Assessing inter and intrafraction uncertainties in adult brain cancer patients using 2D/3D kV and CBCT imaging.

METHOD: 2D/3D kV imaging and CBCT data using 6 degrees of freedom (6DoF) were compared to evaluate inter and intrafraction motion. RESULTS: Results showed that intrafraction errors were low and interfraction levels were within institutional protocols. CONCLUSION: Confidence was given to use low dose 2D/3D kV imaging to confirm daily patient set up errors, and to use pre-treatment CBCT only once weekly for additional imaging information. IMPLICATIONS FOR PRACTICE: Further research is necessary to assess other uncertainties, to enable the calculation of a margin and determining the feasibility of further reduction of this.

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT.

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/ß)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/ß)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

Simultaneous 68Ga DOTATATE Positron Emission Tomography/Magnetic Resonance Imaging in Meningioma Target Contouring: Feasibility and Impact Upon Interobserver Variability Versus Positron Emission Tomography/Computed Tomography and Computed Tomography/Magnetic Resonance Imaging.

AIMS: The increasing use of highly conformal radiation techniques to treat meningioma confers a greater need for accurate targeting. Several groups have shown that positron emission tomography/computed tomography (PET/CT) information alters meningioma targets contoured by single observers, but whether this translates into improved accuracy has not been defined. As magnetic resonance imaging (MRI) is the cornerstone of meningioma target contouring, simultaneous PET/MRI may be superior to PET/CT. We assessed whether 68Ga DOTATATE PET imaging (from PET/CT and PET/MRI) reduced interobserver variability (IOV) in meningioma target volume contouring. MATERIALS AND METHODS: Ten patients with meningioma underwent simultaneous 68Ga DOTATATE PET/MRI followed by PET/CT. They were selected as it was anticipated that target volume definition in their cases would be particularly challenging. Three radiation oncologists contoured target volumes according to an agreed protocol: gross tumour volume (GTV) and clinical target volume (CTV) on CT/MRI alone, CT/MRI+PET(CT) and CT/MRI+PET(MRI). GTV/CTV Kouwenhoven conformity levels (KCL), regions of contour variation and qualitative differences between PET(CT) and PET(MRI) were evaluated. RESULTS: There was substantial IOV in contouring. GTV mean KCL: CT/MRI 0.34, CT/MRI+PET(CT) 0.38, CT/MRI+PET(MRI) 0.39 (P = 0.06). CTV mean KCL: CT/MRI 0.31, CT/MRI+PET(CT) 0.35, CT/MRI+PET(MRI) 0.35 (P = 0.04 for all groups; P > 0.05 for individual pairs). One observer consistently contoured largest and one smallest. Observers rarely decreased volumes in relation to PET. Most IOV occurred in bone followed by dural tail, postoperative bed and venous sinuses. Tumour edges were qualitatively clearer on PET(MRI) versus PET(CT), but this did not affect contouring. CONCLUSION: IOV in contouring challenging meningioma cases was large and only slightly improved with the addition of 68Ga DOTATATE PET. Simultaneous PET/MRI for meningioma contouring is feasible, but did not improve IOV versus PET/CT. Whether volumes can be safely reduced according to PET requires evaluation.

Radiation exposure to comforters and carers during paediatric molecular radiotherapy.

BACKGROUND: To show whether the incidental radiation exposure received by comforters and carers of children undergoing molecular radiotherapy was kept as low as reasonably achievable and was within English national dose constraints. PROCEDURE: The radiation exposure of adult comforters and carers was routinely monitored with a whole body personal dose meter while the child was in hospital. Data were collected on iodine-131 meta-iodobenzylguanidine (131 I-mIBG), lutetium-177 DOTATATE (177 Lu-DOTATATE), and iodine-131 sodium iodide (131 I-NaI) treatments. RESULTS: Data were available for 50 treatments with high-administered activity double-infusion 131 I-mIBG and 12 single administrations; 15 177 Lu-DOTATATE treatments and 28 131 I-NaI administrations. The median age was 7 years (1-18). The median administered activity of: 131 I-mIBG was 16.2 GBq (6.8-59 GBq) for double infusion patients and 8.1 GBq (5.26-16.25 GBq) for single administrations; 177 Lu-DOTATATE was 7.2 GBq (2.5-7.5 GBq); and 131 I-NaI was 3 GBq for thyroid remnant ablation and 5.5 GBq for cancer therapy. The median number of comforters and carers for all administrations was 2 (range 1-9). The median exposure values for comforters and carers for high-administered activity 131 I-mIBG administrations was 302 µSv (0-5282 µSv); for single fraction 131 I-mIBG 163 µSv (3-3104 µSv); 177 Lu-DOTATATE 6 µSv (1-79 µSv); and 131 I-NaI 37 µSv (0-274 µSv). Only one of the comforters and carers exceeded the dose constraint of 5 mSv. CONCLUSIONS: Doses to comforters and carers were in all but one case within the dose constraint nationally recommended by the Health Protection Agency, now part of Public Health England. New evidence is presented which show that comforter and carer radiation exposure levels from paediatric molecular radiotherapy in routine clinical practice are acceptably low. Pediatr Blood Cancer 2015;62:235-239. © 2014 Wiley Periodicals, Inc.

Controversies in radiotherapy for meningioma.

