Cluster Analysis of DSC MRI, Dynamic Contrast-Enhanced MRI, and DWI Parameters Associated with Prognosis in Patients with Glioblastoma after Removal of the Contrast-Enhancing Component: A Preliminary Study.

BACKGROUND AND PURPOSE: No report has been published on the use of DSC MR imaging, DCE MR imaging, and DWI parameters in combination to create a prognostic prediction model in glioblastoma patients. The aim of this study was to develop a machine learning-based model to find preoperative multiparametric MR imaging parameters associated with prognosis in patients with glioblastoma. Normalized CBV, volume transfer constant, and ADC of the nonenhancing T2 high-signal-intensity lesions were evaluated using K-means clustering. MATERIALS AND METHODS: A total of 142 patients with glioblastoma who underwent preoperative MR imaging and total resection were included in this retrospective study. From the normalized CBV, volume transfer constant, and ADC maps, the parametric data were sorted using the K-means clustering method. Patients were divided into training and test sets (ratio, 1:1), and the optimal number of clusters was determined using receiver operating characteristic analysis. Kaplan-Meier survival analysis and log-rank tests were performed to identify potential parametric predictors. A multivariate Cox proportional hazard model was conducted to adjust for clinical predictors. RESULTS: The nonenhancing T2 high-signal-intensity lesions were divided into 6 clusters. The cluster (class 4) with the relatively low normalized CBV and volume transfer constant value and the lowest ADC values was most associated with predicting glioblastoma prognosis. The optimal cutoff of the class 4 volume fraction of nonenhancing T2 high-signal-intensity lesions predicting 1-year progression-free survival was 9.70%, below which the cutoff was associated with longer progression-free survival. Two Kaplan-Meier curves based on the cutoff value showed a statistically significant difference (P = .037). When we adjusted for all clinical predictors, the cluster with the relatively low normalized CBV and volume transfer constant values and the lowest ADC value was an independent prognostic marker (hazard ratio, 3.04; P = .048). The multivariate Cox proportional hazard model showed a concordance index of 0.699 for progression-free survival. CONCLUSIONS: Our model showed that nonenhancing T2 high-signal-intensity lesions with the relatively low normalized CBV, low volume transfer constant values, and the lowest ADC values could serve as useful prognostic imaging markers for predicting survival outcomes in patients with glioblastoma.

Dynamic Contrast-Enhanced MR Imaging of Nonenhancing T2 High-Signal-Intensity Lesions in Baseline and Posttreatment Glioblastoma: Temporal Change and Prognostic Value.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging on nonenhancing T2 high-signal-intensity lesions in patients with glioblastoma has not been thoroughly elucidated to date. We evaluated the temporal change and prognostic value for progression-free survival of dynamic contrast-enhanced MR imaging-derived pharmacokinetic parameters on nonenhancing T2 high-signal-intensity lesions in patients with glioblastoma before and after standard treatment, including gross total surgical resection. MATERIALS AND METHODS: This retrospective study included 33 patients who were newly diagnosed with glioblastoma and treated with gross total surgical resection followed by concurrent chemoradiation therapy and adjuvant chemotherapy with temozolomide in a single institution. All patients underwent dynamic contrast-enhanced MR imaging before surgery as a baseline and after completion of maximal surgical resection and concurrent chemoradiation therapy. On the whole nonenhancing T2 high-signal-intensity lesion, dynamic contrast-enhanced MR imaging-derived pharmacokinetic parameters (volume transfer constant [K trans], volume of extravascular extracellular space [v e], and blood plasma volume [vp ]) were calculated. The Cox proportional hazards regression model analysis was performed to determine the histogram features or percentage changes of pharmacokinetic parameters related to progression-free survival. RESULTS: Baseline median K trans, baseline first quartile K trans, and posttreatment median K trans were significant independent variables, as determined by univariate analysis (P < .05). By multivariate Cox regression analysis including methylation status of O6-methylguanine-DNA methyltransferase, baseline median K trans was determined to be the significant independent variable and was negatively related to progression-free survival (hazard ratio = 1.48, P = .003). CONCLUSIONS: Baseline median K trans from nonenhancing T2 high-signal-intensity lesions could be a potential prognostic imaging biomarker in patients undergoing gross total surgical resection followed by standard therapy for glioblastoma.

