Radiotherapy Advances in Paediatric Medulloblastoma Treatment.

Radiotherapy is an essential element in the multidisciplinary management of children with medulloblastoma and postoperative craniospinal axis radiotherapy is considered to be the cornerstone of curative treatment. With modern multidisciplinary management, more than 80% of children with standard-risk medulloblastoma and up to 70% of children with high-risk medulloblastoma are long-term survivors. Current clinical trials are evaluating risk-adapted radiotherapy in standard-risk medulloblastoma to reduce long-term sequelae, whereas the research approach in high-risk medulloblastoma is to improve clinical outcome with dose-intensification of chemotherapy and the use of hyperfractionated radiotherapy regimens. Technological advances, such as tomotherapy, volumetric modulated arc therapy and proton therapy, may further improve the therapeutic ratio by reducing radiotherapy toxicities. A selected group of children with recurrent disease after treatment for standard-risk medulloblastoma may be considered for re-irradiation.

Current Management of Intracranial Germ Cell Tumours.

Intracranial germ cell tumours (icGCTs) are uncommon tumours occurring in children and young adults. They are usually segregated into germinomas and non-germinomatous tumours (NGGCTs) in most classifications. Germinomas are highly curable tumours with multimodality treatment, but NGGCTs are associated with poorer survival outcomes. There are some differences in the approach to the management of icGCTs globally. Current research generally focuses on reducing treatment intensity, particularly the dose and volume of radiotherapy, in order to minimise the risks of late sequelae while maintaining high cure rates in icGCTs.

Borderline Sarcomas and Smooth Muscle Tumours of Uncertain Malignant Potential.

Borderline sarcomas and smooth muscle tumours of uncertain malignant potential (STUMP) have an unpredictable clinical behaviour with frequent local recurrences and rarely, metastases. We review the current management of common subtypes of borderline sarcomas and STUMP.

The value of image-guided intensity-modulated radiotherapy in challenging clinical settings.

OBJECTIVE: To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the "standard" indications for IMRT. METHODS: Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV). RESULTS: All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by >3 mm in 19% of fractions, and by >5 mm in 9%. CONCLUSION: IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance. ADVANCES IN KNOWLEDGE: IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.

Assessment of ovarian movement on consecutive pelvic MRI examinations in patients with gynaecological malignancies: what is the planning organ-at-risk volume for radiotherapy?

OBJECTIVES: The aims of this study are to assess the extent of ovarian movement on consecutive MRI examinations in patients with gynaecological malignancies and to define potential safety volumes around the ovaries that may avoid ovarian ablation during pelvic irradiation. METHODS: Patients with cervical, vaginal and endometrial cancer who underwent MRI examinations of the pelvis before and during radiotherapy were included in the study. The position of the ovaries was retrospectively determined on two consecutive axial and sagittal T(2) weighted MRI examinations of the pelvis. Ovarian movement was determined in craniocaudal, anteroposterior and mediolateral directions. Safety volumes were calculated by computing elliptical volumes based on the derived 95% and 99% reference intervals. RESULTS: 30 patients with a gynaecological malignancy were included. Both ovaries could be identified on the MRI examinations in all cases. The safety volumes around the ovaries encompassing 95% and 99% of ovarian movement were 11 and 25 cm(3) (95%), and 24 and 54 cm(3) (99%), for the left and right ovary, respectively. CONCLUSION: Adding a safety volume around the ovaries may reduce the high radiation dose to the ovaries. This could potentially avoid ovarian ablation, reducing significant fertility morbidity.

Fractionated conformal radiotherapy in vestibular schwannoma: early results from a single centre.

AIMS: To assess the local control and cranial nerve toxicity in vestibular schwannoma patients treated with fractionated conformal radiotherapy delivered using a linear accelerator. MATERIALS AND METHODS: Ninety-five patients were referred for consultation to the Oncology Department in Addenbrookes Hospital between 1996 and 2005. The 42 cases who received fractionated conformal radiotherapy are the subject of this analysis. All patients had radiological or symptomatic progression. Conformal radiotherapy was prescribed at 50Gy in 30 fractions over 6 weeks, delivered using a linear accelerator. Patients were immobilised using either a beam direction shell or a Gill Thomas Cosman relocatable stereotactic head frame. RESULTS: The median age was 63 years (range 28-81) with 57% men. The average tumour size was 21.5mm on magnetic resonance imaging. Before treatment, 20 (48%) patients were deemed to have useful hearing on the affected side. The median follow-up was 18.6 months (range 0.3-6.5 years) and the actuarial local control rate at 2.5 years was 96.9% (one patient progressed after treatment). In previously hearing patients, the actuarial rate of useful hearing preservation was 100%, and the rate of mild hearing loss was 20% at 1 year and 26.7% at 2.5 years of follow-up. There were five neurofibromatosis type 2 patients treated, two of whom had useful hearing before radiotherapy. In one patient this was affected, with a 20dB loss, although he still has useful hearing. In those with normal facial nerve function before radiotherapy (n=40), this was preserved in 96.8% at 2.5 years. Trigeminal nerve function was preserved in all patients (n=38) who had normal nerve function before radiotherapy. CONCLUSION: Although follow-up was relatively short in this single institution series, fractionated linear accelerator radiotherapy gave excellent local control, useful hearing preservation and retained cranial nerve function in vestibular schwannoma.

