A standardised pathway for the surveillance of stable vestibular schwannoma.

Introduction Conservative management of patients with a stable vestibular schwannoma (VS) places a significant burden on National Health Service (NHS) resources and yet patients' surveillance management is often inconsistent. Our unit has developed a standardised pathway to guide surveillance imaging of patients with stable VS. In this article, we provide the basis for our imaging protocol by reviewing the measurement, natural history and growth patterns of VS, and we present a cost analysis of implementing the pathway both regionally and nationally. Methods Patients with an extrameatal VS measuring ≤20mm in maximal diameter receive magnetic resonance imaging (MRI) six months after their index imaging, followed by three annual MRI scans, two two-year interval MRI scans, a single three-year interval MRI scan and then five-yearly MRI scans to be continued lifelong. Patients with purely intrameatal tumours follow the same protocol but the initial six-month imaging is omitted. A cost analysis of the new pathway was modelled on our unit's retrospective data for 2015 and extrapolated to reflect the cost of VS surveillance nationally. Results Based on an estimation that imaging surveillance would last approximately 25 years (+/- 10 years), the cost of implementing our regional surveillance programme would be £151,011 per year (for 99 new referrals per year) and it would cost the NHS £1,982,968 per year if implemented nationally. Conclusions A standardised surveillance pathway promotes safe practice in the conservative management of VS. The estimated cost of a national surveillance programme compares favourably with other tumour surveillance initiatives, and would enable the NHS to provide a safe and economical service to patients with VS.

Has the survival of patients with glioblastoma changed over the years?

BACKGROUND: Over the last decade, the approach to the management of brain tumours and the understanding of glioblastoma tumour biology has advanced and a number of therapeutic interventions have evolved, some of which have shown statistically significant effects on overall survival (OS) and progression-free survival in glioblastoma. The aim of this study is to compare survival in glioblastoma patients over a 10-year period (1999-2000 and 2009-2010). METHODS: A retrospective cohort study was performed. Identification of all histologically confirmed glioblastoma in a single centre in years 1999, 2000, 2009 and 2010, and production of survival analysis comparing 1999-2000 and 2009-2010 were achieved. RESULTS: A total of 317 patients were included in the analysis (133 in year 1999-2000, and 184 in year 2009-2010). Cox regression analysis showed that the survival was significantly longer in patients in years 2009-2010 than those in 1999-2000 at P<0.001 with HR=0.56, confidence interval (CI) (0.45-0.71). The 1- and 3-year survival rates were 20.7% and 4.4%, respectively, for patients in 1999-2000, improving to 40.0% and 10.3%, respectively, for patients in 2009-2010. The comparisons between the two groups in survival at 1, 2 and 3 years are all statistically significant at P<0.001, respectively. The median OS was 0.36 and 0.74 in 1999-2000 and 2009-2010 groups, respectively. CONCLUSIONS: Over this period, OS from glioblastoma has increased significantly in our unit. We believe this is due to the institution of evidence-based surgical and oncological strategies practised in a multidisciplinary setting.

Neurobehavioural changes in patients following brain tumour: patients and relatives perspective.

PURPOSE: Patients and relatives experiences of behavioural and personality changes following brain tumour were assessed to determine whether these changes are more prominent in the experience of patients with frontal tumours and their relatives as a first step to evaluate the need to develop appropriate support and management of such changes, which have a substantial impact on social functioning, and ultimately to improve quality of life. METHODS: Patients and relatives rated the patients' current levels of apathy, disinhibition and executive dysfunction on the Frontal Systems Behaviour Scale. Patients also completed the Hospital Anxiety and Depression Scale. The data from 28 patients with frontal tumours and 24 of their relatives, and 27 patients with nonfrontal tumours and 25 of their relatives, were analysed. RESULTS: Patients with frontal tumours rated themselves significantly higher than patients with nonfrontal tumours on all frontal systems-related behaviours. The number of patients reporting clinical levels of difficulty was significantly greater in patients with frontal tumours for disinhibition. The ratings of relatives of patients with frontal tumours were significantly higher than those of relatives of patients with nonfrontal tumours for apathy. Clinically significant levels of apathy and executive dysfunction were however reported by at least 40 % of patients and relatives regardless of tumour location. Clinical levels of anxiety were reported by significantly more patients with frontal tumours than those with nonfrontal tumours. CONCLUSION: Support and management of behavioural and personality change for patients with brain tumours and their relatives, regardless of tumour location, would be most appropriate.

