Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine.

BACKGROUND AND PURPOSE: Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. MATERIALS AND METHODS: A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. RESULTS: Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. CONCLUSIONS: This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.

Mechanisms of post-radiation injury: cerebral microinfarction not a significant factor.

Post-radiation leukoencephalopathy is characterized by cognitive impairment and white matter alternations on imaging. Cerebral small vessel disease (SVD) is one of several suggested etiologies. Cerebral microinfarction (CMI) is a recently described marker of SVD. We sought to examine the rate of CMI as a biomarker of ongoing ischemia among patients who underwent brain radiotherapy (RT). 110 patients treated with RT for primary or metastatic brain tumors were enrolled. A total of 685 brain MRI tests performed 1-108 months post-radiation were examined. The annual incidence of CMI was calculated. Only 2 definite CMI were found (2/685, 0.3 %). The calculated annual incidence of CMI was 0.11. This incidence is similar to the normal population, and lower than the reported incidence in patients with intracerebral hemorrhage or cognitive impairment. CMI incidence in patients treated with brain RT is similar to the general population. This finding suggests that post-radiation leukoencephalopathy and cognitive impairment are not due to active SVD solely but rather secondary to other causes such as inflammation, metabolic or direct cell damage.

Early Biomarkers from Conventional and Delayed-Contrast MRI to Predict the Response to Bevacizumab in Recurrent High-Grade Gliomas.

BACKGROUND AND PURPOSE: The interpretation of the radiologic response of bevacizumab-treated patients with recurrent high-grade gliomas represents a unique challenge. Delayed-contrast MR imaging was recently introduced for calculating treatment-response-assessment maps in patients with brain tumors, providing clear separation between active tumor and treatment effects. We studied the application of standard and delayed-contrast MR imaging for assessing and predicting the response to bevacizumab. MATERIALS AND METHODS: Twenty-four patients with recurrent high-grade gliomas were scanned before and during bevacizumab treatment by standard and delayed-contrast MR imaging. The mean change in lesion volumes of responders (overall survival, ≥1 year) and nonresponders (overall survival, <1 year) was studied. The lesion volumes at baseline and the changes in lesion volumes 1 month after treatment initiation, calculated from standard and delayed-contrast MRIs, were studied as possible predictors of outcome. In scans acquired at progression, the average change in lesion volume from previous follow-up in standard and delayed-contrast MRIs was compared. RESULTS: Response and progression patterns were identified from the mean change in lesion volumes, depicted from conventional T1WI, delayed contrast-enhanced MR imaging, and DSC MR imaging. Thresholds for early prediction of response were calculated by using these sequences. For each predictor, sensitivity, specificity, positive predictive values, and negative predictive values were calculated, reaching 85.7%, 87.5%, 75%, and 93.3% for conventional T1WI; 100%, 87.5%, 77.8%, and 100% for delayed-contrast MR imaging; and 75%, 78.6%, 50%, and 91.7% for DSC MR imaging. The benefit of delayed-contrast MR imaging in separating responders and nonresponders was further confirmed by using log-rank tests (conventional T1WI, P = .0022; delayed-contrast MR imaging, P < .0001; DSC MR imaging, P = .0232) and receiver operating characteristic analyses. At progression, the increase in lesion volumes in delayed-contrast MR imaging was 37.5% higher than the increase in conventional T1WI (P < .01); these findings suggest that progression may be depicted more effectively in treatment-response-assessment maps. CONCLUSIONS: The benefit of contrast-enhanced MR imaging for assessing and predicting the response to bevacizumab was demonstrated. The increased sensitivity of the treatment-response-assessment maps reflects their potential contribution to the management of bevacizumab-treated patients with recurrent high-grade glioma.

The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter?

The FDA-approved schedule and dose of bevacizumab (BVZ) for recurrent glioblastoma (rGB) (10 mg/kg q 2 weeks) were adopted from systemic cancer protocols. No dose-defining studies have been performed for glioblastoma. We began using BVZ for the treatment of rGB in 2005 at the dose of 5 mg/kg every 2 weeks combined with irinotecan, and later as single agent. Our previous report of 20 patients treated with BVZ 5 mg/kg every 2 weeks showed similar response rates and overall survival (OS) compared to other BVZ treatment protocols, with less adverse effects. In this study we retrospectively reviewed our 7 year experience with BVZ in 162 rGB patients. Treatment outcomes were analyzed from 87 patients who received BVZ at 5 mg/kg and 75 patients at 10 mg/kg. While median age was similar in both groups, the median KPS was significantly higher in the group treated with 10 mg/kg BVZ (85 versus 60). There was no significant difference in OS or progression free survival (PFS) between the groups treated with BVZ 5 versus 10 mg/kg. Overall survival was significantly improved in the subgroup treated with cytotoxic therapy in addition to BVZ 10 mg/kg. There were more adverse events seen with BVZ 10 mg/kg. There is no significant difference in OS for rGB treated with BVZ 5 mg/kg versus 10 mg/kg when given as monotherapy. The smaller dose was slightly less toxic. Addition of cytotoxic therapy resulted in prolongation of OS in a small subgroup of BVZ 10 mg/kg.

