Patient Selection For Clinical Trials Research Articles

Selection of patients for clinical trials: an interactive web-based system

The purpose of a clinical trial is to evaluate a new treatment procedure. When medical researchers conduct a trial, they recruit participants with appropriate health problems and medical histories. To select participants, they analyze medical records of the available patients, which has traditionally been a manual procedure. We describe an expert system that helps to select patients for clinical trials. If the available data are insufficient for choosing patients, the system suggests additional medical tests and finds an ordering of the tests that reduces their total cost. Experiments show that the system can increase the number of selected patients. We also present an interface that enables a medical researcher to add clinical trials and selection criteria without the help of a programmer. The addition of a new trial takes 10–20 min, and novice users learn the functionality of the interface in about an hour.

2003: The year in heart failure*1

2003: The year in heart failure*1

Selection of patients with melanoma brain metastases for aggressive treatment.

The purpose of this study was to determine prognostic factors for patients with melanoma brain metastases that can be recommended for patient selection for clinical trials. A retrospective review was conducted of 65 patients irradiated for brain metastases from 1990 to 1997. Pretreatment factors analyzed for influence on survival included age, stage, Karnofsky Performance Status (KPS), extracranial metastases, the number and location of brain lesions, disease-free interval from initial diagnosis, total dose of radiation, and number of fractions administered. Prognosis was also analyzed by Radiation Therapy Oncology Group recursive partitioning analyses (RPA) classes. The data were analyzed using the Kaplan-Meier method. Median survival was 4 months. RPA class distribution was I-25%, II-48%, and III-28% with a median survival of 6.5, 3.5, and 2.5 months, respectively (p = 0.0098 by log-rank test). KPS less than 70% (p = 0.0039), and the presence of extracranial metastases (p = 0.03), predicted a worse prognosis on univariate analysis. Both factors remained significant on multivariate analysis. The prognosis of patients receiving radiotherapy for brain metastases is related to RPA class, the presence of extracranial metastases, and KPS. These criteria should be employed in selecting patients for aggressive protocol treatment, or for more protracted brain irradiation off protocol.

Patient selection for clinical trials: the reliability of the early spinal cord injury examination.

Patients with incomplete spinal cord injuries can spontaneously recover motor function. Because of this, phase I and II trials of invasive interventions for acute spinal cord injury will likely involve neurologically complete injuries. It is therefore important to reliably identify complete injuries as early as possible. We examined the reliability of the early examination in motor complete spinal cord injuries by retrospectively analyzing the stability of baseline neurological status determined within 2 days of injury in 103 subjects. Baseline neurological status was compared to neurological status at follow-up, preferably within one week (101 of 103 subjects). When available (n = 68), neurological status at 1 year or later was also compared. Overall, 6.2% (5/81) of motor complete, sensory complete (ASIA A) subjects converted to motor complete, sensory incomplete status (ASIA B) between the initial and follow-up assessments; however, none exhibited motor recovery (ASIA C or D). At initial follow-up, 9.3% (4/43) of ASIA A subjects with factors affecting examination reliability were reclassified as ASIA B injuries compared to 2.6% (1/38) of ASIA A subjects without such factors. At year 1 or later, 6.7% (2/30) of ASIA A subjects without factors affecting exam reliability, converted to ASIA B status. None developed volitional motor function below the zone of injury. For subjects with factors affecting exam reliability, 17.4% (4/23) of ASIA A subjects converted to incomplete status and 13.0% (3/23) regained some motor function by one year or later (ASIA C or D). These data suggest that it is possible to identify within 48 h of injury, a subset of patients with a negligible chance for motor recovery who would be suitable candidates for future clinical trials of invasive treatments.

Progress in imaging stroke: emerging clinical applications.

Recent years have seen major advances in the imaging of cerebrovascular disease. Although quantitative positron emission tomography (PET) has continued to be the gold standard in acquiring functional imaging data, with recent developments continuing to bear fruit, it remains a complex, costly, and not readily available technique. The emphasis in this overview is in the development of the newer magnetic resonance (MR) techniques, such as diffusion-weighted (DWI) and perfusion-weighted imaging (PWI), which allow rapid assessment of the underlying pathophysiology in acute ischaemic stroke. This is of major importance in classifying patients according to pathophysiology rather than clinical and structural imaging data, which may be essential in deciding therapy such as thrombolysis (which has proven benefit within 3-6 h of clinical onset, but can also lead to harmful haemorrhagic transformation) and/or neuroprotection, as well as patient selection in clinical trials. In conjunction with magnetic resonance angiography (MRA), DWI-PWI has been shown to improve the diagnosis and clinical management of stroke. Other novel MR techniques which have yet to reach the clinician, such as spectroscopic imaging, diffusion tensor imaging (DTI) and blood oxygenation level-dependent functional MRI (BOLD-fMRI), are currently established research tools which provide data about infarct evolution, fibre disruption and the mechanisms of stroke recovery. Electrophysiological methods including transcranial magnetic stimulation (TMS) and magneto-encephalography (MEG) will not be addressed here.

