Experimental investigation of the implementation of Fermi-Eyges-Hogstrom electron beam model of the Pinnacle3 system at extended SSDs.

A commercially available ADAC Pinnacle(3) radiation treatment planning system has been used to model electron beams from a Varian Clinac 2300C/D in the energy range of 6 to 22 MeV. Prior to clinical use, the dosimetric characteristics of the beams have to be modeled accurately. As a first step for beam modeling, a number of dose profile and depth dose measurements were taken at standard source-to-surface distance (SSD) of 100 cm. Dose profiles and depth dose measurements at extended SSDs up to 120 cm are important for ascertaining accuracy of the model, as well as their clinical usefulness in the treatment of some sites (e.g., head-and-neck tumors). Modeled and measured beam data were compared. Over 98% of comparison points (modeled vs. measured) at 100-cm SSD were within 2.5% or 2.5 mm. At 110 cm SSD, over 98% of compared points were within 4% or 4 mm, and at 120-cm SSD, over 98% of compared points were within 5% or 5 mm. Overall, more than 98% of compared points were within 4% or 4 mm. Better models were produced for lower energies (6 to 15 MeV) than higher energies (18 and 22 MeV). For 6, 9, 12, and 15 MeV, 89% of compared points were within 2% or 2 mm. For 18- and 22-MeV electron energies, 75% and 67%, respectively, were within 2% or 2 mm. These results are consistent with the recommendations of AAPM Task Group Report 53.     

Use of Yttrium-90 TheraSphere for the treatment of unresectable hepatocellular carcinoma

This is a retrospective analysis of a new treatment modality, intra-arterial administration of Yttrium-90 TheraSphere, for unresectable hepatocellular carcinoma (HCC). Patients with HCC not amenable to surgical treatment who had satisfactory physiological function without comorbid disease or significant pulmonary shunting were eligible for treatment. Patients were categorized into complete, partial, or no response based on serum alpha-fetoprotein (AFP) levels and CT or MRI imaging. Fourteen patients were considered candidates for treatment. Three patients were excluded due to significant hepatopulmonary shunting. Eleven patients were treated with TheraSphere. One patient (9%) had a complete response, eight patients (78%) had a partial response, and two patients (18%) showed no response. Partial and complete responders with AFP-associated HCC demonstrated a median decrease in AFP levels of 79 per cent at 73 days. No patients developed liver toxicity nor died due to treatment. Five patients (45%) died of progressive disease at a median of 7 months post-treatment. Six patients (54%) were alive at a median of 11 months (range, 9 to 20 months). Okuda stage 2 and 3 patients showed a median survival of 11 months and 7 months, respectively. Yttrium-90 TheraSphere treatment for unresectable hepatocellular carcinoma is well tolerated and appears to extend survival.     

A novel magnetic approach to enhance the efficacy of cell-based gene therapies

Attempts have been made to use various forms of cellular vectors to deliver therapeutic genes to diseased tissues like malignant tumours. However, this approach has proved problematic due to the poor uptake of these vectors by the target tissue. We have devised a novel way of using magnetic nanoparticles (MNPs) to enhance the uptake of such 'therapeutically armed' cells by tumours. Monocytes naturally migrate from the bloodstream into tumours, so attempts have been made to use them to deliver therapeutic genes to these sites. However, transfected monocytes injected systemically fail to infiltrate tumours in large numbers. Using a new in vitro assay for assessing monocyte extravasation, we show that the ability of transfected human monocytes to migrate across a human endothelial cell layer into a 3D tumour spheroid is markedly increased when cells are pre-loaded with MNPs and a magnetic force is applied close to the spheroid. Furthermore, systemic administration of such 'magnetic' monocytes to mice bearing solid tumours led to a marked increase in their extravasation into the tumour in the presence of an external magnet. This new magnetic targeting approach could be used to increase the targeting, and thus the efficacy, of many cell-based gene therapies in vivo.     