The value of ventriculo-peritoneal shunting in patients with glioblastoma multiforme and ventriculomegaly.

BACKGROUND: Patients with an advanced-stage glioblastoma multiforme (GBM) often show general motor, gait, and cognitive deterioration. Some have radiological evidence of ventriculomegaly, but the relevance of this to their symptoms may be unclear. Distinction between tumour patients who have dilated fluid spaces as a consequence of tissue loss from surgery or treatment, and those who have a symptomatic hydrocephalic process, one who may gain benefit from insertion of a ventriculo-peritoneal shunt, is an important clinical challenge. METHODS: From a series of 530 GBM patients treated by a single surgeon (ZR), we retrospectively reviewed 16 patients with advanced-stage GBM who had presented with non-obstructive ventriculomegaly and clinical deterioration not explained by progressive disease. Each had been treated by insertion of a ventriculo- peritoneal shunt (VPS). Assessments included clinical features, Karnofsky Performance Scale, motor and cognitive findings, complications and survival. FINDINGS: Ten patients benefited from insertion of the shunt, with moderate to significant cognitive improvement. Of seven patients who presented with motor symptoms, such as gait instability, general weakness, and slowness, four patients showed significant motor improvement in addition to major cognitive improvement. Early infectious complication occurred in five patients; a late shunt infection in one; one patient had symptoms related to overdrainage; and in another a mechanical shunt malfunction occurred. Three patients died from shunt-related complications. CONCLUSIONS: Insertion of a ventriculo-peritoneal shunt can improve cognitive and motor function in a small subset of patients with advanced-stage glioblastoma multiforme and ventriculomegaly. Infection is a major risk in this patient population.

Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis.

A 67-year-old man sequentially developed anti-Ma2-associated paraneoplastic encephalitis (PNE) and contralateral herpes simplex encephalitis (HSE). Brain biopsy 1 month before HSE revealed extensive infiltrates of T cells, B cells, and plasma cells. Most T cells expressed the cytotoxic granule-associated protein TIA-1 and the membranolytic protein granzyme-B. Although recovery was thought to be unlikely, treatment of the PNE with corticosteroids and resection of the associated lung cancer resulted in dramatic improvement for 21 months.

Efficacy of local dipyridamole therapy in a porcine model of arteriovenous graft stenosis.

Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.

Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM.

Primary glioblastoma multiforme (GBM) commonly overexpresses the epidermal growth factor receptor (EGFR) gene and its ligand-independent mutant, EGFRvIII. Amplification of the EGFR gene has been implicated in the pathogenesis of primary GBM, in particular the small cell phenotype, and this finding may contribute to its aggressive clinical behavior. Anti-EGFR clinical trials for GBM are being conducted, and it would be useful to identify a rapid technique to determine whether EGFR expression and the small cell phenotype are associated with a response to therapy. In the present study we examined 56 cases of GBM using chromogenic in situ hybridization (CISH). CISH analysis and morphology identified 22 small cell (SCGBM) and 22 non-small cell glioblastoma (NSCGBM), and 12 cases of a mixed phenotype. Fourteen cases of SCGBM (14/22) showed EGFR amplification, while only 5 NSCGBM (5/22) cases showed amplification. We have therefore used CISH as an efficient, economic and reliable means for routinely assessing EGFR amplification in GBM, including the small cell variant.

Preparedness for clinical practice: reports of graduating residents at academic health centers.

