Surgical resection versus watchful waiting in low-grade gliomas.

BACKGROUND: Infiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers. MATERIALS AND METHODS: Population-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival. RESULTS: A total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5-7.2) in region A compared with 14.4 years (95% CI 10.4-18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001). CONCLUSION: In parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.

Surgery for chronic subdural hematoma in nonagenarians: A Scandinavian population-based multicenter study.

OBJECTIVE: Chronic subdural hematoma (cSDH) is a prevalent condition often seen in the elderly, with surgery being the treatment of choice when symptomatic. So far, few have explored the surgical outcomes in patients 90 years or older. The aim of this study was to investigate outcome after cSDH surgery in nonagenarians (≥90 y/o group) compared to younger adult patients (<90 y/o group). MATERIALS: In a Scandinavian population-based cohort we conducted a retrospective review of 1,254 patients undergoing primary burr-hole procedures for cSDH between January 1, 2005 and December 31, 2010 at three neurosurgical centers. In a comparative analysis, the primary end-point was difference in hematoma recurrence rates between the ≥90 y/o and <90 y/o groups. The secondary end-points were differences in perioperative morbidity and mortality between groups. RESULTS: 75 patients were 90 years or older. There was no significant difference in recurrences resulting in reoperation between the age groups (10.7% vs 13.6%, P=.47). There was also no significant difference in overall complication rate (4.1% vs 8.1%, P=.21) or severe complications (1.4% vs 2.0%, P=.68). There were three (4.0%) perioperative deaths within 30 days in the ≥90 y/o group and 40 (3.4%) in the <90 y/o group (P=.78). CONCLUSION: Patients 90 years or older had similar rates of recurrence, perioperative morbidity and perioperative mortality as compared to younger patients. Age alone should not be a contraindication for surgery in patients with cSDH.

Fertility and gonadal function after adjuvant therapy in women diagnosed with a malignant ovarian germ cell tumor (MOGCT) during the "cisplatin era".

PURPOSE: By self-report and serum levels of anti-Mullerian hormone (AMH) this study aims to assess post-treatment fertility after modern treatment of women with malignant ovarian germ cell tumors (MOGCT). PATIENTS AND METHODS: In 2013 a questionnaire-based survey was performed in 61 MOGCT patients diagnosed at age <40years from 1980-2009. Forty-nine of them also attended the out-patient clinic. The event of first post-treatment pregnancy ("fertility") was documented as cumulative estimates for all 61 patients and within each of 4 treatment groups: Group 1: Surgery only (n=10); Group 2: ≤3cycles of cisplatin-based chemotherapy (CBCT) (n=20); Group 3: >3cycles of CBCT (n=15) and Group 4: other adjuvant treatment (n=16). AMH was determined in 22 women <40years at survey. Statistics were based on Kaplan Meier procedure, log-rank test and a significance level p<0.05. RESULTS: At least one post-treatment pregnancy was reported by 34 of 39 MOGCT survivors who attempted motherhood after treatment. The 15-year cumulative post-treatment fertility estimate was 28% (95% CI: 26-30) for all 61 survivors and was significantly higher in patients treated with 3 or fewer cycles of CBCT (53% [95% CI: 50-55]) than those treated with more than 3cycles (20% [95% CI: 17-22]) (P=0.03). Of 22 AMH levels, two were <3pmol/l, with one women being pregnant at survey. CONCLUSION: After fertility-sparing surgery and modern cisplatin-based chemotherapy, fertility is preserved in most MOGCT survivors though dependent on the number of cycles. AMH's role as a biomarker of gonadal function seems promising but requires further research.

Prognostic factors in malignant ovarian germ cell tumours (The Surveillance, Epidemiology and End Results experience 1978-2010).