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by a symmetrical, inflammatory arthropathy that frequently results in damage to synovial-lined joints with consequent pain, stiffness, and reduced functional capacity. The prevalence of RA is 0.8–1% in Western Europe and North America, and it is believed to arise from an interplay between genetics and the environment. Smoking is known to be a major risk factor particularly for anticitrullinated protein antibody-positive RA (1), whereas consumption of alcohol reduces both the risk and the severity of RA (2). The severity of RA varies from a mild condition with little joint damage to an unremitting condition that leads to extensive bone and cartilage damage. The radiological severity of damage to the hands and feet is widely used to measure outcome of RA and has been shown to have a significant genetic component (3, 4). Loci genetically associated with radiological damage include DRB1 (5), CD40 (6) and TRAF1/C5 (7), IL-4 (8), and IL-15 (9).A genome-wide association study involving 12,277 RA cases and 28,975 controls, all of European descent, reported association of rs26232 in the first intron of chromosome 5 open reading frame 30 (C5orf30) with risk of RA (10). Importantly linkage disequilibrium did not extend to genes in the flanking regions, indicating that the association was arising from C5orf30. This association was subsequently replicated in a British study of 6,108 RA cases and 13,009 controls (11). In a study of three large European RA populations (n = 1,884), we reported an allele dose association of rs26232 with radiological damage (12).The biological activities of human C5orf30 are unknown, and the precise roles it plays in RA have not yet been reported. There is indirect evidence linking human C5orf30 with immune function via its association with intracellular UNC119 (13); the latter increasing both T-cell activation by up-regulating Lck/Fyn activity and Src kinases regulating macrophages activation (14, 15). There are, however, no studies of the biological functions of human C5orf30 and, in view of the genetic association with RA susceptibility and severity, we have undertaken in silico analysis and both in vitro and in vivo experiments to determine its functional activities in RA. Here, we report C5orf30 to be a yet unidentified negative regulator of tissue damage in RA, acting by modulating the autoaggressive phenotype that is characteristic of RA synovial fibroblasts (RASF). It is highly expressed in the synovium of RA patients compared with healthy and osteoarthritis (OA) predominately by RASF in the lining and sublining layer. These cells play an important role in the initiation and perpetuation of RA and are implicated in cartilage destruction (16). Targeting C5orf30 expression by using siRNA technology resulted in increased invasiveness, proliferation and migration of RASFs in vitro, and modulated expression of genes in RA-relevant pathways including migration and adhesion. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis (CIA) model mice markedly accentuated joint inflammation and cartilage destruction. These data confirm C5orf30 as a previously unidentified regulator of tissue destruction in RA.     

The use of RapidArc volumetric-modulated arc therapy to deliver stereotactic radiosurgery and stereotactic body radiotherapy to intracranial and extracranial targets

Twenty-three targets in 16 patients treated with stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) were analyzed in terms of dosimetric homogeneity, target conformity, organ-at-risk (OAR) sparing, monitor unit (MU) usage, and beam-on time per fraction using RapidArc volumetric-modulated arc therapy (VMAT) vs. multifield sliding-window intensity-modulated radiation therapy (IMRT). Patients underwent computed tomography simulation with site-specific immobilization. Magnetic resonance imaging fusion and optical tracking were incorporated as clinically indicated. Treatment planning was performed using Eclipse v8.6 to generate sliding-window IMRT and 1-arc and 2-arc RapidArc plans. Dosimetric parameters used for target analysis were RTOG conformity index (CI_RTOG), homogeneity index (HI_RTOG), inverse Paddick Conformity Index (PCI), D_mean and D5–D95. OAR sparing was analyzed in terms of D_max and D_mean. Treatment delivery was evaluated based on measured beam-on times delivered on a Varian Trilogy linear accelerator and recorded MU values. Dosimetric conformity, homogeneity, and OAR sparing were comparable between IMRT, 1-arc RapidArc and 2-arc RapidArc plans. Mean beam-on times ± SD for IMRT and 1-arc and 2-arc treatments were 10.5 ± 7.3, 2.6 ± 1.6, and 3.0 ± 1.1 minutes, respectively. Mean MUs were 3041, 1774, and 1676 for IMRT, 1-, and 2-arc plans, respectively. Although dosimetric conformity, homogeneity, and OAR sparing were similar between these techniques, SRS and SBRT fractions treated with RapidArc were delivered with substantially less beam-on time and fewer MUs than IMRT. The rapid delivery of SRS and SBRT with RapidArc improved workflow on the linac with these otherwise time-consuming treatments and limited the potential for intrafraction organ and patient motion, which can cause significant dosimetric errors. These clinically important advantages make image-guided RapidArc useful in the delivery of SRS and SBRT to intracranial and extracranial targets.     