CONTEXT: Medical educators are seeking improved measures to assess the clinical competency of residents as they complete their graduate medical education. OBJECTIVE: To assess residents' perceptions of their preparedness to provide common clinical services during their last year of graduate medical education. DESIGN, SETTING, AND PARTICIPANTS: A 1998 national survey of residents completing their training in 8 specialties (internal medicine, pediatrics, family practice, obstetrics/gynecology, general surgery, orthopedic surgery, psychiatry, and anesthesiology) at academic health centers in the United States. A total of 2626 residents responded (response rate, 65%). MAIN OUTCOME MEASURES: Residents' reports of their preparedness to perform clinical and nonclinical tasks relevant to their specialties. RESULTS: Residents in all specialties rated themselves as prepared to manage most of the common conditions they would encounter in their clinical career. However, more than 10% of residents in each specialty reported that they felt unprepared to undertake 1 or more tasks relevant to their disciplines, such as caring for patients with human immunodeficiency virus/acquired immunodeficiency syndrome or substance abuse (family practice) or nursing home patients (internal medicine); performance of spinal surgery (orthopedic surgery) or abdominal aortic aneurysm repair (general surgery); and management of chronic pain (anesthesiology). CONCLUSIONS: Overall, residents in their last year of training at academic health centers rate their clinical preparedness as high. However, opportunities for improvement exist in preparing residents for clinical practice.

Personal, organizational, and market level influences on physicians' practice patterns: results of a national survey of primary care physicians.

BACKGROUND: One of the principal tenets of managed care is that physicians' clinical decisions can be influenced both to improve the quality and consistency of care and to decrease health care expenditures. Medical decision making, however, remains a complex phenomenon and the most important determinants of physicians' approaches to clinical decision making remain poorly understood. OBJECTIVES: To determine how clinical decisions are associated with individual characteristics, practice setting and organizational characteristics, attributes of the patient population under care, and the market environment. RESEARCH DESIGN: Cross-sectional, nationally representative survey of patient-care physicians. SUBJECTS: Primary care physicians who provide direct patient care at least 20 hours per week. MEASURES: Proportion of physicians who would order a referral, diagnostic test, or treatment for 5 clinical scenarios thought to be representative of discretionary medical decisions. RESULTS: Responses were received from 4,825 primary care physicians who cared for adult patients (Response Rate 65%). The distribution of results for each of the five clinical scenarios demonstrates significant variability both within and between physicians. No evidence was seen of a consistent practice style across the vignettes (eg, "aggressive" or "conservative"). The organizational setting of practice was the most consistent predictor of behavior across all the clinical scenarios, with the exception of back pain, which was minimally related to any of the environmental factors. When compared to physicians in solo practice, physicians in all other practice settings were less likely to order a test or referral or pursue treatment. Practice involvement with managed care and measures of financial influences and administrative strategies associated with managed care were minimally and inconsistently associated with reported physician behaviors. CONCLUSIONS: The ability of managed care to improve the quality and consistency of care while also controlling the costs of care depends on its ability to influence medical decisions. Our findings generally demonstrate that managed care has a weak influence on discretionary medical decisions and that the influence of managed care pales in comparison to personal and practice setting influences.

Modified order of allelic replication in lymphoma patients at different disease stages.

Asynchronous replication of homologous loci was reported in lymphocytes of patients with lymphoma, ovarian and renal cancer as well as in lymphocytes of patients with premalignant conditions, for example, essential mixed cryoglobulinemia associated with hepatitis C virus and in monoclonal gammopathy of unknown significance. In the present study we evaluated the replication pattern in lymphocytes of four groups of patients with intermediate grade of non-Hodgkin lymphoma at various stages of their disease: 1) at diagnosis; 2) during cytotoxic treatment; 3) in remission; and 4) in relapse. A significantly higher proportion of the asynchronous pattern of replication at diagnosis, during cytotoxic treatment, and in relapse was noted as compared to healthy controls and to patients who achieved remission of their lymphoma. Also, the frequency of the two doublets (DD) pattern in every group studied was significantly lower than in the controls. If our findings can be confirmed in larger, long-term prospective studies, it may allow the use of a simple and inexpensive tool to closely observe patients with lymphoma who are at high risk for relapse.

Improving preventive care by prompting physicians.