CT of the chest can hinder the management of seminoma of the testis; it detects irrelevant abnormalities.

To evaluate the role of chest CT in the initial staging of testicular seminomatous germ cell tumours. All patients referred to Addenbrooke's Hospital with testicular seminoma from 1 January 2000 to 31 December 2005 were included and case notes retrospectively reviewed. One hundred and eighty-two patients with testicular seminoma were identified, with a median age of 37 years (range 19-74). Most patients had stage I disease (86%). Twenty-four patients had abnormal abdominal CT findings. One hundred and fifty-eight had normal abdominal CT findings but, on initial staging, chest CT reported abnormalities in 13 patients, which, on further follow-up CT were deemed to be irrelevant to the diagnosis of seminoma. There was a further patient with a normal CT abdomen in whom chest CT detected obvious metastatic disease, which was seen on chest x-ray. Overall 18 cases required additional investigations and follow-up for abnormalities subsequently found to be benign. There was a false-positive rate of 10% for initial staging with chest CT. This is the largest reported series of staging CT chest in testicular seminoma. In all patients with normal abdominal CT, normal chest x-ray and abnormal chest CT, subsequent follow-up investigations demonstrated that the lung lesions were incidental findings.

Pelvic radiotherapy in patients with hydronephrosis in stage IIIB cancer of the cervix: renal effects and the optimal timing for urinary diversion?

BACKGROUND AND PURPOSE: Many patients with Stage IIIB cervix cancer (Ca) and hydronephrosis will require ureteral stenting. The timing is important as delays or prolonged overall treatment times adversely affect outcome. Our aim was to measure the effect of pelvic radiotherapy (R/T) on renal function and identify a subset of patients at high risk of acute urinary obstruction during R/T. PATIENTS AND METHODS: From 1/1/2000 to 1/1/2002, all patients with Stage IIIB cervix Ca and hydronephrosis were analysed retrospectively. To quantify the impact of pelvic R/T, all eligible patients from 1/7/2002-1/7/2004 had prospectively recorded baseline biochemistry, creatinine clearance and renal ultrasounds; these were repeated weekly to detect any change in renal function or degree of hydronephrosis. RESULTS: 13 eligible patients were analysed retrospectively, 5 with unilateral hydronephrosis with 40% requiring urinary diversion (UD). 8 had bilateral hydronephrosis, with 75% requiring UD; 50% before R/T and 35% during R/T. Average creatinine clearance (CrCl) was 74 mL/min (1.24 mL/s) in unilateral hydronephrosis , bilateral = 52 mL/min (0.87 mL/s), in those stented during R/T it was < 40 mL/min (0.67 mL/s). The resulting break in R/T was 6 and 19 days. In the prospective study, 5 patients were eligible and 4 consented. 75% had unilateral hydronephrosis and did not require UD with an average CrCl = 71 mL/min (1.19 mL/s). 1 patient with bilateral hydronephrosis had a CrCl of < 20 mL/min (0.33 mL/s) with bilateral stents placed before R/T. CONCLUSIONS: Patients with bilateral hydronephrosis and a low CrCl < 50 mL/min (0.84 mL/s) should be considered for elective UD prior to R/T. Pelvic R/T did not induce any deterioration in renal function or degree of hydronephrosis.

Functional antagonists of sonic hedgehog reveal the importance of the N terminus for activity.

During development, sonic hedgehog functions as a morphogen in both a short-range contact-dependent and in a long-range diffusable mode. Here, we show using a panel of sonic hedgehog variants that regions near the N terminus of the protein play a critical role in modulating these functions. In the hedgehog responsive cell line C3H10T1/2, we discovered that not only were some N-terminally truncated variants inactive at eliciting a hedgehog-dependent response, but they competed with the wild-type protein for function and therefore served as functional antagonists. These variants were indistinguishable from wild-type sonic hedgehog in their ability to bind the receptor patched-1, but failed to induce the hedgehog-responsive markers, Gli-1 and Ptc-1, and failed to promote hedgehog-dependent differentiation of the cell line. They also failed to support the adhesion of C3H10T1/2 cells to hedgehog-coated plates under conditions where wild-type sonic hedgehog supported binding. Structure-activity data indicated that the N-terminal cysteine plays a key regulatory role in modulating hedgehog activity. The ability to dissect patched-1 binding from signaling events in C3H10T1/2 cells suggests the presence of unidentified factors that contribute to hedgehog responses.

Monitoring CP-93,393 reaction mixtures by flow-injection analysis-mass spectrometry.