Prognosis in Acute Occupational Low Back Pain: Methodologic and Practical Considerations

Work-related or occupational low back pain (OLBP) is the leading cause of disability due to work-related conditions. The clinical course of this disorder is highly variable. Accurate prediction of disability outcomes in acute OLBP can lead to better selection of those likely to benefit from intensive interventions, identification of specific issues for intervention, and more efficient patient selection in clinical trials. The basis for disability prognostication has been developed through studies of outcomes in acute OLBP. These include investigations based on administrative data, workplace studies, and clinical studies in physicians' offices or workplaces. Each study design has inherent strengths and limitations that affect the accuracy of the resulting predictive models. Practical concerns for use of prognostic models in clinical settings include generalizability of results, feasibility of data collection and interpretation, acceptability to patients, cost, and linking prognosis to effective interventions. Ethical concerns include informed consent, confidentiality issues and inappropriate negative labeling. An informed choice of prognostic model and associated measures based on specific goals is needed to develop an appropriate application for a particular clinical or research situation. Future research may lead to greater use of these models, improving outcomes for workers with OLBP.

Farnesyltransferase inhibitors

The targeting of molecular abnormalities in neoplasms may provide an opportunity to improve the selectivity of cancer therapy. Ras mutations are a common genetic event in human cancers. Other genetic changes in tumors can signal through ras-dependent pathways as well. The targeting of ras through the inhibition of Ras protein farnesylation is one new cancer treatment strategy under clinical evaluation. Several farnesyl-transferase inhibitors (FTIs) have been evaluated in phase I trials. The toxicity and maximally tolerated doses of several FTIs have been determined, and clinical trials are underway to evaluate FTIs in combination with conventional cytotoxic chemotherapy agents. Also underway are attempts to develop assays to measure the biological effects of the FTI in patients. Inhibition of farnesylation of a number of surrogate markers are currently being investigated. These efforts may provide insight into the mechanism of action of these compounds and lead to improved patient selection for clinical trials.

Diffusion-weighted MRI in acute subcortical infarction.

Conventional imaging lacks sensitivity and specificity for the detection of early subcortical cerebral infarction. The purposes of our study were (1) to determine the accuracy of diffusion-weighted (DW) MRI for early subcortical infarction and (2) to determine the efficacy of DW MRI for differentiating acute from nonacute subcortical infarctions when conventional MR demonstrates multiple infarctions. Thirty-nine patients with clinically diagnosed acute subcortical infarction and 17 control subjects were imaged with both conventional and DW MRI from 7 hours to 4 days (mean, 2.0 days) after onset of symptoms. All images were read blinded to specific clinical findings. In all cases, the precise neuroanatomic locations of lesions were noted. These lesions were subsequently correlated by an experienced stroke neurologist to determine whether their locations correlated to the patients' symptoms. The accuracy of DW MRI for acute subcortical infarction was 94.6%. In 4 of 39 cases, the acute infarction was not detected on conventional MRI. In 24 of 39 cases, conventional MRI showed the acute lesion as well as multiple other subcortical lesions. In each of these 24 cases, the DW MRI showed a single lesion to be acute, and in all 24 cases, that lesion corresponded to the patients' acute symptoms. DW MRI has very high accuracy for acute subcortical infarction and can differentiate acute from nonacute lesions. These data have significant implications in guiding patient management and patient selection for clinical trials.

THE ROLE OF MR IMAGING IN THE SELECTION OF THERAPY FOR PROSTATE CANCER

Combined modality staging is a methodology in which all of the pretreatment clinical factors that are found to have independent prognostic significance on multivariable analysis for predicting a given outcome (e.g., pathologic stage) are used to determine the initial management. This method of staging provides an optimized assessment of the pathologic extent of local disease prior to management, and therefore is better able to define those patients in whom local only therapy is likely to be curative. Knowing more about the pathologic extent of disease prior to therapy provides a rationale for patient selection in clinical trials that test new management strategies against the current standards. The preoperative endorectal coil MR imaging study results have been shown on multivariable analysis (which included PSA, clinical stage, and biopsy Gleason score) to provide statistically independent prognostic information about the outcomes of pathologic stage, margin status, postoperative PSA failure, and the prediction of local only failure in the positive margin patient.

