Economic evaluation of prophylactic antiemetic regimens for prevention of chemotherapy -induced nausea and vomiting (CINV)

New antiemetic agents, aprepitant and palonosetron have been approved for prevention of chemotherapy-induced nausea and vomiting (CINV). The objectives of the two phases of the study were: (1) to conduct cost-effectiveness analysis of antiemetic regimens for prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC) and in patients receiving moderately emetogenic chemotherapy (MEC) using decision models, and (2) to determine the monetary value of improved emesis control and conduct cost-benefit analysis of the new antiemetic regimens. Regimen A, one of the four antiemetic strategies included in the HEC decision model was a combination of aprepitant and the standard regimen of ondansetron+dexamethasone. The other three regimens had standard regimen in the acute phase but differed in the delayed phase regimens: regimen B - dexamethasone only, regimen C - dexamethasone+metoclopramide and regimen D - dexamethasone+ondansetron. The four antiemetic strategies for prevention of CINV due to MEC were: regimen (1) IV palonosetron, (2) IV ondansetron, (3) ondansetron+dexamethasone in acute phase, only dexamethasone in delayed phase, (4) ondansetron+dexamethasone in acute and delayed phase. The outcome measure was the incremental cost-effectiveness ratios (ICER) measured as cost/patient with complete control of emesis. For the HEC model, the ICER of regimen A compared to C was {dollar}3,363.18 and {dollar}2,881.61 per patient with complete control of emesis, from payer and societal perspectives respectively. One-way and probabilistic sensitivity analyses indicated that the conclusions were relatively stable to variations in multiple parameters. For MEC model, regimen 1 was found to be most cost-effective with ICER of {dollar}3,582.48 and {dollar}3,549.02, from payer and societal perspectives respectively. Overall, the ICER results showed that the regimen A and regimen 1 could be considered cost-effective therapies for prevention of CINV. In phase II, a contingent valuation survey was developed and administered to 120 cancer patients who were either receiving or had received chemotherapy. The results showed that respondents were willing-to-pay on average {dollar}83.50 for a single dose of palonosetron and {dollar}89.90 for a three-day regimen of aprepitant. Phase II qualitative results also emphasized that cancer patients receiving chemotherapy placed a high importance on receiving even a modest improvement in the control of CINV

Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ

Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ

Diffusion MRI Characteristics after Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma

The standard of care for newly diagnosed glioblastoma (GBM) is surgery first, radiotherapy (RT) with concurrent temozolomide (TMZ) second, and adjuvant TMZ last. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT + TMZ and before adjuvant TMZ would have a significantly shorter progression-free survival (PFS) and overall survival (OS). To test this hypothesis, we evaluated 120 patients with newly diagnosed GBM receiving RT + TMZ followed by adjuvant TMZ. Magnetic resonance imaging was performed after completing RT + TMZ and before initiating adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 μm2/ms and ADCH value of 1.6 μm2/ms were used to stratify patients into high- and low-risk categories. Results suggested that patients with a low ADCL had a significantly shorter PFS (Cox hazard ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 versus 644 days (Cox hazard ratio = 0.31, P = 0.047). ADCH did not predict PFS or OS when accounting for age and ADCL. In summary, after completing RT + TMZ, newly diagnosed glioblastoma patients with a low ADCL are likely to progress and die earlier than patients with a higher ADCL. ADC histogram analysis may be useful for patient-risk stratification after completing RT + TMZ

A gene expression signature predicts recurrence-free survival in meningioma

BACKGROUND Meningioma is the most common primary brain tumor and has a variable risk of local recurrence. While World Health Organization (WHO) grade generally correlates with recurrence, there is substantial within-grade variation of recurrence risk. Current risk stratification does not accurately predict which patients are likely to benefit from adjuvant radiation therapy (RT). We hypothesized that tumors at risk for recurrence have unique gene expression profiles (GEP) that could better select patients for adjuvant RT. METHODS We developed a recurrence predictor by machine learning modeling using a training/validation approach. RESULTS Three publicly available AffymetrixU133 gene expression datasets (GSE9438, GSE16581, GSE43290) combining 127 primary, non-treated meningiomas of all grades served as the training set. Unsupervised variable selection was used to identify an 18-gene GEP model (18-GEP) that separated recurrences. This model was validated on 62 primary, non-treated cases with similar grade and clinical variable distribution as the training set. When applied to the validation set, 18-GEP separated recurrences with a misclassification error rate of 0.25 (log-rank p=0.0003). 18-GEP was predictive for tumor recurrence [p=0.0008, HR=4.61, 95%CI=1.89-11.23)] and was predictive after adjustment for WHO grade, mitotic index, sex, tumor location, and Simpson grade [p=0.0311, HR=9.28, 95%CI=(1.22-70.29)]. The expression signature included genes encoding proteins involved in normal embryonic development, cell proliferation, tumor growth and invasion (FGF9, SEMA3C, EDNRA), angiogenesis (angiopoietin-2), cell cycle regulation (CDKN1A), membrane signaling (tetraspanin-7, caveolin-2), WNT-pathway inhibitors (DKK3), complement system (C1QA) and neurotransmitter regulation (SLC1A3, Secretogranin-II). CONCLUSIONS 18-GEP accurately stratifies patients with meningioma by recurrence risk having the potential to guide the use of adjuvant RT

Tumor-Suppressive miR148a Is Silenced by CpG Island Hypermethylation in IDH1-Mutant Gliomas

PurposeIDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.Experimental designTo identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified.ResultsWe identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1.ConclusionsWe identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications

Long-term Efficacy of Vedolizumab for Ulcerative Colitis

The GEMINI long-term safety [LTS] study is a continuing phase 3 trial investigating the safety and efficacy of vedolizumab, an α4β7 integrin antagonist for ulcerative colitis [UC] and Crohn's disease. We provide an interim analysis of efficacy in patients with UC. Patients from the C13004 and GEMINI 1 studies and a cohort of vedolizumab-naïve patients received open-label vedolizumab every 4 weeks. Interim data were collected from May 22, 2009 to June 27, 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life [HRQL] were assessed for up to 152 weeks of cumulative treatment in the efficacy population. As of June 27, 2013, 63% of the efficacy population [n = 532/845] were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88% [n = 120/136] were in remission after 104 weeks of exposure (96% [n = 70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI 1 [n = 32] before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41% and 28%, respectively, after 52 weeks, an increase from 19% and 6%, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior tumour necrosis factor-antagonist exposure. Durable benefits on HRQL were also observed. Patients with UC experienced clinical and HRQL improvements with continued vedolizumab treatment. Increased dosing frequency to every 4 weeks was beneficial in patients who had loss of response to 8-weekly dosin