Prognostic Predictions for Patients with Glioblastoma after Standard Treatment: Application of Contrast Leakage Information from DSC-MRI within Nonenhancing FLAIR High-Signal-Intensity Lesions.

BACKGROUND AND PURPOSE: Attempts have been made to quantify the microvascular leakiness of glioblastomas and use it as an imaging biomarker to predict the prognosis of the tumor. The purpose of our study was to evaluate whether the extraction fraction value from DSC-MR imaging within nonenhancing FLAIR hyperintense lesions was a better prognostic imaging biomarker than dynamic contrast-enhanced MR imaging parameters for patients with glioblastoma. MATERIALS AND METHODS: A total of 102 patients with glioblastoma who received a preoperative dynamic contrast-enhanced MR imaging and DSC-MR imaging were included in this retrospective study. Patients were classified into the progression (n = 87) or nonprogression (n = 15) groups at 24 months after surgery. We extracted the means and 95th percentile values for the contrast leakage information parameters from both modalities within the nonenhancing FLAIR high-signal-intensity lesions. RESULTS: The extraction fraction 95th percentile value was higher in the progression-free survival group of >24 months than at ≤24 months. The median progression-free survival of the group with an extraction fraction 95th percentile value of >13.32 was 17 months, whereas that of the group of ≤13.32 was 12 months. In addition, it was an independent predictor variable for progression-free survival in the patients regardless of their ages and genetic information. CONCLUSIONS: The extraction fraction 95th percentile value was the only independent parameter for prognostic prediction in patients with glioblastoma among the contrast leakage information, which has no statistically significant correlations with the DCE-MR imaging parameters.

Antiangiogenic Effect of Bevacizumab: Application of Arterial Spin-Labeling Perfusion MR Imaging in a Rat Glioblastoma Model.

BACKGROUND AND PURPOSE: The usefulness of arterial spin-labeling for the evaluation of the effect of the antiangiogenic therapy has not been elucidated. Our aim was to evaluate the antiangiogenic effect of bevacizumab in a rat glioblastoma model based on arterial spin-labeling perfusion MR imaging. MATERIALS AND METHODS: DSC and arterial spin-labeling perfusion MR imaging were performed by using a 9.4T MR imaging scanner in nude rats with glioblastoma. Rats were randomly assigned to the following 3 groups: control, 3-day treatment, and 10-day treatment after bevacizumab injection. One-way analysis of variance with a post hoc test was used to compare perfusion parameters (eg, normalized CBV and normalized CBF from DSC MR imaging and normalized CBF based on arterial spin-labeling) with microvessel area on histology. The Pearson correlations between perfusion parameters and microvessel area were also determined. RESULTS: All of the normalized CBV from DSC, normalized CBF from DSC, normalized CBF from arterial spin-labeling, and microvessel area values showed significant decrease after treatment (P < .001, P < .001, P = .005, and P < .001, respectively). In addition, normalized CBV and normalized CBF from DSC and normalized CBF from arterial spin-labeling strongly correlated with microvessel area (correlation coefficient, r = 0.911, 0.869, and 0.860, respectively; P < .001 for all). CONCLUSIONS: Normalized CBF based on arterial spin-labeling and normalized CBV and normalized CBF based on DSC have the potential for evaluating the effect of antiangiogenic therapy on glioblastomas treated with bevacizumab, with a strong correlation with microvessel area.

Cytomorphological characteristics of low-grade papillary urothelial carcinoma for differential diagnosis from benign papillary urothelial lesions: logistic regression analysis in SurePath(™) liquid-based voided urine cytology.

OBJECTIVE: The diagnosis of low-grade papillary urothelial carcinoma (LGPUC) in urine cytology specimens is challenging because of its subtle, minimally atypical findings. Furthermore, as SurePath(™) liquid-based cytology (LBC) is becoming a widely used method in urine cytology, the inevitable cytomorphological alterations resulting from this technique call for new morphological diagnostic criteria in LGPUC. METHODS: Logistic regression analysis was carried out on SurePath slides from surgically proven voided urine specimens. The study was designed to include a test set (n = 141) and a validation set (n = 61), and evaluated significant discriminative parameters between LGPUC and benign papillary urothelial neoplasm (BPUN). RESULTS: Of the seven cytological findings that were found to have statistical significance in univariate analysis, five were found to be independent variables: loss of polarity of papillaroid clusters, irregular contours, absence of columnar cells, hobnail features and hyperchromasia. These independent variables had an area under the curve (AUC) of 0.781. CONCLUSIONS: The distinctive cytological criteria identified above may prove to be helpful in cases in which other conventional criteria for LGPUC are insufficient for diagnosis.

Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation are considered mutually exclusive in nonsmall-cell lung cancer (NSCLC). However, sporadic cases having concomitant EGFR and ALK alterations have been reported. The present study aimed to assess the prevalence of NSCLCs with concomitant EGFR and ALK alterations using mutation detection methods with different sensitivity and to propose an effective diagnostic and therapeutic strategy. PATIENTS AND METHODS: A total of 1458 cases of lung cancer were screened for EGFR and ALK alterations by direct sequencing and flourescence in situ hybridization (FISH), respectively. For the 91 patients identified as having an ALK translocation, peptide nucleic acid (PNA)-clamping real-time PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays were carried out to detect EGFR mutation. RESULTS: EGFR mutations and ALK translocations were observed in 42.4% (612/1445) and 6.3% (91/1445) of NSCLCs by direct sequencing and FISH, respectively. Concomitant EGFR and ALK alterations were detected in four cases, which accounted for 4.4% (4/91) of ALK-translocated NSCLCs. Additional analyses for EGFR using PNA real-time PCR and ultra-deep sequencing by NGS, mutant-enriched NGS increased the detection rate of concomitant EGFR and ALK alterations to 8.8% (8/91), 12.1% (11/91), and 15.4% (14/91) of ALK-translocated NSCLCs, respectively. Of the 14 patients, 3 who were treated with gefitinib showed poor response to gefitinib with stable disease in one and progressive disease in two patients. However, eight patients who received ALK inhibitor (crizotinib or ceritinib) showed good response, with response rate of 87.5% (7/8 with partial response) and durable progression-free survival. CONCLUSIONS: A portion of NSCLC patients have concomitant EGFR and ALK alterations and the frequency of co-alteration detection increases when sensitive detection methods for EGFR mutation are applied. ALK inhibitors appear to be effective for patients with co-alterations.

Effect of value-added utilities on prescription refill compliance and health care expenditures for hypertension.

A randomised trial was undertaken to discern the effect of pharmacy-based value-added utilities on prescription refill compliance with antihypertensive therapy and subsequent health care expenditures. The subjects were 304 Medicaid beneficiaries from the state of Florida, previously untreated for mild to moderate hypertension, prescribed 240 mg of calcium channel antagonist verapamil once daily and monitored regarding prescription refill compliance and health service utilisation for one year. Subjects provided informed consent and were randomly assigned to one of four experimental groups: (1) the control cohort received standard pharmaceutical care with each dispensing of antihypertensive therapy, (2) the second cohort received standard pharmaceutical care and was mailed a medication-refill reminder ten days prior to each sequential refill date, (3) the third cohort received standard pharmaceutical care and was provided unit-of-use packaging with each prescription-refill request and (4) the fourth cohort received standard pharmaceutical care, mailed medication-refill reminders and unit-of-use packaging. Analysis of variance (ANOVA) procedures revealed that patients receiving mailed prescription-refill reminders, unit-of-use packaging or a combination of both interventions achieved a significant (P < or = 0.05) increase in the Medication Possession Ratio (MPR) for antihypertensive therapy relative to controls. Receipt of both interventions resulted in a significant (P < or = 0.05) improvement in the MPR for antihypertensive therapy relative to all other groups no significant difference was discerned between groups receiving either mailed prescription-refill reminders or unit-of-use packaging.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of a sustained-release formulation for antihypertensive therapy.

