A natural food sweetener with anti-pancreatic cancer properties

A natural food sweetener with anti-pancreatic cancer properties

Oncogenesis 5, e217 (April 2016). doi:10.1038/oncsis.2016.28

Authors: C Liu, L-H Dai, D-Q Dou, L-Q Ma & Y-X Sun

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Effects of marital status and economic resources on survival after cancer: A population-based study

BACKGROUND

Although married cancer patients have more favorable survival than unmarried patients, reasons underlying this association are not fully understood. The authors evaluated the role of economic resources, including health insurance status and neighborhood socioeconomic status (nSES), in a large California cohort.

METHODS

From the California Cancer Registry, we identified 783,167 cancer patients (386,607 deaths) who were diagnosed during 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex and were followed through 2012. Age-stratified and stage-stratified Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause mortality associated with marital status, adjusted for cancer site, race/ethnicity, and treatment.

RESULTS

Compared with married patients, unmarried patients had an elevated risk of mortality that was higher among males (HR, 1.27; 95% CI, 1.26-1.29) than among females (HR, 1.19; 95% CI, 1.18-1.20; P_interaction < .001). Adjustment for insurance status and nSES reduced the marital status HRs to 1.22 for males and 1.15 for females. There was some evidence of synergistic effects of marital status, insurance, and nSES, with relatively higher risks observed for unmarried status among those who were under-insured and living in high nSES areas compared with those who were under-insured and living in low nSES areas (P_interaction = 6.8 × 10⁻⁹ among males and 8.2 × 10⁻⁸ among females).

CONCLUSIONS

The worse survival of unmarried than married cancer patients appears to be minimally explained by differences in economic resources. Cancer 2016. © 2016 American Cancer Society.

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Differences in marital status and mortality by race/ethnicity and nativity among California cancer patients

BACKGROUND

It has been observed that married cancer patients have lower mortality rates than unmarried patients, but data for different racial/ethnic groups are scarce. The authors examined the risk of overall mortality associated with marital status across racial/ethnic groups and sex in data from the California Cancer Registry.

METHODS

California Cancer Registry data for all first primary invasive cancers diagnosed from 2000 through 2009 for the 10 most common sites of cancer-related death for non-Hispanic whites (NHWs), blacks, Asians/Pacific Islanders (APIs), and Hispanics were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for marital status in relation to overall mortality by race/ethnicity and sex. The study cohort included 393,470 male and 389,697 female cancer patients and 204,007 and 182,600 deaths from all causes, respectively, through December 31, 2012.

RESULTS

All-cause mortality was higher in unmarried patients than in married patients, but there was significant variation by race/ethnicity. Adjusted HRs (95% CIs) ranged from 1.24 (95% CI, 1.23-1.26) in NHWs to 1.11 (95% CI, 1.07-1.15) in APIs among males and from 1.17 (95% CI, 1.15-1.18) in NHWs to 1.07 (95% CI, 1.04-1.11) in APIs among females. All-cause mortality associated with unmarried status compared with married status was higher in US-born API and Hispanic men and women relative to their foreign-born counterparts.

CONCLUSIONS

For patients who have the cancers that contribute most to mortality, being unmarried is associated with worse overall survival compared with being married, with up to 24% higher mortality among NHW males but only 6% higher mortality among foreign-born Hispanic and API females. Future research should pursue the identification of factors underlying these associations to inform targeted interventions for unmarried cancer patients. Cancer 2016. © 2016 American Cancer Society.