WHAT IS THE OPTIMAL PATIENT SELECTION FOR COMBINED ANDROGEN ABLATIVE AND RADIATION THERAPY?: The Role of Combined Modality Staging

The 5-year results of neoadjuvant androgen suppression and external beam radiation therapy for locally advanced prostate cancer show a benefit in local, distant, and biochemical control when compared with external beam radiation therapy alone. Further follow-up will ascertain if these findings translate into a survival benefit. Combined modality staging is a methodology in which all of the pretreatment clinical factors that are found to have independent prognostic significance on multivariable analysis for predicting a given outcome (for example, pathologic stage) are used to determine the initial management. This method of staging is able to provide an optimized assessment of the pathologic extent of local disease prior to management, and therefore it is better able to define those patients in whom local-only therapy is likely to be curative. Knowing more reliably the pathologic extent of disease prior to therapy also provides a rationale for patient selection in clinical trials that are currently testing the impact on overall survival of combining androgen suppression and external beam radiation therapy for early stage (T1b-T2b) prostate cancer.

An analysis of the time course of postoperative prostate-specific antigen failure in patients with positive surgical margins: Implications on the use of adjuvant therapy

The role of adjuvant therapy in the postprostatectomy setting for positive margin patients is an unresolved issue. The purpose of this study is to provide the rationale for patient selection in Phase III trials that test the impact of adjuvant therapy on survival in positive margin prostate cancer patients. Early (12 months or less) and delayed (more than 12 months) postoperative prostate-specific antigen (PSA) failure have been correlated with distant and local failure, respectively, as the site of first failure. In this study, a Cox regression multivariate analysis was used to determine the significant independent clinical and pathologic predictors of early and delayed postoperative PSA failure in 143 margin-positive prostate cancer patients. Margin-positive patients with positive pelvic lymph nodes, seminal vesicle invasion, or prostatectomy Gleason sum 8 or higher were excluded. For the remaining patients, a prostatectomy Gleason sum of 7, preoperative PSA more than 20 ng/mL, and an endorectal coil magnetic resonance imaging (erMRI) scan showing extensive disease were significant independent predictors of early postoperative PSA failure. Conversely, a prostatectomy Gleason sum of 6 or less, preoperative PSA 20 ng/mL or less, and an erMRI showing limited disease predicted delayed PSA failure. Preliminary data suggest that the pattern of first failure can be predicted by the time course of rise in the postoperative PSA. The preliminary results of this study suggest that patient selection for clinical trials examining the efficacy of postoperative adjuvant therapy in the positive margin patient may be determined on the basis of the clinical and pathologic characteristics that predict early versus delayed postoperative PSA failure.

Incidence and follow-up of Braunwald subgroups in unstable angina pectoris

This study was performed to establish the prognosis of patients with unstable angina within the subgroups of the Braunwald classification. Among many classifications of unstable angina, the Braunwald classification is frequently used. However, the incidence and risk for each subgroup in clinical practice have not been established. Prospective data for 417 consecutive patients admitted for suspected unstable angina were analyzed. Patients were classified according to Braunwald criteria and followed up for 6 months. Survival, infarct-free survival and infarct-free survival without intervention are reported for each class. After in-hospital observation the final diagnosis was acute myocardial infarction in 26 patients (6%), noncoronary chest pain in 109 (26%) and definite unstable angina in 282 (68%). Recurrence of chest pain was significantly different for the different severity classes (28%, 45% and 64% for classes I [accelerated angina], II [subacute angina at rest] and III [acute angina at rest], respectively) but not for clinical circumstances (49% and 53% for classes B [primary unstable angina] and C [postinfarction unstable angina], respectively). Six-month and infarct-free survival (96% and 88%, respectively) were not significantly different between severity classes but were significantly different (p = 0.01) between classes B (97% and 89%) and C (89% and 80%). Infarct-free survival without intervention was best for class II (72%), intermediate for class I (53%) and worst for class III (35%). In multivariate analysis, elderly age, male gender, hypertension, class C and maximal (intravenous) therapy were independent predictors for death; elderly age and class C for infarct-free survival; and male gender, class III, class C, electrocardiographic changes and maximal therapy were associated with infarct-free survival without intervention. Braunwald classification is an appropriate instrument to predict outcome. Risk stratification by these criteria provides a tool for patient selection in clinical trials and for evaluation of treatment strategies.

Validation of Somatostatin Receptor Scintigraphy in the Localization of Neuroendocrine Tumors

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers.

