Regression of glioma tumor growth in F98 and U87 rat glioma models by the Nitrone OKN-007

Background

Glioblastoma multiforme, a World Health Organization grade IV glioma, has a poor prognosis in humans despite current treatment options. Here, we present magnetic resonance imaging (MRI) data regarding the regression of aggressive rat F98 gliomas and human U87 glioma xenografts after treatment with the nitrone compound OKN-007, a disulfonyl derivative of α-phenyl-tert-butyl nitrone.

Methods

MRI was used to assess tumor volumes in F98 and U87 gliomas, and bioluminescence imaging was used to measure tumor volumes in F98 gliomas encoded with the luciferase gene (F98_luc). Immunohistochemistry was used to assess angiogenesis (vascular endothelial growth factor [VEGF] and microvessel density [MVD]), cell differentiation (carbonic anhydrase IX [CA-IX]), hypoxia (hypoxia-inducible factor-1α [HIF-1α]), cell proliferation (glucose transporter 1 [Glut-1] and MIB-1), proliferation index, and apoptosis (cleaved caspase 3) markers in F98 gliomas. VEGF, CA-IX, Glut-1, HIF-1α, and cleaved caspase 3 were assessed in U87 gliomas.

Results

Animal survival was found to be significantly increased (P < .001 for F98, P < .01 for U87) in the group that received OKN-007 treatment compared with the untreated groups. After MRI detection of F98 gliomas, OKN-007, administered orally, was found to decrease tumor growth (P < .05). U87 glioma volumes were found to significantly decrease (P < .05) after OKN-007 treatment, compared with untreated animals. OKN-007 administration resulted in significant decreases in tumor hypoxia (HIF-1α [P < .05] in both F98 and U87), angiogenesis (MVD [P < .05], but not VEGF, in F98 or U87), and cell proliferation (Glut-1 [P < .05 in F98, P < .01 in U87] and MIB-1 [P < .01] in F98) and caused a significant increase in apoptosis (cleaved caspase 3 [P < .001 in F98, P < .05 in U87]), compared with untreated animals.

Conclusions

OKN-007 may be considered as a promising therapeutic addition or alternative for the treatment of aggressive human gliomas.     

Evaluation of penile erection rigidity in healthy men using virtual touch tissue quantification

Background

The aim of the study was to describe the shear wave velocity (SWV) values of the penis by virtual touch tissue quantification (VTTQ) and to examine the clinical usefulness of this procedure in evaluation of the rigidity changes in penile erection.

Patients and methods.

VTTQ was performed in 37 healthy volunteers. In the course of erection, SWV values of glans penis, corpus penis and radix penis were quantified and grades of erection were documented. The SWV values at different grades of erection were compared.

Results

The axial and radial SWV values of glans penis, corpus penis and radix penis all significantly decreased from Grade 0 to Grade 4 of erection. At Grade 4, they were less than one-third of that at Grade 0 (axial direction: 0.79 ± 0.13 vs. 2.79 ± 0.32 for glans penis, P<0.001; 0.77 ± 0.19 vs. 2.84 ± 0.30 for corpus penis, P<0.001 and 0.76 ± 0.15 vs. 2.81 ± 0.34 for radix penis, P<0.001; radial direction: 0.82 ± 0.15 vs. 2.83 ± 0.31 for glans penis, P<0.001; 0.79 ± 0.18 vs. 2.81 ± 0.27 for corpus penis, P<0.001 and 0.81 ± 0.16 vs. 2.82 ± 0.33 for radix penis, P<0.001).

Conclusions

VTTQ can provide numerical measurements of penile rigidity and can effectively and sensitively indicate the axial and radial rigidity changes in penile erection, which provide a new approach to assessing the erectile function.     

Experimental validation of 5 in-silico predicted glioma biomarkers

Background

Glioblastoma multiforme (GBM) is a high-grade glioma with poor prognosis. Identification of new biomarkers specific to GBM could help in disease diagnosis. We have developed and validated a bioinformatics method to predict proteins likely to be suitable as glioma biomarkers via a global microarray meta-analysis to identify uncharacterized genes consistently coexpressed with known glioma-associated genes.

Methods

A novel bioinformatics method was implemented called global microarray meta-analysis, using ∼16 000 microarray experiments to identify uncharacterized genes consistently coexpressed with known glioma-associated genes. These novel biomarkers were validated as proteins highly expressed in human gliomas varying in tumor grades using immunohistochemistry. Glioma gene databases were used to assess delineation of expression of these markers in varying glioma grades and subtypes of GBM.

