaemia was noted in 10.3% (n = 6) and was persistent in one case. GH deficiency and "any degree of hypopituitarism" positively correlated with the radiotherapy dose to the hypothalamic-pituitary axis. HP axis XRT dose thresholds for the development of GHD, LH/FSH, ACTH and TSH deficiency were established at 10, 30, 32 and 40.8 Gy, respectively. A gradual increase in the prevalence of all anterior pituitary hormone deficits was observed throughout the follow-up period. CONCLUSIONS: Hypopituitarism post-cXRT in adults with gliomas is a frequent, progressive and dose-dependent phenomenon. Dose thresholds suggest long-term endocrine surveillance is important where the HP axis XRT dose is higher than 30 Gy. Identification of deficits to allow early and appropriate hormone replacement therapy is important to improve well-being in these individuals with limited prognosis.

Intra-fraction motion gating during frameless Gamma Knife® Icon™ therapy: The relationship between cone beam CT assessed intracranial anatomy displacement and infrared-tracked nose marker displacement.

METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Validity of the use of nose tip motion as a surrogate for intracranial motion in mask-fixated frameless Gamma Knife® Icon™ therapy.

This study investigates the validity of monitoring nose movement, using an infrared stereoscopic camera system (HDMM), to evaluate intracranial movement during treatment with the Icon™-model Gamma Knife®. METHODS: The HDMM was validated by comparison against known displacements. Next, an anthropomorphic phantom was rotated to register nose displacements on the HDMM, which were compared to the displacements of seven intracranial locations determined by cone-beam CT (CBCT). Similarly, CBCT-calculated intracranial displacements were compared against HDMM-reported nose displacements for patients. RESULTS: HDMM-indicated displacements were accurate within 0.06mm mean. In the phantom, CBCT-calculated nose displacements agreed within 0.05mm (mean) of HDMM-reported nose displacements. In 16 instances intracranial displacements exceeded nose displacements; at the most extreme by 73% (2.76mm versus 1.59mm). Overall, intracranial anatomy displaced by 43% (mean) less than the nose. Patient data included no intracranial target displacements exceeding nose displacements. CONCLUSIONS: Intracranial phantom and patient anatomy displaced by approximately half that of the nose, suggesting nose movement is generally a suitable surrogate for intracranial movement. The study constitutes the presentation of a simple, robust method that can be applied to determine the relationship between nose tip and intracranial motion in real patients undergoing frameless treatments on Icon™.

Pituitary dysfunction following cranial radiotherapy for adult-onset nonpituitary brain tumours.

OBJECTIVE: 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.

Radiotherapy for benign disease; assessing the risk of radiation-induced cancer following exposure to intermediate dose radiation.

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.

Quantifying and improving the efficiency of Gamma Knife treatment plans for brain metastases: results of a 1-year audit.

OBJECT: 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. METHODS: 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). RESULTS: 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, 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). CONCLUSIONS: 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 for the treatment of brain metastases: impact of cerebral disease burden on survival.

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 treated < 5000 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 volume > 10,000 mm(3). In addition, largest treated lesion < 5000 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 (p < 0.01) 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.

Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.

BACKGROUND AND PURPOSE: Standard treatment for rectal cancer which threatens the expected plane of resection on MRI imaging is long-course, pre-operative chemoradiotherapy (1.8-2Gy, 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 (5x5Gy) 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.

Clinical grade OK432-activated dendritic cells: in vitro characterization and tracking during intralymphatic delivery.

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.

Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy.

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.

Involved-field, low-dose chemoradiotherapy for early-stage anal carcinoma.

PURPOSE: To report the results of patients with early-stage anal cancer treated using a low-dose, reduced-volume, involved-field chemoradiotherapy protocol. METHODS AND MATERIALS: 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 tumor <2 cm in diameter (T1). All were considered to have Stage N0 disease radiologically. RESULTS: 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. CONCLUSION: 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.

Allogeneic tumor cells expressing fusogenic membrane glycoproteins as a platform for clinical cancer immunotherapy.

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.

Web-based three-dimensional Virtual Body Structures: W3D-VBS.

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.

Volumetric virtual body structures.

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.