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Richard Sylvester

Publications and source records attributed to Richard Sylvester.

At least 19 recordsLinked to original sources
PubMed2006

Visual FMRI responses in human superior colliculus show a temporal-nasal asymmetry that is absent in lateral geniculate and visual cortex.

Eye patching has revealed enhanced saccadic latencies or attention effects when orienting toward visual stimuli presented in the temporal versus nasal hemifields of humans. Such behavioral advantages have been tentatively proposed to reflect possible temporal-nasal differences in the retinotectal pathway to the superior colliculus, rather than in the retinogeniculate pathway or visual cortex. However, this has not been directly tested with physiological measures in humans. Here, we examined responses of the human superior colliculus (SC) to contralateral visual field stimulation, using high spatial resolution fMRI, while manipulating which hemifield was stimulated and orthogonally which eye was patched. The SC responded more strongly to visual stimulation when eye-patching made this stimulation temporal rather than nasal. In contrast, the lateral geniculate nucleus (LGN) plus retinotopic cortical areas V1-V3 did not show any temporal-nasal differences and differed from the SC in this respect. These results provide the first direct physiological demonstration in humans that SC shows temporal-nasal differences that LGN and early visual cortex apparently do not. This may represent a temporal hemifield bias in the strength of the retinotectal pathway, leading to a preference for the contralateral hemifield in the contralateral eye.

Adult↗
PubMed2006

A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma.

OBJECTIVES: This study compared the complications and the cancer control of elective nephron-sparing surgery (NSS) and radical nephrectomy (RN) in patients with a small (<or=5 cm), solitary, low-stage N0 M0 tumour suspicious for renal cell carcinoma (RCC) and a normal contralateral kidney. METHODS: 541 patients were randomised in a prospective, multicentre, phase 3 trial to undergo NSS (n=268) or RN (n=273) together with a limited lymph node dissection. RESULTS: This publication reports only on the complications reported for both surgical methods. The rate of perioperative blood loss<0.5l was slightly higher after RN (96.0% vs. 87.2%) and the rate of severe haemorrhage was slightly higher after NSS (3.1% vs. 1.2%). Ten patients (4.4%), all of whom were treated with NSS, developed urinary fistulas. Pleural damage (11.5% for NSS vs. 9.3% for RN) and spleen damage (0.4% for NSS and 0.4% for RN) were observed with similar rates in both groups. Postoperative computed tomography scanning abnormalities were seen in 5.8% of NSS and 2.0% of RN patients. Reoperation for complications was necessary in 4.4% of NSS and 2.4% of RN patients. CONCLUSIONS: NSS for small, easily resectable, incidentally discovered RCC in the presence of a normal contralateral kidney can be performed safely with slightly higher complication rates than after RN. The oncologic results are eagerly awaited to confirm that NSS is an acceptable approach for small asymptomatic RCC.

Aged↗
PubMed2006

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.

BACKGROUND: Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS: Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS: 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION: Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Aged↗
PubMed2006

Progression-free survival rate as primary end point for phase II cancer clinical trials: application to mesothelioma--The EORTC Lung Cancer Group.

PURPOSE: Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma. MATERIALS AND METHODS: The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA. RESULTS: The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA. CONCLUSION: These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.

Adult↗
PubMed2006

Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.

Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out. Thirty-seven patients were included at 14 different dose-levels (10 to 6400 ng/kg). The complete clinical results are presented elsewhere. A 2-step CRM design enables one to speed-up the study and most importantly to obtain an accurate estimate of the maximum tolerated dose (MTD). Different management issues related to a multicenter study are illustrated and we show how the method can go wrong when severe toxicity, or dose limiting toxicity (DLT), is not considered by the clinician as being sufficient to limit dose escalation (here a grade 3 asthenia related to the drug). This would have affected any dose finding methods. We believe that CRM is a good alternative to the standard method from both a statistical and a practical point of view but further methodological research is necessary to address the issues related to the composite nature of the endpoint.

Adolescent↗
PubMed2006

Heterogeneity in disease free survival between centers: lessons learned from an EORTC breast cancer trial.