PURPOSE: To evaluate the prognostic significance of age at diagnosis, extent of the disease (EOD) and socioeconomic (SES) and sociodemographic status (civil status, residency) on cause specific survival (CSS) in patients with malignant ovarian germ cell tumours (MOGCTs). To explore the cumulative incidence of a second cancer in 10-year MOGCT survivors. PATIENTS AND METHODS: 2541 patients with MOGCT, reported to the Surveillance, Epidemiology and End Results programme (1978-2010), were identified. The above mentioned prognostic factors were assessed separately for dysgerminoma and non-dysgerminoma, using Kaplan-Meier estimates and Cox Hazards Models, providing 95% confidence intervals (95% CI). RESULTS: Five-year CSS was 97% (95% CI, 96-98%), and 92% (95% CI, 91-93%), respectively for dysgerminoma, and non-dysgerminoma. Age >40 years at diagnosis and presence of metastases were significantly associated with cause specific mortality. Among non-dysgerminoma patients, decreasing SES (hazard ratio (HR), 1.59; 95% CI, 1.11-2.28) and treatment before 1990 (HR, 2.65; 95% CI, 1.83-3.85) increased mortality. In the adjusted analysis, patients from Michigan were almost 2.5 times more likely to die from MOGCT than patients from other states (HR, 2.48; 95% CI, 1.17-5.25). Second cancer was diagnosed in 10% of 10-year survivals who underwent radiotherapy and in 2% of survivals in non-radiotherapy group (p=.002). CONCLUSIONS: Increased attention should be directed towards the management of elderly MOGCT patients and those with non-dysgerminoma histology with low SES. Radiotherapy should be avoided as much as possible. Survival differences related to residency may occur when new cancer treatments are introduced.

Validation of model-guided placement of external ventricular drains.

PURPOSE: Inaccurate placement of external ventricular drains (EVDs) is a common issue in cerebrospinal diversion procedures. The conventional freehand technique results in a high fraction of sub-optimally placed catheters, and the use of image guidance can improve these results. The purpose of this paper is the validation of the use of an average model for guidance of EVD procedures. METHODS: Three neurosurgeons have tested the model-based technique on three normal volunteers, and we have compared the model-based technique to the freehand technique and neuronavigation based on volunteer-specific images. RESULTS: Our results show that the surgeons perform significantly better when using the model-based technique than when using the freehand technique. CONCLUSIONS: Our results suggest that the use of an average model may improve the accuracy of catheter placements. However, further refinement of the method and testing in a clinical setting is required.

Malignant ovarian germ cell tumors: presentation, survival and second cancer in a population based Norwegian cohort (1953-2009).

PURPOSE: To quantify and compare survival in women with malignant ovarian germ cell tumors (MOGCTs) in Norway before and after the introduction of cisplatin-based chemotherapy (around 1980), and to explore the association between different types of treatment and the development of a second cancer. PATIENTS AND METHODS: We identified 351 patients diagnosed with MOGCTs from 1953 to 2009 in the Cancer Registry of Norway. Ovarian cancer-specific survival was calculated separately for patients diagnosed before and after 1980. Patients were divided into subgroups by histological subtype (pure dysgerminoma, malignant teratoma, other MOGCTs) and extent of disease (localized and metastatic). We estimated the cumulative incidence of a second cancer in 10-year MOGCT survivors. Kaplan-Meier estimates were used, and p<0.05 was considered significant. RESULTS: 20-Year ovarian cancer-specific survival increased from 59% (95% CI 51% to 66%) before 1980 to 88% (95% CI 83%-93%) thereafter. Significant improvement was observed in all subgroups. No second cancer was diagnosed in any of 31 10-year MOGCT survivors treated with surgery only; second cancer was diagnosed in 23 of 139 patients who underwent cytotoxic treatment (98 radiotherapy ± chemotherapy, 41 chemotherapy only; p=0.08). Patients aged >50 years had a significantly poorer ovarian cancer-specific survival than younger patients (HR=5.98, 95% CI 3.39-10.57) after adjustment for histological subtype and stage at presentation. Our results favor the treatment of patients with metastatic MOGCTs at large cancer centers. CONCLUSION: Today women with MOGCTs have an excellent prognosis if treated according to modern therapeutic principles.

A method for estimating the fibre length in fibre-PLA composites.

Wood pulp fibres are an important component of environmentally sound and renewable fibre-reinforced composite materials. The high aspect ratio of pulp fibres is an essential property with respect to the mechanical properties a given composite material can achieve. The length of pulp fibres is affected by composite processing operations. This thus emphasizes the importance of assessing the pulp fibre length and how this may be affected by a given process for manufacturing composites. In this work a new method for measuring the length distribution of fibres and fibre fragments has been developed. The method is based on; (i) dissolving the composites, (ii) preparing the fibres for image acquisition and (iii) image analysis of the resulting fibre structures. The image analysis part is relatively simple to implement and is based on images acquired with a desktop scanner and a new ImageJ plugin. The quantification of fibre length has demonstrated the fibre shortening effect because of an extrusion process and subsequent injection moulding. Fibres with original lengths of >1 mm where shortened to fibre fragments with length of <200 µm. The shortening seems to be affected by the number of times the fibres have passed through the extruder, the amount of chain extender and the fraction of fibres in the polymer matrix.