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Characterisation of the triple negative breast cancer phenotype associated with the development of central nervous system metastases

Katerin L Rojas, Angelo Gámez-Pozo, Juan Sepúlveda, Luis Manso, Rocío López-Vacas, Tomás Pascual, Juan A Fresno Vara and Eva Ciruelos

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Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures

Abstract

Glioblastomas always recur despite surgery, radiotherapy and chemotherapy. A key player in the therapeutic resistance may be immature tumor cells with stem-like properties (TSCs) escaping conventional treatment. A group of promising molecular targets are microRNAs (miRs). miRs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. In this study we aimed to identify over-expressed TSC-related miRs potentially amenable for therapeutic targeting. We used non-differentiated glioblastoma spheroid cultures (GSCs) containing TSCs and compared these to xenografts using a NanoString nCounter platform. This revealed 19 over-expressed miRs in the non-differentiated GSCs. Additionally, non-differentiated GSCs were compared to neural stem cells (NSCs) using a microarray platform. This revealed four significantly over-expressed miRs in the non-differentiated GSCs in comparison to the NSCs. The three most over-expressed miRs in the non-differentiated GSCs compared to xenografts were miR-126, -137 and -128. KEGG pathway analysis suggested the main biological function of these over-expressed miRs to be cell-cycle arrest and diminished proliferation. To functionally validate the profiling results suggesting association of these miRs with stem-like properties, experimental over-expression of miR-128 was performed. A consecutive limiting dilution assay confirmed a significantly elevated spheroid formation in the miR-128 over-expressing cells. This may provide potential therapeutic targets for anti-miRs to identify novel treatment options for GBM patients.

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The first comprehensive report on Indigenous Australian women's inequalities in cervical screening: A retrospective registry cohort study in Queensland, Australia (2000-2011)

BACKGROUND

The Australian National Cervical Screening Program, introduced more than 20 years ago, does not record the Indigenous status of screening participants. This article reports the first population-based estimates of participation in cervical screening for Indigenous and non-Indigenous Australian women.

METHODS

This was a retrospective, population-based study of 1,334,795 female Queensland residents, aged 20 to 69 years, who participated in cervical screening from 2000 to 2011; 26,829 were identified as Indigenous through linkage to hospitalization records. Participation rates were calculated as the number of women screened divided by the average estimated resident population, with adjustments made for hysterectomies, for each 2-, 3-, and 5-year screening period. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), which were adjusted for age group, place of residence, and socioeconomic disadvantage.

RESULTS

In 2010-2011, the 2-year participation rate was 55.7% (95% CI, 55.6%-55.9%) for non-Indigenous women and 33.5% (95% CI, 32.9%-34.1%) for Indigenous women; this represented a decrease from 2000-2001 (57.7% [95% CI, 57.6%-57.9%] and 35.3% [95% CI, 34.5%-36.1%], respectively). The difference between Indigenous and non-Indigenous women was greatest for those aged 45 to 49 years. The 3- and 5-year participation rates were higher within both groups, and the absolute differences between the 2 groups were larger. Significant interactions between the Indigenous status and the place of residence and socioeconomic disadvantage highlight that the Indigenous/non-Indigenous differential was evident in all places of residence except for very remote areas (OR, 0.99; 95% CI, 0.95-1.02) and was greatest in the most affluent areas (OR, 0.26; 95% CI, 0.24-0.27).

CONCLUSIONS

Indigenous Australian women participate less than non-Indigenous women, and this gap has not closed. These results provide important benchmarks for the new Australian cervical screening program commencing in 2017, which will provide opportunities to reduce inequities for Indigenous women and address longstanding data deficiencies in the collection of the Indigenous status. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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Large-volume low apparent diffusion coefficient lesions predict poor survival in bevacizumab-treated glioblastoma patients

Background

Glioblastomas treated with bevacizumab may develop low-signal apparent diffusion coefficient (low-ADC) lesions, which may reflect increased tumor cellularity or atypical necrosis. The purpose of this study was to examine the relationship between low-ADC lesions and overall survival (OS). We hypothesized that growing low-ADC lesions would be associated with shorter OS.

Methods

We retrospectively identified 52 patients treated with bevacizumab for the first (n = 42, 81%) or later recurrence of primary glioblastoma, who had low-ADC lesions and 2 post-bevacizumab scans ≤90 days apart. Low-ADC lesion volumes were measured, and normalized 5th percentile histogram low-ADC values were recorded. Using OS as the primary endpoint, semiparametric Cox models were fitted to ascertain univariate and multivariate hazard ratios (HRs) with significance at P = .05.