Permanent prostate brachytherapy: a century of technical evolution.

PURPOSE: To summarise the practical aspects of the development of techniques of interstitial permanent prostate brachytherapy (PPB) implantation. Prostate brachytherapy dates back to Pasteau's publication in 1913 describing the insertion of a radium capsule into the prostatic urethra to treat carcinoma of the prostate. Various implantation methods were employed but with unsatisfactory results until the development of the transrectal ultrasound in the 1980s. The subsequent two-stage Seattle technique allowed for a planned homogenous distribution of radioactive sources throughout the gland resulting in biochemical control comparable to surgical and external beam radiotherapy series. With the advent of advanced computer software and improved imaging, the technique has developed accordingly to a single stage procedure with on-table dosimetric assessment. The principles of targeting dose to the prostate while avoiding surrounding organs at risk remain as relevant today as nearly a century ago. There is an array of techniques to consider for the novice PPB provider. Whether the evolution of PPB techniques will translate into improved biochemical control is yet to be seen.

Using combined x-ray and MR imaging for prostate I-125 post-implant dosimetry: phantom validation and preliminary patient work.

Post-implantation dosimetry is an important element of permanent prostate brachytherapy. This process relies on accurate localization of implanted seeds relative to the surrounding organs. Localization is commonly achieved using CT images, which provide suboptimal prostate delineation. On MR images, conversely, prostate visualization is excellent but seed localization is imprecise due to distortion and susceptibility artefacts. This paper presents a method based on fused MR and x-ray images acquired consecutively in a combined x-ray and MRI interventional suite. The method does not rely on any explicit registration step but on a combination of system calibration and tracking. A purpose-built phantom was imaged using MRI and x-rays, and the images were successfully registered. The same protocol was applied to three patients where combining soft tissue information from MRI with stereoscopic seed identification from x-ray imaging facilitated post-implant dosimetry. This technique has the potential to improve on dosimetry using either CT or MR alone.

Cerebral haemangiopericytoma treated with conservative surgery and radiotherapy.

Cerebral haemangiopericytomas are rare tumours that resemble meningiomas but behave more aggressively, with a tendency to metastasize. We report two patients with haemangiopericytoma who had limited surgical resections owing to perioperative blood loss but who had massive tumour shrinkage after a course of radical radiotherapy. We suggest a more conservative surgical approach to the management of these tumours.

A prospective study of PET-FDG imaging for the assessment of head and neck squamous cell carcinoma.

The main aim of the study was to evaluate the use of positron emission tomography using fluoro-deoxyglucose (PET-FDG) imaging for the detection of squamous cell carcinoma of the head and neck. Fifty-four consecutive patients with malignancies involving the head and neck were studied prospectively. Thirty-one patients presented with primary disease and 23 were suspected of recurrent or residual disease. All patients underwent full clinical staging, PET-FDG scans and anatomical imaging, 37 underwent computed tomography (CT), 13 magnetic resonance (MR) and four had both CT and MR. Clinical assessment, CT/MR, PET-FDG and histological examination were all evaluated independently of each other. All 31 primary head and neck malignant tumours were detected by PET-FDG. Based on 16 patients who underwent neck dissections, the sensitivity and specificity of PET-FDG for detecting nodal disease was 67% and 100% respectively, compared with clinical assessment of 58% and 75% and CT/MR of 67% and 25%. In all 12 patients, PET-FDG correctly identified the presence of absence or recurrent or residual disease. PET-FDG staged 13 post-treatment necks with an accuracy of 100% as compared to CT/MR which was accurate in 7 of 13 and clinical assessment which was accurate in eight. Three sites of abnormal tracer uptake unrelated to malignancy were recorded as incidental findings (mandibular osteomyelitis, 1: post glossectomy site, 2). PET-FDG was more accurate than CT/MR for identifying primary and recurrent tumours as well as metastatic lesions in the neck. If these diagnostic properties of PET-FDG are confirmed in further prospective studies, it could prove a valuable adjunct for the management of head and neck cancer.