Meningiomas are the most common primary intracranial tumour. Although external beam radiotherapy and radiosurgery are well-established treatments, affording local control rates of 85-95% at 10 years, the evidence base is mainly limited to single institution case series. This has resulted in inconsistent practices. It is generally agreed that radiotherapy is an established primary therapy in patients requiring treatment for surgically inaccessible disease and postoperatively for grade 3 tumours. Controversy exists surrounding whether radiotherapy should be upfront or reserved for progression for incompletely excised and grade 2 tumours. External beam radiotherapy and radiosurgery have not been directly compared, but seem to offer comparable rates of control for benign disease. Target volume definition remains contentious, including the inclusion of hyperostotic bone, dural tail and surrounding brain, but pathological studies are shedding some light. Most agree that doses around 50-54 Gy are appropriate for benign meningiomas and ongoing European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group studies are evaluating dose escalation for higher risk disease. Here we address the 'who, when and how' of radiotherapy for meningioma.

Sequential transformation of mesenchymal stem cells is associated with increased radiosensitivity and reduced DNA repair capacity.

We used sequentially transformed mesenchymal stem cells to investigate how the events that lead to tumorigenicity influence the cellular response to radiation. Bone marrow derived SH2(+), SH4(+), Stro-1(+) mesenchymal stem cells (MSC) were transformed stepwise by retroviral transfection of hTERT, HPV-16 E6 and E7, SV40 small T antigen and oncogenic H-ras. Cells at three different stages of transformation were irradiated and compared using assays for cytotoxicity, apoptosis, DNA double-strand break (DSB) repair and checkpoint signaling. The effects of inhibition of cell cycle checkpoint signaling on radiosensitivity were investigated using RNA interference. During stepwise transformation, specifically after HPV-16 E6 and E7 transduction, MSCs became more sensitive to radiation. This was associated with increased residual DNA DSB at 24 h and increased apoptosis. Enhanced checkpoint signaling occurred during transformation and there was a differential effect of checkpoint targeting in cells at different stages; Chk1 knockdown enhanced radiosensitivity in all cells while Chk2 knockdown only affected non-transformed cells. These data show that transformation of MSC is associated with a reduction in DNA DSB repair capacity and increased radiosensitivity. Up-regulation of checkpoint signaling does not overcome this and the effect of checkpoint inhibition may change with transformation status.

The association between metal ions from hip resurfacing and reduced T-cell counts.

We have studied the relationship between metal ion levels and lymphocyte counts in patients with metal-on-metal hip resurfacings. Peripheral blood samples were analysed for lymphocyte subtypes and whole blood cobalt and chromium ion levels in 68 patients (34 with metal-on-metal hip resurfacings and 34 with standard metal-on-polyethylene total hip replacements). All hip components were radiologically well-fixed and the patients were asymptomatic. Cobalt and chromium levels were significantly elevated in the patients with metal-on-metal hip resurfacings, compared with the patients with standard metal-on-polyethylene designs (p < 0.0001). There was a statistically significant decrease in the level of CD8(+) cells (T-cytotoxic/suppressor) (p = 0.005) in the metal-on-metal hip resurfacing group. A threshold level of blood cobalt and chromium ions was associated with reduced CD8(+) T-cell counts. We have no evidence that our patients suffered as a result of this reduced level of CD8(+) T-cells.

The role of radiotherapy in the management of elevated calcitonin after surgery for medullary thyroid cancer.

Among 139 patients with medullary thyroid cancer (MTC) treated at the Royal Marsden Hospital between 1957-1998, 51 had persistently elevated calcitonin levels after initial surgery in the absence of clinically or radiologically demonstrable residual disease. Of these, 24 were treated with radiotherapy because of advanced local disease at presentation; this resulted in normalization of calcitonin in only 1 patient, although 10 remained free of clinical recurrence. Surveillance alone was used in the remaining 27 patients, of whom 8 (30%) remained free of overt disease. Local relapse rate was significantly lower after radiotherapy (29% vs. 59%) but there was no significant difference in 10-year survival between the two groups (72% vs. 60%). In view of this favorable long-term survival of patients with elevated calcitonin on observation, we cannot recommend the routine use of radiotherapy. However, it does appear to have a role in those presenting with more advanced disease to reduce the incidence of loco-regional relapse.

Axonal growth on astrocytes is not inhibited by oligodendrocytes.

Axon growth in vitro may be inhibited by contact with oligodendrocytes, but most axons grow readily on the surface of astrocyte monolayers. Since both cell types are in close contact with one another in the damaged nervous system, we have examined the growth of axons on cultures which contain both astrocytes and oligodendrocytes. Cultures derived from neonatal rat forebrain develop with a monolayer of large flat astrocytes attached to the culture dish, and with many smaller cells of the oligodendrocyte lineage on their surface. Dorsal root ganglia placed on these cultures grow axons readily, the overall extent of growth being unaffected by the presence or absence of oligodendrocytes, many of which express galactocerebroside and the inhibitory molecule janusin. A previous set of experiments had shown that growth of these axons is inhibited by oligodendrocytes by themselves. Scanning electron microscopy coupled with silver-intensified immunostaining reveals that the axons grow on the surface of the astrocytic layer, underneath the oligodendrocytes, and are therefore in contact with both cell types as they grow. The presence of astrocytes therefore alters the results of axonal contact with oligodendrocytes.