CP-93,393 is a drug candidate at Pfizer. Flow-injection analysis-mass spectrometry (FIA-MS) was used to monitor reaction completion for CP-93,393 reaction mixtures. FIA-MS provides essentially instantaneous results, is relatively simple to operate, and is a universal system that can be used to monitor any reaction as long as the product has a molecular weight that differs from the molecular weights of the reactants. The mass spectrometer for these studies employed atmospheric pressure chemical ionization. Samples were introduced into the mass spectrometer with a flowing stream of solvent.

Compound mutants for the paralogous hoxa-4, hoxb-4, and hoxd-4 genes show more complete homeotic transformations and a dose-dependent increase in the number of vertebrae transformed.

The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In the mouse, several single mutants for Hox genes show variably penetrant, partial homeotic transformations of vertebrae at their anterior limits of expression, suggesting that compound Hox mutants might show more complete transformations with greater penetrance than the single Hox mutants. Compound mutants for the paralogous group 3 genes, hoxa-3 and hoxd-3, show deletion of a cervical vertebrae, which is not readily interpretable in terms of an alteration in regional identity. Here, we report the skeletal phenotypes of compound mutants in the group 4 Hox genes, hoxa-4, hoxb-4, and hoxd-4. Mice mutant for each of these genes were intercrossed to generate the three possible double mutant combinations and the triple mutant. In contrast to the hoxa-3, hoxd-3 double mutants, group 4 Hox compound mutants displayed clear alterations in regional identity, including a nearly complete transformation of the second cervical vertebrae toward the morphology of the first cervical vertebra in one double mutant combination. In comparing the types of homeotic transformations observed, different double mutant combinations showed different degrees of synergism. These results suggest a certain degree of functional redundancy among paralogous genes in specifying regional identity. Furthermore, there was a remarkable dose-dependent increase in the number of vertebrae transformed to a first cervical vertebra identity, including the second through the fifth cervical vertebrae in the triple mutant. Thus, these genes are required in a larger anteroposterior domain than is revealed by the single mutant phenotypes alone, such that multiple mutations in these genes result in transformations of vertebrae that are not at their anterior limit of expression.

Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function.

Hoxd-4 (previously known as Hox-4.2 and -5.1) is a mouse homeobox-containing gene homologous to the Drosophila homeotic gene Deformed. During embryogenesis, Hoxd-4 is expressed in the presumptive hindbrain and spinal cord, prevertebrae, and other tissues. In the adult, Hoxd-4 transcripts are expressed predominantly in the testis and kidney, and to a lesser extent in intestine and heart. To understand the role of Hoxd-4 during mouse embryogenesis, we generated Hoxd-4 mutant mice. Mice heterozygous or homozygous for the Hoxd-4 mutation exhibit homeotic transformations of the second cervical vertebrae (C2) to the first cervical vertebrae (C1) and malformations of the neural arches of C1 to C3 and of the basioccipital bone. The phenotype was incompletely penetrant and showed variable expressivity on both an F2 hybrid and 129 inbred genetic background. The mutant phenotype was detected in the cartilaginous skeleton of 14.5-day (E14.5) mutant embryos but no apparent differences were detected in the somites of E9.5 mutant embryos, suggesting that the abnormalities develop after E9.5 perhaps during or after resegmentation of the somites to form the prevertebrae. These results suggest that Hoxd-4 plays a role in conferring position information along the anteroposterior axis in the skeleton. The phenotypic similarities and differences between Hoxd-4 and previously reported Hoxa-4 and Hoxb-4 mutant mice suggest that Hox gene paralogs have both redundant and unique functions.

Homeotic transformation of cervical vertebrae in Hoxa-4 mutant mice.

Hoxa-4 (previously known as Hox-1.4) is a mouse homeobox-containing gene that is expressed in the presumptive hindbrain and spinal cord, prevertebrae, and other tissues during embryogenesis. To understand the role of Hoxa-4 during development, we generated Hoxa-4 mutant mice. Homozygous mutants were viable and fertile. Analysis of neonatal skeletons revealed the development of ribs on the seventh cervical vertebra at variable penetrance and expressivity. A low frequency of alterations in sternal morphogenesis was also observed. In addition, we analyzed the skeletons of transgenic mice that overexpress Hoxa-4 and found that the formation of the small rib anlagen that often develop on the seventh cervical vertebra was suppressed. Analysis of adult homozygous mutant skeletons revealed that the dorsal process normally associated with the second cervical vertebra was also found on the third cervical vertebra. These results demonstrate that Hoxa-4 plays a role in conferring positional information along the anteroposterior axis to specify the identity of the third and the seventh cervical vertebrae.

Normal long bone growth and development in type X collagen-null mice.

To investigate the role of type X collagen in skeletal development, we have generated type X collagen-null mice. Surprisingly, mice without type X collagen were viable and fertile and had no gross abnormalities in long bone growth or development. No differences were detected between the type X collagen-null mice and controls when growth plates of both newborn and 3-week old mice were examined by histology and by immunostaining for extracellular matrix components of bone including osteopontin, osteocalcin and type II collagen. Our results suggest that type X collagen is not required for long bone development. However, mice and humans with dominant acting type X collagen mutations have bone abnormalities, suggesting that only the presence of abnormal type X collagen can modify bone growth and development.