Results

Median OS was 9.1 months (95% CI = 7.2–14.3). At the second post-bevacizumab scan, the volume of the low-ADC lesion (median: 12.94 cm³) was inversely associated with OS, with larger volumes predicting shorter OS (HR = 1.014 [95% CI = 1.003–1.025], P = .009). The percent change in low-ADC volume (median: 6.8%) trended toward increased risk of death with growing volumes (P = .08). Normalized 5th percentile low-ADC value and its percent change were not associated with OS (P > .51). Also correlated with shorter OS were the pre-bevacizumab nonenhancing volume (P = .025), the first post-bevacizumab enhancing volume (P = .040), and the second post-bevacizumab enhancing volume (P = .004).

Conclusions

The volume of low-ADC lesions at the second post-bevacizumab scan predicted shorter OS. This suggests that low-ADC lesions may be considered important imaging markers and included in treatment decision algorithms.

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PIK3CA mutations in meningioma

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Prognostic relevance of epilepsy at presentation in glioblastoma patients

Background

Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients.

Methods

Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment.

Results

Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61–0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment.

Conclusion

Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.

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Highlights from the Literature

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MicroRNAs provide a novel pathway toward combinatorial immune checkpoint blockade

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Statistical considerations on prognostic models for glioma

Given the lack of beneficial treatments in glioma, there is a need for prognostic models for therapeutic decision making and life planning. Recently several studies defining subtypes of glioma have been published. Here, we review the statistical considerations of how to build and validate prognostic models, explain the models presented in the current glioma literature, and discuss advantages and disadvantages of each model. The 3 statistical considerations to establishing clinically useful prognostic models are: study design, model building, and validation. Careful study design helps to ensure that the model is unbiased and generalizable to the population of interest. During model building, a discovery cohort of patients can be used to choose variables, construct models, and estimate prediction performance via internal validation. Via external validation, an independent dataset can assess how well the model performs. It is imperative that published models properly detail the study design and methods for both model building and validation. This provides readers the information necessary to assess the bias in a study, compare other published models, and determine the model's clinical usefulness. As editors, reviewers, and readers of the relevant literature, we should be cognizant of the needed statistical considerations and insist on their use.

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Different spatial distributions of brain metastases from lung cancer by histological subtype and mutation status of epidermal growth factor receptor

Background

The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases.

Methods

CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed.

Results

The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6–21.9) for exon 19 deleted EGFR, 11.5 mm (6.6–16.8) for L858R mutated, and 15.0 mm (10.0–20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P < .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002).

Conclusion

This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer.

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Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are tumor-suppressor syndromes. Each syndrome is an orphan disease; however, the tumors that arise within them represent the most common tumors of the nervous system worldwide. Systematic investigation of the pathways impacted by the loss of function of neurofibromin (encoded by NF1) and merlin (encoded by NF2) have led to therapeutic advances for patients with NF1 and NF2. In the syndrome of SWN, the genetic landscape is more complex, with 2 known causative genes (SMARCB1 and LZTR1) accounting for up to 50% of familial SWN patients. The understanding of the molecular underpinnings of these syndromes is developing rapidly and offers more therapeutic options for the patients. In addition, common sporadic cancers harbor somatic alterations in NF1 (ie, glioblastoma, breast cancer, melanoma), NF2 (ie, meningioma, mesothelioma) and SMARCB1 (ie, atypical teratoid/rhabdoid tumors) such that advances in management of syndromic tumors may benefit patients both with and without germline mutations. In this review, we discuss the clinical and genetic features of NF1, NF2 and SWN, the therapeutic advances for the tumors that arise within these syndromes and the interaction between these rare tumor syndromes and the common tumors that share these mutations.

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Inactivating MUTYH germline mutations in pediatric patients with high-grade midline gliomas

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MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints

Background

Antibody therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4) and programmed cell death 1 (PD-1) has demonstrated marked tumor regression in clinical trials. MicroRNAs (miRNAs) can modulate multiple gene transcripts including possibly more than one immune checkpoint and could be exploited as immune therapeutics.