BACKGROUND: Large phase III clinical trials convey a lot of important information besides the main analysis of the treatment effect. For example, the use of multicenter clinical trial data to identify prognostic indices is now common. In addition, the study of heterogeneity in patient outcome between centers has received considerable attention in recent years. In this paper, we explain and illustrate a method used to investigate such heterogeneity with data from an early breast cancer clinical trial. METHODS: The inclusion of a random effect for center in a Cox proportional hazards model allows us to study the heterogeneity in time-to-event outcomes between centers. Such a model has the major advantage that it provides a measure of the spread of outcomes over centers. This technique is illustrated using data from EORTC trial 10854, a randomized phase III trial comparing perioperative chemotherapy with no perioperative chemotherapy for early breast cancer; 2793 patients were entered by 14 centers. RESULTS: Substantial heterogeneity between centers was detected for disease-free survival. This can be explained by the geographical area in which the center is located, with better outcomes achieved in France as compared with southern Europe and South Africa. None of the prognostic factors considered could explain this heterogeneity. CONCLUSION: Although clinical trials are run with the objective of removing as much heterogeneity as possible, some heterogeneity in the outcome of patients between centers may remain, as was the case in our study. The use of a random effect for center within a Cox PH model is an excellent method to investigate this heterogeneity. Such types of analyses, although exploratory, provide further insight into possible factors which may have an impact on the patient's outcome.

Breast Neoplasms↗
PubMed2005

A Bayesian approach to jointly estimate centre and treatment by centre heterogeneity in a proportional hazards model.

When multicentre clinical trial data are analysed, it has become more and more popular to look for possible heterogeneity in outcome between centres. However, beyond the investigation of such heterogeneity, it is also interesting to consider heterogeneity in treatment effect over centres. For time-to-event outcomes, this may be investigated by including a random centre effect and a random treatment by centre interaction in a Cox proportional hazards model. Assuming independence between the random effects, we propose a Bayesian approach to fit our proposed model. The parameters of interest are the variance components sigma(0) (2) and sigma(1) (2) of these random effects, which can be interpreted as a measure of centre and treatment effect over centres heterogeneity of the hazard. These variance components are estimated from their marginal posterior density after integrating out the fixed treatment effect and the random effects. As this integration cannot be performed analytically, the marginal posterior density is approximated using the Laplace integration technique. Statistical inference is then based on the characteristics of the posterior marginal density, such as the mode and the standard deviation. We demonstrate the proposed technique using data from a pooled database of seven EORTC bladder cancer clinical trials. Substantial centre and treatment effect over centres heterogeneity in disease-free interval was found.

Bayes Theorem↗
PubMed2005

Extraretinal saccadic signals in human LGN and early retinotopic cortex.

In the human LGN and V1, saccades in darkness lead to enhanced activity while saccades made during strong visual stimulation suppress activity [Sylvester, R., Haynes, J.D., and Rees, G., 2005. Saccades differentially modulate human LGN and V1 responses in the presence and absence of visual stimulation. Curr. Biol. 15, 37-41]. Here, we explored this differential modulation further using graded changes in the strength of visual stimulation by changing the mean luminance of a flickering visual stimulus. We replicate the finding of differential modulation of activity in human LGN and V1, and show that this relationship also holds in retinotopic areas V2 and V3. Suppression of visually evoked activity during saccades was detectable during strong visual stimulation, but not during weaker stimulation. This suggests that the activation of visual cortex by saccades in darkness represents a signal that persists irrespective of the state of visual stimulation, masking suppressive effects of saccades when visual stimulation is weak. Such a signal may represent a motor signal in a sensory area. We discuss the possible role of oculomotor corollary discharge in changes in visual perception that occur peri-saccadically, which contribute to the successful negation of the disruptive effects of saccades on our seamless visual experience of the world.

Adult↗
PubMed2005

Blinking suppresses the neural response to unchanging retinal stimulation.

Blinks profoundly interrupt visual input but are rarely noticed, perhaps because of blink suppression, a visual-sensitivity loss that begins immediately prior to blink onset. Blink suppression is thought to result from an extra-retinal signal that is associated with the blink motor command and may act to attenuate the sensory consequences of the motor action. However, the neural mechanisms underlying this phenomenon remain unclear. They are challenging to study because any brain-activity changes resulting from an extra-retinal signal associated with the blink motor command are potentially masked by profound neural-activity changes caused by the retinal-illumination reduction that results from occlusion of the pupil by the eyelid. Here, we distinguished direct top-down effects of blink-associated motor signals on cortical activity from purely mechanical or optical effects of blinking on visual input by combining pupil-independent retinal stimulation with functional MRI (fMRI) in humans. Even though retinal illumination was kept constant during blinks, we found that blinking nevertheless suppressed activity in visual cortex and in areas of parietal and prefrontal cortex previously associated with awareness of environmental change. Our findings demonstrate active top-down modulation of visual processing during blinking, suggesting a possible mechanism by which blinks go unnoticed.

Adult↗
PubMed2005

Saccades differentially modulate human LGN and V1 responses in the presence and absence of visual stimulation.