Female double urethra: a case report

Female double urethra is a very rare anomaly, with less than 40 cases reported since 1970. Most reported cases of double urethra are in the sagittal plane and tend to be stenotic. We describe a 4-year-old girl with double urethra, which was not stenotic and was in the coronal plane. Double urethra should be excluded among other causes in any girl who is incontinent beyond the continence age.     

Mathematical modeling predicts synergistic antitumor effects of combining a macrophage-based, hypoxia-targeted gene therapy with chemotherapy

Tumor hypoxia is associated with low rates of cell proliferation and poor drug delivery, limiting the efficacy of many conventional therapies such as chemotherapy. Because many macrophages accumulate in hypoxic regions of tumors, one way to target tumor cells in these regions could be to use genetically engineered macrophages that express therapeutic genes when exposed to hypoxia. Systemic delivery of such therapeutic macrophages may also be enhanced by preloading them with nanomagnets and applying a magnetic field to the tumor site. Here, we use a new mathematical model to compare the effects of conventional cyclophosphamide therapy with those induced when macrophages are used to deliver hypoxia-inducible cytochrome P450 to locally activate cyclophosphamide. Our mathematical model describes the spatiotemporal dynamics of vascular tumor growth and treats cells as distinct entities. Model simulations predict that combining conventional and macrophage-based therapies would be synergistic, producing greater antitumor effects than the additive effects of each form of therapy. We find that timing is crucial in this combined approach with efficacy being greatest when the macrophage-based, hypoxia-targeted therapy is administered shortly before or concurrently with chemotherapy. Last, we show that therapy with genetically engineered macrophages is markedly enhanced by using the magnetic approach described above, and that this enhancement depends mainly on the strength of the applied field, rather than its direction. This insight may be important in the treatment of nonsuperficial tumors, where generating a specific orientation of a magnetic field may prove difficult. In conclusion, we demonstrate that mathematical modeling can be used to design and maximize the efficacy of combined therapeutic approaches in cancer.     

The University of California, Irvine experience with tomotherapy using the Peacock system.

Our institutional experience using the Peacock system for intensity-modulated radiation therapy (IMRT) is summarized. Over 100 patients were treated using this system, which is fitted to a Clinac 600C linac. Both cranial and extracranial lesions have been treated using this modality. Immobilization is achieved either with the Talon system for cranial sites or an Aquaplast cast. Target volumes up to 500 cm3 have been treated. Multiple lesions (up to 3) were treated in one setup. The range of dose/fractionation schemes used was 15 Gy/1 fx (radiosurgical treatment) - 80 Gy/40 fx. Dose validation studies were carried out using film and ion chamber dosimetry in a specially designed phantom. Optimal dose distributions were attainable using inverse treatment planning for IMRT delivery. These were found to encompass the target volumes accurately using dose validation phantom studies. Immobilization methods used were accurate to within 1 mm, as evidenced by daily portal films. IMRT using the Peacock system offers the advantage of delivery of conformal therapy to high doses safely and accurately. This provides the opportunity for dose escalation studies, retreatment of previously treated tumors, as well as treating multiple targets in one setup. The system may be fitted to a conventional linac without major modifications.