Did survival improve after the implementation of intraoperative neuronavigation and 3D ultrasound in glioblastoma surgery? A retrospective analysis of 192 primary operations.

BACKGROUND: Numerous observational studies indicate that more aggressive resection may prolong survival in glioblastoma patients. In Trondheim, Norway, intraoperative 3D ultrasound has been in increasing use since November 1997. The aim of the present study was to examine if the introduction of 3D ultrasound and neuronavigation (i. e., the SonoWand® system) may have had an impact on overall survival. PATIENTS/MATERIAL AND METHODS: Patient data were obtained retrospectively for the 192 glio-blastoma patients who received surgery and postoperative radiotherapy between 1990 and 2005. Overall survival, before and after 1997, was compared using the log rank test. Possible confounders were adjusted for in a multivariate Cox regression analysis. RESULTS: We observed an increase in survival for patients in the last study period (9.6 vs. 11.9 months; HR = 0.7; p = 0.034). The significant improvement in the latest time period was sustained after adjusting for age, WHO performance status (≥2) and type of radiotherapy (normofractioned or hypofractioned), and chemotherapy (yes/no), p = 0.034. 10 out of 14 patients who survived more than 3 years received treatment after the implementation of 3D ultrasound. CONCLUSION: Our study demonstrates that survival has improved within the same period that intraoperative ultrasound and neuronavigation was introduced and established in our department. The demonstrated association is a necessity for causation, but given the nature of this study, one must be cautious to claim causality. The improvement was, however, significant after adjustment for known major prognostic factors.

A new system for 3D ultrasound-guided placement of cerebral ventricle catheters.

PURPOSE: We present a new system for 3D ultrasound-guided placement of cerebral ventricle catheters. The system has been developed with the aim to provide accurate ultrasound-based guidance with only minimal changes to the current surgical technique and workflow. METHODS: The system consists of a pre-calibrated navigation adapter for the catheter and a reference frame attached to a standard surgical retractor in addition to an ultrasound-based navigation system with a probe that fits on top of a standard burr hole. RESULTS: The accuracy of the pre-calibrated system has been evaluated, and our measurements indicate that the accuracy of the pre-calibrated system is better than 3 mm. We also present a clinical case. CONCLUSIONS: The navigation accuracy is considered sufficient for clinical use, and initial clinical tests are promising. Further testing will be necessary to fully evaluate the performance of the system in a clinical setting.

Surgical resection of brain metastases: the prognostic value of the graded prognostic assessment score.

There is a need for better predictors for short survival in patients with brain metastases undergoing open surgery. The graded prognostic assessment (GPA) has recently been developed to predict survival in patients with brain metastases. We explored the prognostic capabilities of GPA in a consecutive neurosurgical population of brain metastases. Secondarily, we evaluated if GPA scores can provide information on safety of the operation and postoperative functional outcome. We retrospectively included all adult (≥ 18 years) patients undergoing open surgery for brain metastases from 2004 through 2009 (n = 141). The population was grouped into GPA 0-1 (n = 22, 16%), GPA 1.5-2.5 (n = 90, 64%), GPA 3 (n = 19, 14%), and GPA 3.5-4 (n = 10, 7%) according to the prognostic indices. Median survival times were 6.3 months (range 0.8-23.7) in GPA 0-1, 7.8 months in GPA 1.5-2.5 (range 0.2-75.0), 14.0 months in GPA 3 (range 0.0-77.4), and 18.4 months in GPA 3.5-4 (range 0.1-63.7). This represents a significant difference between groups (P = 0.010). There were no associations between GPA and 30-day mortality (P = 0.871), 3-month mortality (P = 0.750), complications (P = 0.330) or change in Karnofsky Performance status postoperatively (P = 0.558). GPA scores hold prognostic properties in patients operated for brain metastases. However, GPA did not predict short-term mortality, limiting the clinical usefulness in a neurosurgical population. The prognostic indices cannot be used alone to decide if surgery is warranted on an individual basis, or to evaluate risks and benefits of surgery.

Integrated pre- and intraoperative imaging in a patient with an arteriovenous malformation located in eloquent cortex.