Results

We have identified 5 potential biomarkers—spondin1, Plexin-B2, SLIT3, fibulin-1, and LINGO1—that were validated as proteins highly expressed on the surface of human gliomas using immunohistochemistry. Expression of spondin1, Plexin-B2, and SLIT3 was significantly higher (P < .01) in high-grade gliomas than in low-grade gliomas. These biomarkers were significant discriminators in grade IV gliomas compared with either grade III or II tumors and also distinguished between GBM subclasses.

Conclusions

This study strongly suggests that this type of bioinformatics approach has high translational potential to rapidly discern which poorly characterized proteins may be of clinical relevance.     

Differentiation of high-grade and low-grade diffuse gliomas by intravoxel incoherent motion MR imaging

Background

Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs).

Methods

Forty-five patients with diffuse glioma (age 50.9 ± 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0–1000 s/mm²) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm²). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29).

Results

Both D (1.26 ± 0.37 mm²/s in LGG, 0.94 ± 0.19 mm²/s in HGG; P < .001) and ADC (1.28 ± 0.35 mm²/s in LGG, 1.03 ± 0.19 mm²/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D*.

Conclusion

IVIM imaging is useful in differentiating HGGs from LGGs.     

Imaging of gliomas at 1.5 and 3 Tesla - A comparative study

Background

Glioma follow-up is based on MRI parameters, which are correlated with survival. Although established criteria are used to evaluate tumor response, radiological markers may be confounded by differences in instrumentation including the magnetic field strength. We assessed whether MRIs obtained at 3 Tesla (T) and 1.5T provided similar information.

Methods

We retrospectively compared imaging features of 30 consecutive patients with WHO grades II and III gliomas who underwent MRI at 1.5T and 3T within a month of each other, without any clinical changes during the same period. We compared lesion volumes on fluid attenuation inversion recovery (FLAIR), ratio of cerebral blood volume (rCBV) on perfusion-weighted imaging, contrast-to-noise ratio (CNR) on FLAIR, and on post-gadolinium 3D T1-weighted sequences between 1.5T and 3T using intraclass correlation coefficient (ICC). Concordance between observers within and between modalities was evaluated using weighted-kappa coefficient (_wκ).

Results

The mean ± SD delay between modalities (1.5T and 3T MRI) was 8.6 ± 5.6 days. Interobserver/intraobserver concordance for lesion volume was almost perfect for 1.5T (ICC = 0.96/0.97) and 3T (ICC = 0.99/0.98). Agreement between observers for contrast enhancement was excellent at 1.5T (_wκ = 0.92) and 3T (_wκ = 0.92). The tumor CNR was significantly higher for FLAIR at 1.5T (P < .001), but it was higher at 3T (P = .012) for contrast enhancement. Correlations between modalities for lesion volume (ICC = 0.97) and for rCBV values (ICC = 0.92) were almost perfect.

Conclusions

In the follow-up of WHO grades II and III gliomas, 1.5T and 3T provide similar MRI features, suggesting that monitoring could be performed on either a 1.5 or a 3T MR magnet.     

Imaging growth and isocitrate dehydrogenase 1 mutation are independent predictors for diffuse low-grade gliomas

Background

We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults.

Methods

One hundred thirty-one adult patients with newly diagnosed supratentorial diffuse low-grade gliomas were retrospectively studied.

Results

Isocitrate dehydrogenase 1 mutations were present in 107 patients. The mean spontaneous velocity of diametric expansion was 5.40 ± 5.46 mm/y. During follow-up (mean, 70 ± 54.7 mo), 56 patients presented a malignant transformation and 23 died. The median malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (149 and 198 mo, respectively) than in cases of fast velocity of diametric expansion (46 and 82 mo; P < .001 and P < .001, respectively) and in cases with IDH1 mutation (100 and 198 mo, respectively) than in cases without IDH1 mutation (72 mo and not reached; P = .028 and P = .001, respectively). In multivariate analyses, spontaneous velocity of diametric expansion and IDH1 mutation were independent prognostic factors for malignant progression-free survival (P < .001; hazard ratio, 4.23; 95% CI, 1.81–9.40 and P = .019; hazard ratio, 2.39; 95% CI, 1.19–4.66, respectively) and for overall survival (P < .001; hazard ratio, 26.3; 95% CI, 5.42–185.2 and P = .007; hazard ratio, 17.89; 95% CI, 2.15–200.1, respectively).

Conclusions

The spontaneous velocity of diametric expansion and IDH1 mutation status are 2 independent prognostic values that should be obtained at the beginning of the management of diffuse low-grade gliomas in adults.     

[18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology,but not all that glitters is glioma

Background

To assess the sensitivity and specificity of [¹⁸F]-fluoro-ethyl-l-tyrosine (¹⁸F-FET) PET in brain tumors and various non-neoplastic neurologic diseases.