Saccades occur several times each second in normal human vision. The visual image moves across the retina at high velocity during a saccade, yet no blurring of the visual scene is perceived . Active suppression of visual input may account for this perceptual continuity, but the neural mechanisms underlying such saccadic suppression remain unclear. We used functional MRI to specifically examine responses in the lateral geniculate nucleus (LGN) and primary visual cortex (V1) during saccades. Activity in both V1 and LGN was strongly modulated by saccades. Furthermore, this modulation depended on whether visual stimulation was present or absent. In complete darkness, saccades led to reliable signal increases in V1 and LGN, whereas in the presence of visual stimulation, saccades led to suppression of visually evoked responses. These findings represent unequivocal evidence for saccadic suppression in human LGN and retinotopically defined V1 and are consistent with the earliest site of saccadic suppression lying at or before V1.

Geniculate Bodies↗
PubMed2005

Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials.

PURPOSE: Malignant pleural mesothelioma (MPM) carries a poor prognosis due to chemoresistance. The European Organisation for Research and Treatment of Cancer (EORTC) prognostic model was reported to predict survival in MPM. Our retrospective analysis set out to test the validity of the model as a prognostic tool in patients treated in three phase II trials at St Bartholomew's Hospital (London, United Kingdom) between 1999 and 2003. PATIENTS AND METHODS: A total of 145 patients were treated in three phase II trials; vinorelbine (VIN; 70 patients), vinorelbine/oxaliplatin (VO; 26 patients), and irinotecan/cisplatin/mitomycin C (IPM; 49 patients). Two subgroups, high-risk and low-risk, were defined by EORTC prognostic score (EPS). EPS was determined by a five-parameter model incorporating age, sex, histology, probability of diagnosis, and leukocyte count. An EPS cutoff of less than 1.27 (low risk) or more than 1.27 (high risk) was used to stratify Kaplan-Meier survival curves. Each of the EPS variables exhibited either trends or significant stratification of overall survival (OS). RESULTS: Multivariate analysis confirmed leukocyte count, Eastern Cooperative Oncology Group performance status, and sarcomatous histology as independent prognostic variables. EPS stratified OS in both individual and pooled trial datasets. No association between objective tumor response and EPS classification was identified by multinomial logistic regression. EPS stratified progression-free survival for the VO and IPM cohorts, but not for VIN. CONCLUSION: This study validates the EPS system as a robust tool for stratifying small trials into low- and high-risk subgroups. EPS should facilitate patient selection and analysis in randomized clinical trials.

Adult↗
PubMed2005

EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ.

OBJECTIVES: On behalf of the European Association of Urology (EAU), guidelines for the diagnosis, therapy and follow-up of patients with urothelial carcinoma in situ (CIS) have been established. METHOD: The recommendations in these guidelines are based on a recent comprehensive overview and meta-analysis in which two panel members have been involved (RS and AVDM). A systematic literature search was conducted using Medline, the US Physicians' Data Query (PDQ), the Cochrane Central Register of Controlled Trials, and reference lists in trial publications and review articles. RESULTS: Recommendations are provided for the diagnosis, conservative and radical surgical treatment, and follow-up of patients with CIS. Levels of evidence are influenced by the lack of large randomized trials in the treatment of CIS.

Carcinoma in Situ↗
PubMed2005

Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum.

BACKGROUND AND OBJECTIVES: Sepsis is the leading cause of morbidity and mortality for patients admitted to an intensive care unit. The evaluation of new therapies has been hampered by the underdevelopment of outcome measures used to detect biological activity and patient-centered benefit in a complex and highly heterogeneous patient population. We sought to evaluate existing approaches and to draw on insights from other disciplines to propose a comprehensive approach to outcome evaluation in sepsis clinical trials. METHODS: An expert colloquium organized by the International Sepsis Forum brought together sepsis researchers, clinical epidemiologists, and experts in the development and implementation of outcome measures in rheumatology, neurology, and oncology. RESULTS: The translation of an evolving understanding of the biology of sepsis into effective new therapies for critically ill patients requires a reevaluation of the end points used to determine response to intervention. These represent a continuum that measures biological activity against the target at one end and sustained improvement in survival or quality of life at the other. Early phase research should determine whether an intervention works in vivo, using measures that are responsive and informative to provide proof of principle, to aid in selecting optimal patient populations for study, and to gain insights into optimal dose and duration of therapy. After in vivo biology has been demonstrated and the possibility of efficacy inferred by plausible improvements in surrogate physiologic measures, definitive studies should seek robust evidence of benefit using end points that measure important, patient-centered benefit, including intermediate and longer term survival and health-related quality of life. Nonmortal measures of benefit assume particular importance for populations, such as children, whose mortality risk is low, or who have significant rates of comorbidities that independently limit survival. Composite measures that integrate morbidity and mortality effects may provide the most meaningful information about therapeutic efficacy. CONCLUSIONS: The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill.

Clinical Trials as Topic↗
PubMed2004

Construction and validation of a prognostic model across several studies, with an application in superficial bladder cancer.