INTRODUCTION: The use of integrated pre- and intraoperative imaging may be useful when resecting brain lesions in close proximity to eloquent areas, such as the primary motor cortex and language cortices. CASE REPORT: A 32-year-old woman with an arteriovenous malformation (AVM) located in the primary motor cortex underwent surgery using functional neuronavigation. Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) and diffusion tensor tractography (DTT) were used for preoperative mapping of primary motor areas and the corticospinal tracts, respectively. The BOLD fMRI activations and DTT tractograms were integrated into the neuronavigation system and visualized intraoperatively throughout the operation. Furthermore, stereoscopic visualizations of the angioarchitecture based on 3D MRI angiograms were used to rehearse the surgical approach to the feeder vessels. Finally, intraoperative ultrasound was used to locate and clip the feeding vessels. CONCLUSION: The AVM was carefully resected with the aid of the above-mentioned imaging techniques, and the intuitive usefulness of the techniques was further substantiated by the rewarding postoperative outcome.

Surgical resection of high-grade gliomas in eloquent regions guided by blood oxygenation level dependent functional magnetic resonance imaging, diffusion tensor tractography, and intraoperative navigated 3D ultrasound.

OBJECTIVE: The aims of this study of patients with high-grade gliomas in eloquent brain areas were 1) to assess the postoperative functional outcome, 2) to determine the extent of tumour resection in these difficult locations, 3) to evaluate the practical usefulness of navigated blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography. PATIENTS AND METHODS: 25 consecutive patients were included in the study. The patients' gross functional neurological status was determined using the 7-step modified Rankin scale. The extent of tumour resection was determined using pre- and postoperative T(1)-weighted or T(1)-weighted, contrast-enhanced MRI images. RESULTS: The average preoperative modified Rankin scale was 1.56+/-0.77, whereas the average postoperative modified Rankin scale was 1.08+/-1.29. There was a significant improvement in mean modified Rankin scale score after surgery. The mean percentage of residual tumour was calculated to 16+/-22% of the original tumour volume (median 8%). Blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography were performed in 23 and 18 patients, respectively. Blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography facilitated identification of probable functional regions in 91% and 94% of the respective investigations. CONCLUSION: We feel that the combination of blood oxygenation level-dependent functional magnetic resonance imaging, diffusion tensor tractography, and 3D ultrasound facilitated maximal tumour resection with minimal deficits. The method permits an image-based functional monitoring of the brain during surgery that may aid the preservation of motor and language function.

Rapid and severe rise in static and pulsatile intracranial pressures during a generalized epileptic seizure.

In a patient with no prior history of seizures we were able to record static (mean) intracranial pressure (ICP) and pulsatile ICP (mean ICP wave amplitude) continuously during a first-time generalized epileptic seizure. The patient experienced episodic headache five months after a subarachnoid haemorrhage. In order to rule out low-pressure hydrocephalus she was admitted for a 24-hour intracranial pressure registration. ICP parameters were normal prior to the seizure. We observed an immediate and enormous rise in both static (mean) ICP and pulsatile ICP (mean ICP wave amplitude). Mean ICP and ICP wave amplitude peaked at 93 mmHg and 22 mmHg, respectively. Pulsatile ICP remained elevated after normalization of static ICP and may indicate impairment of intracranial compliance even after the static ICP was normalized.

Quality of life in adult patients with primary intracranial arachnoid cysts.

BACKGROUND: Primary arachnoid cysts are benign developmental lesions of arachnoid mater. Arachnoid cysts may be detected due to various neurological symptoms, or they may be encountered as incidental findings of neuroimaging. Consequently, a significant share of the patients seems asymptomatic. There are diverging opinions about the clinical importance of cyst sizes, cyst location and degree of volume reduction after surgery, hence contributing to controversies regarding indications for surgical treatment. We present the first study assessing internationally established parameters of quality of life and mental health in a clinical-outcome analysis of adult patients with arachnoid cysts. METHOD: Ninety-two adult patients with arachnoid cysts who had been referred to our department over the last 16 years were included. Forty-seven patients had undergone surgery and 45 patients had not been operated on. Data for analysis was based on both medical records and questionnaires sent out by mail. Quality of life was assessed by the Short Form 36 Health Survey (SF-36), and mental health was further evaluated by the Hospital Anxiety and Depression Scale (HADS). Seventy-one percent of patients responded to our questionnaires. FINDINGS: There was a great variation in the presenting symptoms, seemingly without any relation to cyst localisation. Patients with arachnoid cysts seem to have a reduced quality of life and a very high prevalence of anxiety compared to a healthy normal population. Men presented lower outcome scores than women. Subjects with symptoms, that we retrospectively labeled biologically comprehensible, tended to have higher quality of life, less anxiety and better subjective symptom relief after surgery. CONCLUSION: Our arachnoid cyst population had a low employment status, decreased quality of life scores and prevalent symptoms of anxiety. We argue that the arachnoid cysts are, in most cases, not directly related to these studied parameters. We speculate that our findings may reflect the demographic characteristics of adults likely of being diagnosed with incidental cysts. A better clinical outcome for patients with biologically plausible symptoms supports a neurobiological approach in the selection of patients suited for surgery.