Methods

Using online miRNA targeting prediction algorithms, we searched for miRNAs that were predicted to target both PD-1 and CTLA-4. MiR-138 emerged as a leading candidate. The effects of miR-138 on CTLA-4 and PD-1 expression and function in T cells were determined and the therapeutic effect of intravenous administration of miR-138 was investigated in both immune-competent and -incompetent murine models of GL261 glioma.

Results

Target binding algorithms predicted that miR-138 could bind the 3' untranslated regions of CTLA-4 and PD-1, which was confirmed with luciferase expression assays. Transfection of human CD4+ T cells with miR-138 suppressed expression of CTLA-4, PD-1, and Forkhead box protein 3 (FoxP3) in transfected human CD4+ T cells. In vivo miR-138 treatment of GL261 gliomas in immune-competent mice demonstrated marked tumor regression, a 43% increase in median survival time (P = .011), and an associated decrease in intratumoral FoxP3+ regulatory T cells, CTLA-4, and PD-1 expression. This treatment effect was lost in nude immune-incompetent mice and with depletion of CD4+ or CD8+ T cells, and miR-138 had no suppressive effect on glioma cells when treated directly at physiological in vivo doses.

Conclusions

MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

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MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA

Background

Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity.

Methods

The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd-DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically.

Results

The average size of IL-13-liposome-Gd-DTPA was 137 ± 43 nm with relaxivity of 4.0 ± 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13-liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI.

Conclusions

IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI.

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Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma

Background

Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define.

Methods

We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7.

Results

Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ~9% and ~6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ~7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base.

Conclusion

This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

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Lymphomatosis cerebri: a rare form of primary central nervous system lymphoma. Analysis of 7 cases and systematic review of the literature

Background

Primary central nervous system lymphomas may present as diffuse, nonenhancing infiltrative lesions. This rare variant is termed lymphomatosis cerebri (LC). We did a systematic review and analysis of the literature, adding our own cases, to better characterize LC in order to improve early diagnosis and treatment.

Methods

PubMed, ISI Web of Knowledge, and hospital databases were reviewed. Information was extracted regarding demographic, clinical, histological, cerebrospinal fluid (CSF), neuroimaging, and treatment variables. The impact of single parameters on overall survival (OS) was determined by applying univariate and multivariate analyses.

Results

Forty-two patients were included (median age: 58 y; range: 28–80 y). At consultation, 52% of patients had a poor KPS. The most common presenting symptom was cognitive decline (59.5%). Imaging studies showed supratentorial and infratentorial infiltration in 55% of patients and bilateral hemispheric involvement in 95%. CSF pleocytosis was present in 51.5% of the patients. Median time to diagnosis was 4.5 (range: 1–30) months, and the diagnosis was not established until autopsy for 33% of patients. The median OS was 2.95 (range: 0.33–56) months; however, those patients who received methotrexate had a median OS of 13.8 (range: 0.7–56) months. Analysis identified KPS ≥ 70 (HR: 0.32; 95% CI: 0.114–0.894; P = .03) and treatment with methotrexate (HR: 0.19; 95% CI: 0.041–0.886; P = .034) as independent favorable prognostic factors, whereas T-cell lymphoma was independently related with a worse outcome (HR: 6.62; 95% CI: 1.317–33.316; P = .022).

Conclusions

LC is a misdiagnosed entity associated with considerable diagnostic delay. MRI evidence of bilateral hemispheric involvement and CSF pleocytosis should be alerts for this diagnosis. Treatment with methotrexate-based chemotherapy must be considered, especially for patients with good KPS.

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Coordination of self-renewal in glioblastoma by integration of adhesion and microRNA signaling

Background

Cancer stem cells (CSCs) provide an additional layer of complexity for tumor models and targets for therapeutic development. The balance between CSC self-renewal and differentiation is driven by niche components including adhesion, which is a hallmark of stemness. While studies have demonstrated that the reduction of adhesion molecules, such as integrins and junctional adhesion molecule-A (JAM-A), decreases CSC maintenance. The molecular circuitry underlying these interactions has yet to be resolved.