Many models for clinical prediction (prognosis or diagnosis) are published in the medical literature every year but few such models find their way into clinical practice. The reason may be that since in most cases models have not been validated in independent data, they lack generality and/or credibility. In this paper we consider the situation in which several compatible, independent data sets relating to a given disease with a time-to-event endpoint are available for analysis. The aim is to construct and evaluate a single prognostic model. Building a multivariable model from the available prognostic factors is accomplished within the Cox proportional hazards framework, stratifying by study. Non-linear relationships with continuous predictors are modelled by using fractional polynomials. To assess the discrimination or separation of a survival model, we use the D statistic of Royston and Sauerbrei. D may be interpreted as the separation (log hazard ratio) between the survival distributions for two independent prognostic groups. To evaluate the generality of a prognostic model across the data sets, we propose 'internal-external cross-validation' on D: each study is omitted in turn, the model parameters are estimated from the remaining studies and D is evaluated in the omitted study. Because the linear predictor of a survival model tells only part of the story, we also suggest a method for investigating heterogeneity in the baseline distribution function across studies which involves fitting completely specified, flexible parametric survival models (Royston and Parmar). Our final models combine the prognostic index (obtained with stratification by study) with the pooled baseline survival distribution (estimated parametrically). By applying this methodology, we construct two prognostic scores in superficial bladder cancer. The simpler of the two scores is more suited to clinical application. We show that a three-group prognostic classification scheme based on either score produces well-separated survival curves for each of the data sets, despite identifiable heterogeneity among the baseline distribution functions and to a lesser extent among the prognostic indexes for the individual studies.

Adult↗
PubMed2004

Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.

PURPOSE: Metastatic renal cancer is associated with a poor prognosis. Recent advances in immunotherapy for this problem have rekindled interest in cytoreductive nephrectomy. We report a combined analysis of 2 prospective randomized trials that used an identical study protocol. MATERIALS AND METHODS: A total of 331 patients were randomized to 2 identical protocols comparing cytoreductive nephrectomy plus interferon alpha-2b vs interferon alpha-2b alone in patients with metastatic renal cancer, in whom the primary tumor was present and believed to be resectable. The primary end point for each trial was overall survival with a secondary end point of the response rate. Patients were stratified at pre-randomization by performance status (0 or 1), site of metastases (lung only vs other) and disease measurability. All results were analyzed by intent to treat criteria. Assuming a median survival of 1 year for interferon only, the Southwest Oncology Group trial was designed to detect a 50% improvement in median survival duration and a 15% improvement in response rate with a power of 0.85. The European Organization for the Research and Treatment of Cancer accrued an additional 80 patients in that study. RESULTS: The combined analysis of these 2 trials yielded a median survival of 13.6 months for nephrectomy plus interferon vs 7.8 months for interferon alone. This difference represents a 31% decrease in the risk of death (p = 0.002). There was no evidence of a difference in the size of the treatment effect according to pre-randomization stratification factors. CONCLUSIONS: Cytoreductive nephrectomy appears to improve significantly overall survival in patients with metastatic renal cancer treated with interferon immunotherapy independent of patient performance status, the site of metastases and the presence of measurable disease. Although it is highly statistically significant, the overall survival advantage is only 5.8 months for the entire group. These data emphasize the need to determine if this survival advantage can be further improved using more aggressive immunotherapy or other novel agents in the setting of cytoreductive nephrectomy.

Adult↗
PubMed2004

Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B.

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

Adolescent↗
PubMed2002

Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30: identification and impact on model selection.

Clinical and quality of life (QL) variables from an EORTC clinical trial of first line chemotherapy in advanced breast cancer were used in a prognostic factor analysis of survival and response to chemotherapy. For response, different final multivariate models were obtained from forward and backward selection methods, suggesting a disconcerting instability. Quality of life was measured using the EORTC QLQ-C30 questionnaire completed by patients. Subscales on the questionnaire are known to be highly correlated, and therefore it was hypothesized that multicollinearity contributed to model instability. A correlation matrix indicated that global QL was highly correlated with 7 out of 11 variables. In a first attempt to explore multicollinearity, we used global QL as dependent variable in a regression model with other QL subscales as predictors. Afterwards, standard diagnostic tests for multicollinearity were performed. An exploratory principal components analysis and factor analysis of the QL subscales identified at most three important components and indicated that inclusion of global QL made minimal difference to the loadings on each component, suggesting that it is redundant in the model. In a second approach, we advocate a bootstrap technique to assess the stability of the models. Based on these analyses and since global QL exacerbates problems of multicollinearity, we therefore recommend that global QL be excluded from prognostic factor analyses using the QLQ-C30. The prognostic factor analysis was rerun without global QL in the model, and selected the same significant prognostic factors as before.

Antineoplastic Agents↗