The use of PET-18FDG imaging in the clinical evaluation of head and neck lymphoma.

Four patients with non-Hodgkin's lymphoma in the head and neck region were studied with positron emission tomography (PET), using the radioactive tracer 2-[F-18]-fluoro-2-deoxy-D-glucose (18FDG). This technique, which exploits the high metabolic rate of glucose in tumour tissue, enabled the extent of disease to be visualized. The localization of the tumour was improved by combining the data from the PET scan with those from CT scans or MRI. This technique (of PET-18FDG), using visual and semiquantitative analysis in the form of standardized uptake values, allowed the differentiation between reactive hyperplasia and nodal involvement with lymphoma. We believe that PET using the tracer 18FDG may play an important role in the evaluation of patients with head and neck lymphoma.

Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas.

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

Survival following interstitial brachytherapy for recurrent malignant glioma.

The treatment of recurrent malignant glioma is difficult and at present largely disappointing. Furthermore the results of any treatment modality need to be interpreted with knowledge regarding patient selection and timing of treatment. The results of interstitial brachytherapy using iodine-125 in 23 patients are presented. There were no operative complications. Median survival time from tumour recurrence and implantation was 36 and 25 weeks respectively. Karnofsky Performance Status (KPS) was significantly associated with survival, though patient age, original tumour histology, prior chemotherapy, and time to recurrence were not. Treatment does confer modest survival benefit as compared to controls, but our results are not as impressive as others. Reasons for this finding are discussed.

A pilot study using 99mTc to measure lead and platinum in the human kidney.

A pilot study has been conducted to investigate the hypothesis that the chemotherapeutic drug, cisplatinum, can mobilize skeletal lead. In vivo measurements of lead and platinum in the kidney of chemotherapy patients were performed with the technique of x-ray fluorescence, using 99mTc in a backscatter geometry. The results of the pilot study were inconclusive; the majority of patients exhibited no evidence of kidney lead at the level of system sensitivity, and negligible blood and urine lead levels.

Local control of T2/3 transitional cell carcinoma of bladder is correlated to differences in DNA supercoiling: evidence for two discrete tumor populations.

Single cell tumor suspensions were prepared from biopsy and urine samples from 48 patients with muscle invasive transitional cell carcinoma of the bladder. Prior to therapy, samples were irradiated in vitro with the condensation of DNA supercoils measured by the light scattered within a flow cytometer. Six months after completing a course of radiotherapy, the in vitro data were correlated with the presence or absence of local disease. After 12-Gy irradiation, nucleoid extraction and staining with 50 micrograms/ml ethidium bromide, 2 predominant forms of supercoiling behavior were seen. Nucleoids scattered either approximately 10% (Type I) or 35% (Type II) more light than unirradiated controls. Those patients with residual disease showed more Type I behavior (21 of 25; 84%) than those patients clear of disease (9 of 23; 39%) (P = 0.02). It is proposed that the ability of these tumor samples to adopt positive supercoiling after irradiation is related to a stronger association between individual DNA loops and their attachment to the nuclear matrix. This difference in nucleoid response within these tumor samples may be related both to intrinsic cellular radiosensitivity and, subsequently, to clinical radiocurability.