Maximising biogas in anaerobic digestion by using engine waste heat for thermal hydrolysis pre-treatment of sludge.

Dublin's Ringsend WWTP was designed to serve a population of approximately 1.2 million p.e. with a sludge production of 37,000 dry tonnes per year after upgrading to full secondary treatment. Several technical solutions were put forward as part of a design, build, finance and operate (DBFO) competition, with the chosen solution being a proposal by Black and Veatch for a combination of sequencing batch reactor (SBR) technology and anaerobic digestion with Cambi thermal hydrolysis pre-treatment (THP). The THP plant was built by Cambi and handed over to B&V in 2002. The plant is now operated by Celtic Anglian Water. In September 2004 a test was carried out on the mass and energy balance of the plant following 2 years of operation and is detailed in this paper. The process enables digestion at very high dry solids feed and low hydraulic retention time. The plant was built with three digesters of 4250 m3 each and is fed with hydrolysed sludge at 11% DS. There are four no. 1 MW Jenbacher engines operating mainly on biogas. Each pair of engines is fitted with a waste heat boiler with a capacity of one tonne steam per hour. These boilers have sufficient capacity to provide 80% of the steam required for the THP, which in turn provides all the heat for the subsequent digestion in the form of hydrolysed feed. There are two main biogas boilers for top up steam and other uses of the biogas including thermal oxidation of concentrated odours.

Quality of life after treatment for incidental, unruptured intracranial aneurysms.

BACKGROUND: Discovering an intracranial aneurysm may profoundly affect the patient's quality of life. Patients living with unruptured and untreated aneurysms often report symptoms of anxiety and depression. There are few trials studying the quality of life after treatment of unruptured intracranial aneurysms. We aimed to compare the quality of life and symptoms of anxiety or depression after endovascular coiling or open surgery clipping of unruptured intracranial aneurysms, in patients with no prior subarachnoid haemorrhage. METHOD: 73 living patients were included. 44 had undergone open surgery clipping and 31 had undergone endovascular coiling within the last 5.5 years. We registered a number of parameters from medical records and the patients' current quality of life was assessed by a questionnaire. 63 of 73 (86.3%) returned our questionnaire, which included the Norwegian version of SF-36 and the Hospital Anxiety and Depression Scale (HAD). FINDINGS: Many patients treated for unruptured intracranial aneurysms have a relatively low quality of life. The low scores indicate that the patients experience limitations in their ability to work or accomplish desired activities due to perceived physical or mental handicaps. There were no significant differences between the open surgery group and the endovascular group when comparing quality of life parameters after treatment. A subgroup analysis of patients with a favourable functional outcome also showed reduced quality of life without any differences in the two treatment groups. There were no signs of improvement in quality of life over time. CONCLUSION: Quality of life after treatment does not seem to be a strong argument for choosing one modality of treatment over the other in patients with unruptured intracranial aneurysms. There are no significant differences in the quality of life of patients successfully treated using endovascular technique and patients who underwent craniotomy and clipping. We speculate that the low quality of life scores are due to factors unrelated to the aneurysms. The scores possibly reflect characteristics of a patient group where incidental aneurysms are more frequently diagnosed while undergoing extensive imaging procedures due to unrelated symptoms.

Malignant pleural mesothelioma: US-guided histologic core-needle biopsy.

PURPOSE: To assess the clinical use of ultrasonographically (US) guided core-needle biopsy, performed with a one-hand automatic sampling technique, in the diagnosis of malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: The authors reviewed the findings in 70 patients with a tentative diagnosis of MPM who underwent US-guided core-needle biopsy at our institution during the past 10 years. RESULTS: Fifty-two of the 70 patients who underwent automatic high-speed core-needle biopsy at our institution had MPM; 18 had other disorders. The correct diagnosis was made in 56 patients. Twelve of 14 inadequate biopsy specimens were false-negative for MPM. There were no false-positive biopsy results. In the detection of MPM, US-guided core-needle biopsy had a sensitivity of 77%, specificity of 88%, accuracy of 80%, positive predictive value of 100%, and negative predictive value of 57%. There were no serious complications. CONCLUSION: US-guided core-needle biopsy is highly effective in the diagnosis of MPM. Owing to its simplicity, low cost, and few side effects, it could be the biopsy method of choice for detection of this condition.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.