Somatostatin receptor imaging in the diagnosis and treatment of neuroendocrine tumors

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radioactive isotope-labelled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 30/31 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, 5/7 small cell lung cancers, 6/7 neuroblastomas, 38/49 primary breast cancers, and 0/18 pancreatic adenocarcinomas. Also 11/11 meningiomas, 4/4 astrocytomas and 0/3 glioblastomas could be visualized. Somatostatin receptor receptor is an easy, harmless and painless diagnostic method. It is an in vivo method for the recognition of neuroendocrine cancers. It localizes multiple and/or metastic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers.

Neurophysiological consequences of volatile substance abuse: Authors' reply

<h3>Background and aims</h3> To elucidate the diversity of systemic lupus erythematosus (SLE), we stratified SLE patients based on immunophenotyping. <h3>Methods</h3> Peripheral blood mononuclear cells were obtained from 80 active SLE patients (with one or more BILAG category A, or two or more BILAG category B). Circulating B, T and dendritic cells were defined based on flow cytometric analysis for human immune system termed ”the Human Immunology Project”. Based on these results, the immunophenotype was visualised by principal component analysis and SLE patients classified into subgroups by cluster analysis. <h3>Results</h3> Principal component analysis indicated that the immunophenotype of active SLE patients was consistent with T and B cell axes. Among these correlations, Th17 and Treg cells were statistically close, and showed positive correlation (p&lt;0.001). Furthermore, Tfh and Th1 cells were also statistically close, and showed positive correlation (p=0.04). The same pattern was also noted between Tfh and plasmablasts (p=0.02). Cluster analysis showed that SLE patients were divided into three subgroups (with high proportions of plasmablasts in all groups): patients did not show any characteristic features other than increased plasmablasts (T cell-independent group), patients with high percentage of Tfh cells (Tfh-dominant group), and patients with high proportions of activated Treg and memory Treg and low proportion of naïve Treg (Treg-dominant group). <h3>Conclusions</h3> Our study indicates that SLE patients can be divided into three subgroups based on T cell heterogeneity. This heterogeneity should be taken into consideration not only in basic research but also in patient selection in clinical trials for development of new drugs.

Arthroscopic and synovial correlates of pain in osteoarthritis

PATIENTS AND METHODS D EFINITION OF DISEASE complicates the correlation of pain with other features of knee joint osteoarthritis (OA). Patient selection for clinical trials is limited by the fact that joint pain is often present before joint destruction is demonstrated by radiographs.“* Direct inspection of the joint by knee arthroscopy can detect cartilage degeneration and hence confirm the diagnosis of OA before radiographic changes occur.3 Thus, patients presumed to have an early stage of OA also may be selected for screening of disease. Recently, the American College of Rheumatology (ACR; formerly the American Rheumatism Association) published criteria for classification of OA of the knee.’ These criteria can be tested by arthroscopy. Abnormal cartilage per se may not explain pain in OA because cartilage lacks innervation. However, joint pain in OA could be caused by a pathological process in the synovial membrane. There is controversy regarding the presence or absence of synovitis in OA4*’ based on diverging results in previous studies.“‘* The question has been addressed by a recent arthroscopic study using immunohistologic stains of the synovium.” An intense inflammation was demonstrated in synovium areas near OA cartilage, whereas the remainder of the joint interior remained without inflammation. Biopsies of involved synovium guided by direct visualization microscopically displayed highly inflammatory changes comparable to the synovial changes in rheumatoid arthritis. In contrast, tissues sampled from apparently noninflamed areas lacked immunohistopathologic signs of synovitis. Thus, microscopic examination verified the arthroscopic findings of local synovitis.13 Among the patients referred to the Department of Rheumatology, Huddinge University Hospital, for investigation of knee joint pain, five patients were studied who fulfilled the ACR clinical criteria for classification of OA’ and lacked other signs of a specific form of arthritis. They had given informed consent for the study. Patients were evaluated for the six sets of ACR criteria. Synovial fluid was not available in one of the five patients. No signs of disease in joints other than the knee were apparent at clinical examination. Arthroscopy of the knee joints was performed under local anesthesia. The pressure of irrigating solution was kept below the capillary blood pressure to avoid interference with the synovial circulation. The optics and biopsy forceps were introduced through the joint capsule at different points to enable biopsy sampling under direct vision, as previously described.“.‘4 The synovial biopsy specimens were snapfrozen at 70°C, and frozen sections were examined ,by immunohistochemical single and double stainings with monoclonal antibodies to T lymphocytes, macrophages, HLA-DR antigens, and immunoglobulins, as in earlier studies.‘3,‘4