Stereotactic brachytherapy for malignant glioma using a relocatable frame.

Interstitial brachytherapy for recurrent gliomas normally necessitates the invasive application of a stereotactic frame by screw-fixation which must be kept on for several hours. The use of a relocatable stereotactic frame offers many advantages over conventional systems. We present our experience in 18 patients and verify that the frame used is accurate, comfortable, well tolerated and associated with no major disadvantages.

A correlation between nuclear supercoiling and the response of patients with bladder cancer to radiotherapy.

Single cell tumour suspensions were prepared from biopsy and urine samples from 28 patients with muscle invasive transitional cell carcinoma of the bladder. Nuclear extracts (nucleoids) containing intact chromatin were isolated from these cells and the condensation of DNA supercoils measured by the light scattered from individual nucleoids within a flow cytometer. Exposure of these nucleoids to 10 micrograms ml-1 ethidium bromide produced 78.9% increase in light scatter compared to those treated with 50 micrograms ml-1. This finding is consistent with the known effect of ethidium bromide on DNA supercoiling and confirms that the light scatter signal is responding to changes at this level of DNA organisation. Cell samples were also exposed to 12 Gy of gamma radiation and the effect on nucleoid light scatter recorded. Of the patients studied prior to radiotherapy, those with persistent disease 3 months after treatment generated an increase in nucleoid light scatter of + 9.35 +/- 4.8% after 12 Gy irradiation, of these, 2/14 produced nucleoids that relaxed by more than 10% compared to controls. Those patients with no evidence of disease after radiotherapy gave an increase in nucleoid light scatter after in vitro irradiation of + 19.3 +/- 4.5% of which 10/14 (71%) relaxed by more than 10%. It is proposed that the increased relaxation within the supercoiled DNA from patients whose tumours were undetectable 3 months after therapy, is related to the inherent radiosensitivity of these tumour cells. Such a difference in nucleoid response within tumour cells from patients that responded to radiation may arise due to a decreased affinity of DNA loops for the nuclear matrix. This structural change, at a site associated with the initiation of DNA synthesis, may affect the ability of cells to continue successful cell division after radiation damage.

Yttrium-87 for in vivo imaging.

Yttrium-87 with its daughter strontium-87m have been prepared in a form suitable for injection, and the biodistribution of 87Y-EDTMP determined in Balb/c mice. 87Y is suitable as a tracer for clinical investigations of 90Y.

Cellular radiosensitivity in V79 cells is linked to alterations in chromatin structure.

V79 cells grown as spheroids are more radioresistant than those grown as monolayers. Viable cells from spheroid culture contain restraints to ethidium bromide driven rewinding of DNA supercoils that are absent in monolayer cells. Spheroid cells also contain a DNA-protein matrix that is more resistant to detergent-induced degradation. The increase in structural integrity may be related to a 55-60 kD protein in the nucleoids of spheroid, but not monolayer cells. Spheroid cell radioresistance may therefore be related to a more stable chromatin platform for high fidelity repair of DNA damage.

The increase in radioresistance of Chinese hamster cells cultured as spheroids is correlated to changes in nuclear morphology.

Chinese hamster V79 cells grown as spheroids in roller culture are more radioresistant than those grown as monolayers. The supercoiled structure of chromatin, as salt-extracted nucleoids, has been examined using flow cytometry. Irradiated viable cells from spheroid culture contain restraints to supercoil relaxation that are absent in monolayer cells. Further analysis of the chromatin organization from each growth form shows that the radioresistant spheroid cells contain a DNA-protein matrix that is more resistant to detergent-induced degradation. The increase in structural integrity may be due to the retention of a 55-60 kDa protein that is apparent in the nucleoids of spheroid, but not monolayer cells. The increase in structural integrity of the spheroid cells may explain their greater radioresistance by providing a more stable platform for high-fidelity DNA damage repair.