Methods

We retrospectively evaluated ¹⁸F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). ¹⁸F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense).

Results

Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed ¹⁸F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher ¹⁸F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). ¹⁸F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions.

Conclusions

¹⁸F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood–brain barrier and ¹⁸F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.     

Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas

Background

Supratentorial diffuse low-grade gliomas in adults extend beyond maximal visible MRI-defined abnormalities, and a gap exists between the imaging signal changes and the actual tumor margins. Direct quantitative comparisons between imaging and histological analyses are lacking to date. However, they are of the utmost importance if one wishes to develop realistic models for diffuse glioma growth.

Methods

In this study, we quantitatively compared the cell concentration and the edema fraction from human histological biopsy samples (BSs) performed inside and outside imaging abnormalities during serial imaging-based stereotactic biopsy of diffuse low-grade gliomas.

Results

The cell concentration was significantly higher in BSs located inside (1189 ± 378 cell/mm²) than outside (740 ± 124 cell/mm²) MRI-defined abnormalities (P = .0003). The edema fraction was significantly higher in BSs located inside (mean, 45% ± 23%) than outside (mean, 5 %± 9%) MRI-defined abnormalities (P < .0001). At borders of the MRI-defined abnormalities, 20% of the tissue surface area was occupied by edema and only 3% by tumor cells. The cycling cell concentration was significantly higher in BSs located inside (10 ± 12 cell/mm²), compared with outside (0.5 ± 0.9 cell/mm²), MRI-defined abnormalities (P = .0001).

Conclusions

We showed that the margins of T2-weighted signal changes are mainly correlated with the edema fraction. In 62.5% of patients, the cycling tumor cell fraction (defined as the ratio of the cycling tumor cell concentration to the total number of tumor cells) was higher at the limits of the MRI-defined abnormalities than closer to the center of the tumor. In the remaining patients, the cycling tumor cell fraction increased towards the center of the tumor.     

Chemotherapy for testicular cancer induces acute alterations in diastolic heart function

Background:

After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC.

Methods:

Fourteen TC patients (age 34.6±12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated.

Results:

Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192±27 to 175±26 ml (P<0.05) and 109±18 to 95±16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87±0.43 to 1.64±0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39±0.05 to 0.36±0.05 (P<0.05).

Conclusion:

Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long-term cardiovascular complications.     

Pharmacogenetic variants in the DPYD,TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity

Background:

Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.

Methods:

Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.

Results:

Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3–4 toxicity (P<0.0001). The TYMS 3′-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38–6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand–foot syndrome (P=4.1 × 10⁻⁶, OR=9.99, 95% CI: 3.84–27.8). The linked CDA c.−92A>G and CDA c.−451C>T variants predicted grade 2–4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3–4.2 and P=0.0082, OR=2.3, 95% CI: 1.3–4.2, respectively).

Conclusion:

We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.     

Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study

Background

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival.

Methods

Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9).

Results

Thirty-five evaluable patients (median age 8.4 y [range, 0.6–17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2–26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1–17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6–49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1–2 hypertension in 24, grades 1–2 fatigue in 23, grades 1–2 epistaxis in 18, and grades 1–4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037).

Conclusion

The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.     

Prognostic role of IDH mutations in gliomas: a meta-analysis of 55 observational studies

Background

IDH (Isocitrate dehydrogenase) mutations occur frequently in gliomas, but their prognostic impact has not been fully assessed. We performed a meta-analysis of the association between IDH mutations and survival in gliomas.

Methods

Pubmed and EMBASE databases were searched for studies reporting IDH mutations (IHD1/2 and IDH1) and survival in gliomas. The primary outcome was overall survival (OS); the secondary outcome was progression-free survival (PFS). Hazard ratios (HR) with 95% confidence interval (CI) were determined using the Mantel-Haenszel random-effect modeling. Funnel plot and Egger''s test were conducted to examine the risk of publication bias.

Results

Fifty-five studies (9487 patients) were included in the analysis. Fifty-four and twenty-seven studies investigated the association between IDH1/2 mutations and OS/PFS respectively in patients with glioma. The results showed that patients possessing an IDH1/2 mutation had significant advantages in OS (HR = 0.39, 95%CI: 0.34–0.45; P < 0.001) and PFS (HR = 0.42, 95% CI: 0.35–0.51; P < 0.001). Subgroup analysis showed a consistent result with pooled analysis, and patients with glioma of WHO grade III or II-III had better outcomes.

Conclusions

These findings provide further indication that patients with glioma harboring IDH mutations have improved OS and PFS, especially for patients with WHO grade III and grade II-III.     