OBJECTIVES: To assess the impact of prompting physicians on health maintenance, answer questions regarding the mode of delivery, and identify opportunities and limitations of this information intervention. METHODS: Systematic electronic and manual searches (January 1, 1966, to December 31, 1996) were conducted to identify clinical trial reports on prompting clinicians. Three eligibility criteria were applied: (1) randomized controlled clinical trial, (2) clinician prompt, alert, or reminder in the study group and no similar intervention in the control group, and (3) measurement of the intervention effect on the frequency of preventive care procedures. Data were abstracted by independent reviewers using a standardized abstraction form, and quality of methodology was scored. A series of meta-analyses on triggering clinical actions was performed using the random-effects method. The statistical analyses included 33 eligible studies, which involved 1547 clinicians and 54 693 patients. RESULTS: Overall, prompting can significantly increase preventive care performance by 13.1% (95% confidence interval [CI], 10.5%-15.6%). However, the effect ranges from 5.8% (95% CI, 1.5%-10.1%) for Papanicolaou smear to 18.3% (95% CI, 11.6%-25.1%) for influenza vaccination. The effect is not cumulative, and the length of intervention period did not show correlation with effect size (R = -0.015, P = .47). Academic affiliation, ratio of residents, and technique of delivery did not have a significant impact on the clinical effect of prompting. CONCLUSIONS: Dependable performance improvement in preventive care can be accomplished through prompting physicians. Vigorous application of this simple and effective information intervention could save thousands of lives annually. Health care organizations could effectively use prompts, alerts, or reminders to provide information to clinicians when patient care decisions are made.

Common components of patch-clamp internal recording solutions can significantly affect protein kinase A activity.

Common components of whole-cell internal recording solutions were tested both in vitro and in patch-clamp experiments for their effects on the activity of cAMP-dependent protein kinase. Potassium fluoride (KF), 440 mM trimethylamine chloride and exclusion of bovine serum albumin (BSA) decreased the activity of the enzyme, while ethylene glycol-bis (beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and the potassium salts of aspartate, gluconate, methylsulfate and monobasic phosphate increased its activity. Addition of KF to the internal solution produced a hyperpolarizing shift in the V1/2 of Ih channel activation, consistent with the KF-induced reduction of protein kinase A activity. Therefore, consideration of the composition of internal solutions is warranted when studying channel physiology by patch-clamp techniques.

Primary intracranial neoplasms in patients with HIV.

OBJECTIVE: To report a series of HIV-infected patients with intracranial tumors not known to be associated with immunodeficiency. BACKGROUND: The spectrum of HIV-associated diseases is changing with improved treatments and prolonged patient survival. Although primary central nervous system lymphoma (PCNSL) and toxoplasmosis continue to be the most common intracranial lesions in HIV-infected patients, the recognition of other pathologic entities is increasingly important. METHODS: The clinical characteristics and outcome of eight HIV-infected patients with nine intracranial neoplasms other than PCNSL are reported. In addition, all available pathologic specimens were tested for evidence of either HIV or Epstein-Barr virus (EBV) infection. An additional 28 patients reported in the literature are summarized. RESULTS: Five of eight patients had a glioblastoma multiforme; other tumors included an anaplastic ependymoma, a low-grade glioma, a subependymoma, and a leiomyosarcoma. More than half of the patients developed their tumor > or =6 years after the diagnosis of HIV infection. Patient prognosis and survival was best predicted by tumor histology. Treatment response and outcome did not appear to be influenced by HIV infection. Only the leiomyosarcoma demonstrated evidence of latent EBV infection. CONCLUSIONS: HIV-infected patients are at risk for intracranial neoplasms other than PCNSL, and benefit from aggressive tumor-specific therapy. It is possible that gliomas are occurring at a higher rate than in the general population. There was no evidence of HIV or EBV infection in any glial tumor.

The duration of ambulatory visits to physicians.

BACKGROUND: The objective of our study was to determine the typical length of ambulatory visits to a nationally representative sample of primary care physicians, and the patient, physician, practice, and visit characteristics affecting duration of visit. METHODS: We used an analysis of cross-sectional survey data to determine duration of visit and the characteristics associated with it. The data sources were a random sample of the 19,192 visits by adults to 686 primary care physicians contained in the 1991-1992 National Ambulatory Medical Care Survey, and the results of the Physician Induction Interview conducted by the National Center for Health Statistics. Duration of visit was defined as the total time spent in face-to-face contact with the physician. RESULTS: Mean duration of visit was 16.3 minutes (standard deviation = 9.7). Multivariate analysis allowed the calculation of the independent effect on visit length of a variety of characteristics of patients, physicians, organizational/practice setting, geographic location, and visit content. Certain patient characteristics (increasing age and the presence of psychosocial problems) were associated with increased duration of visit. Visit content was also associated with increased duration, including ordering or performing 4 or more diagnostic tests (71% increase), Papanicolaou smears (34%), ambulatory surgical procedures (34%), patient admission to the hospital (32%), and 3 preventive screening tests (25%). Reduced duration of visit was associated with availability of non-physician support personnel and health maintenance organization and Medicaid insurance. CONCLUSIONS: Multiple factors affect duration of visit. Clinicians, policymakers, and health system managers should take these considerations into account in managing physician resources during daily ambulatory practice.