Recent pharmacotherapeutic advances in the treatment of hypertension have included the development of sustained-release (SR) dosage formulations, providing patients with the convenience of once daily administration. A one year retrospective analysis was undertaken to determine the economic utility of providing prescription coverage for the SR formulation of verapamil, a calcium channel antagonist, under the state of Florida's Medicaid programme. Data for this analysis were derived from the state of Florida's Medicaid computer archive. The study population consisted of 274 ambulatory beneficiaries diagnosed with hypertension and prescribed either the SR or immediate-release (IR) formulation of verapamil. Multivariate regression analysis was used to discern the incremental influence of selected demographic characteristics, utilisation of medical services prior to diagnosis for hypertension and prescribed formulation of verapamil on health care expenditures one year post-diagnosis. Patients prescribed the SR formulation of verapamil achieved a significant (P < or = 0.05) increase in the Medication Possession Ratio (MPR), an index of compliance, (0.87 +/- 0.13) relative to patients prescribed the IR formulation (0.56 +/- 0.10). Results indicate that receipt of verapamil in an SR formulation was associated with a significant (P < or = 0.05) decrease in aggregate health care expenditures of $110.14 over the one year study period. Receipt of the SR formulation was associated with an increase in expenditures for antihypertensive therapy ($117.83, p < or = 0.05) and a decrease in financial commitments for physician ($50.42, p < or = 0.05), hospital ($153.61, p < or = 0.05) and laboratory ($23.94, p < or = 0.05) services.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pharmaceutical formulation for diltiazem on health care expenditures for hypertension.

A 1-year retrospective analysis was undertaken to discern the economic utility of providing prescription coverage for the sustained-release (SR) formulation of diltiazem, a calcium-channel antagonist, under the state of South Carolina's Medicaid program. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 347 ambulatory beneficiaries diagnosed with hypertension for whom either the SR or immediate-release (IR) formulation of diltiazem was prescribed. Multivariate regression analysis was used to discern the incremental influence of selected demographic characteristics, use of medical services prior to diagnosis for hypertension, and prescribed formulation of diltiazem on health care expenditures 1-year postdiagnosis. Patients for whom the SR formulation of diltiazem was prescribed achieved a significant (P < or = 0.05) increase in the medication possession ratio, an index of compliance (SR, 0.63 +/- 0.17) relative to patients for whom the IR formulation was prescribed (IR, 0.44 +/- 0.13). Results indicate that receipt of diltiazem in an SR formulation was associated with a significant decrease in aggregate health care expenditures over the 1-year study period ($258.80, P < or = 0.05). Receipt of the SR formulation was associated with an increase in expenditures for antihypertensive therapy ($109.26, P < or = 0.05), and a decrease in financial commitments for physician ($128.70, P < or = 0.05), hospital ($211.84, P < or = 0.05), and laboratory ($27.52, NS) services. At the managerial and policy levels, these data argue for an increased use of therapeutic alternatives that facilitate a reduction in the patient's daily dosing schedule for antihypertensive therapy.

Effect of value-added utilities on prescription refill compliance and Medicaid health care expenditures--a study of patients with non-insulin-dependent diabetes mellitus.

An estimated 20 million Americans suffer from diabetes. Patients with non-insulin-dependent diabetes mellitus (NIDDM) comprise approximately 90% of the diabetic population. An estimated 10-30% of patients with NIDDM withdraw from their prescribed regimen within 1 year of diagnosis, and of the remainder, nearly 20% administer insufficient medication to facilitate an adequate reduction in blood glucose. A randomized trial was undertaken to discern the effect of pharmacy-based value-added utilities on prescription-refill compliance with sulfonylurea therapy and health service utilization. The subjects were 258 Medicaid beneficiaries from the state of South Carolina, previously untreated for NIDDM, prescribed 5 mg of the second-generation sulfonylurea glyburide twice daily, and monitored with regard to prescription-refill compliance and health service utilization for 1 year. Subjects provided informed consent and were randomly assigned to one of four experimental groups: (i) the control cohort received standard pharmaceutical care with each dispensing of glyburide; (ii) the second cohort received standard pharmaceutical care and was mailed a medication-refill reminder 10 days prior to each sequential refill date; (iii) the third cohort received standard pharmaceutical care and was provided unit-of-use packaging with each prescription-refill request; (iv) the fourth cohort received standard pharmaceutical care, mailed medication-refill reminders, and unit-of-use packaging. Analysis of variance (ANOVA) procedures revealed that patients receiving mailed prescription-refill reminders, unit-of-use packaging, or a combination of both interventions achieved a significant (P < or = 0.05) increase in the Medication Possession Ratio (MPR) for sulfonylurea therapy relative to controls.(ABSTRACT TRUNCATED AT 250 WORDS)