Proposal for a new risk stratification classification for meningioma based on patient age,WHO tumor grade,size, localization,and karyotype

Background

Tumor recurrence remains the major clinical complication of meningiomas, the majority of recurrences occurring among WHO grade I/benign tumors. In the present study, we propose a new scoring system for the prognostic stratification of meningioma patients based on analysis of a large series of meningiomas followed for a median of >5 years.

Methods

Tumor cytogenetics were systematically investigated by interphase fluorescence in situ hybridization in 302 meningioma samples, and the proposed classification was further validated in an independent series of cases (n = 132) analyzed by high-density (500K) single-nucleotide polymorphism (SNP) arrays.

Results

Overall, we found an adverse impact on patient relapse-free survival (RFS) for males, presence of brain edema, younger patients (<55 years), tumor size >50 mm, tumor localization at intraventricular and anterior cranial base areas, WHO grade II/III meningiomas, and complex karyotypes; the latter 5 variables showed an independent predictive value in multivariate analysis. Based on these parameters, a prognostic score was established for each individual case, and patients were stratified into 4 risk categories with significantly different (P < .001) outcomes. These included a good prognosis group, consisting of approximately 20% of cases, that showed a RFS of 100% ± 0% at 10 years and a very poor-prognosis group with a RFS rate of 0% ± 0% at 10 years. The prognostic impact of the scoring system proposed here was also retained when WHO grade I cases were considered separately (P < .001).

Conclusions

Based on this risk-stratification classification, different strategies may be adopted for follow-up, and eventually also for treatment, of meningioma patients at different risks for relapse.     

Dynamic 1H-MRS assessment of brain tumors: A novel approach for differential diagnosis of glioma

Purpose

To determine whether the changes of [Cho/NAA] ratio in patients with glioma, measured by dynamic ¹H-MRS can be used to differentiate between high-grade and low-grade gliomas.

Materials and Methods

This prospective study was approved by the institutional ethics committee. Written informed consent was obtained. Forty-nine patients with biopsy-proven glioma and 20 normal control subjects were recruited in this study. The maximum [Cho/NAA] ratios, acquired at 0 min, and at 6 min, were calculated and assessed from volume of interests (VOI) in the tumor areas and in the surrounding normal tissue for each patient. Absolute difference in the [Cho/NAA] ratios, from MRS acquired at 0 and 6 min, in high-grade glioma, low-grade glioma, and control subjects were compared.

Results

The maximum [Cho/NAA] ratio acquired from the tumor area at the 0 min is 6.08 ± 2.02, which was significantly different (p = .017) from that acquired after 6 min, 4.87 ± 2.13. The [Cho/NAA] ratio from the surrounding normal tissue area did not change significantly from spectra acquired at different times (0 min, 6 min). Absolute difference in [Cho/NAA] ratios acquired at 0 and 6 min time points were significantly higher (P < 0.001) in high-grade glioma (= 3.86 ± 3.31) than in low-grade glioma (= 0.81 ± 0.90), and control subjects (0.061 ± 0.026, P = 0.000), while there was no significantly difference in low-grade glioma and control subjects.

Conclusions

Dynamic ¹H-MRS can be useful for differential diagnosis between high-grade and low-grade gliomas as well as insight into the heterogeneity within the tumor.     

Targeting Wee1 for the treatment of pediatric high-grade gliomas

Background

We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).

Methods

Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of γ-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF^V600E mutation, and 1 xenograft model in which tumor cells were derived from a patient''s DIPG.

Results

Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of γ-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF^V600E model P = .0061 and DIPG brainstem model P = .0163).

Conclusion

Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.     

Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor–based orthotopic xenograft mouse models of pediatric glioma

Background

Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood–brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.

Methods

In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.

Results

SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 × 10¹² viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P < .05). Treatment with neuraminidase and competitive binding using lectins specific for α2,3-linked and/or α2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P < .01).

Conclusion

SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes α2,3-linked and α2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma.     

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis

Background

Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.

Methods

SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between “number of risk alleles” and “age at diagnosis,” adjusted for sex and study site and stratified by tumor grade/histology where appropriate.

Results

Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10⁻²² and P = 9.5 × 10⁻⁷, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10⁻⁴ and P = 2.5 × 10⁻⁴, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.

Conclusions

Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).     

IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

Background

IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas—World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma.

Methods

Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry.

Results

IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P < .001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for >5 cc residual vs not reached for <5 cc, P = .025).

Conclusions

The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.     

Mammographic density and risk of breast cancer by age and tumor characteristics

Introduction

Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models.

Methods

Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (<55, 55–64, and ≥65 years).

Results

MD was positively associated with risk of invasive tumors across all ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55–64 and ≥65 years (P_{age-interaction} = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P’s < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55–64 and ≥65 years (P_{age-interaction} = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group.

Conclusion

MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.