Methods

MicroRNA screening predicted that microRNA-145 (miR-145) would bind to JAM-A. JAM-A overexpression in CSCs was evaluated both in vitro (proliferation and self-renewal) and in vivo (intracranial tumor initiation). miR-145 introduction into CSCs was similarly assessed in vitro. Additionally, The Cancer Genome Atlas dataset was evaluated for expression levels of miR-145 and overall survival of the different molecular groups.

Results

Using patient-derived glioblastoma CSCs, we confirmed that JAM-A is suppressed by miR-145. CSCs expressed low levels of miR-145, and its introduction decreased self-renewal through reductions in AKT signaling and stem cell marker (SOX2, OCT4, and NANOG) expression; JAM-A overexpression rescued these effects. These findings were predictive of patient survival, with a JAM-A/miR-145 signature robustly predicting poor patient prognosis.

Conclusions

Our results link CSC-specific niche signaling to a microRNA regulatory network that is altered in glioblastoma and can be targeted to attenuate CSC self-renewal.

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Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium

Background

Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT).

Methods

Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis.

Results

Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement.

Conclusions

ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials.

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Selective coexpression of VEGF receptor 2 in EGFRvIII-positive glioblastoma cells prevents cellular senescence and contributes to their aggressive nature

Background

In glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression.

Methods

Mining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence.

Results

In human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated β-galactosidase, reduced retinoblastoma phosphorylation, and increased p27^Kip1, all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced.

Conclusions

VEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells.

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Amino acid positron emission tomography to monitor chemotherapy response and predict seizure control and progression-free survival in WHO grade II gliomas

Background

Patients with WHO grade II glioma may respond to chemotherapy that is currently not standardized regarding timing and treatment duration. Metabolic changes during chemotherapy may precede structural tumor volume reductions. We therefore compared time courses of amino acid PET and MRI responses to temozolomide (TMZ) and assessed whether responses correlated with seizure control and progression-free survival (PFS).

Methods

PET and MRI were performed before and during TMZ chemotherapy. Tumor volumes were calculated using regions-of-interest analysis. Amino acid uptake was also quantified as metabolically active tumor volume and tumor-to-cerebellum uptake ratio.

Results

One hundred twenty-five PET and 125 MRI scans from 33 patients were analyzed. Twenty-five patients showed metabolic responses that exhibited an exponential time course with a 25% reduction of the active volume on average after 2.3 months. MRI responses followed a linear course with a 25% reduction after 16.8 months. Reduction of metabolically active tumor volumes, but not reduction of PET uptake ratios or MRI tumor volumes, correlated with improved seizure control following chemotherapy (P = .012). Receiver-operating-characteristic curve analysis showed that a decrease of the active tumor volume of ≥80.5% predicts a PFS of ≥60 months (P = .018) and a decrease of ≥64.5% a PFS of ≥48 months (P = .037).

Conclusions

Amino acid PET is superior to MRI for evaluating TMZ responses in WHO grade II glioma patients. The response delay between both imaging modalities favors amino acid PET for individually tailoring the duration of chemotherapy. Additional studies should investigate whether this personalized approach is appropriate with regard to outcome.

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TNF-{alpha} enhancement of CD62E mediates adhesion of non-small cell lung cancer cells to brain endothelium via CD15 in lung-brain metastasis

Background

CD15, which is overexpressed on various cancers, has been reported as a cell adhesion molecule that plays a key role in non-CNS metastasis. However, the role of CD15 in brain metastasis is largely unexplored. This study provides a better understanding of CD15/CD62E interaction, enhanced by tumor necrosis factor-α (TNF-α), and its correlation with brain metastasis in non–small cell lung cancer (NSCLC).

Methods

CD15 and E-selectin (CD62E) expression was demonstrated in both human primary and metastatic NSCLC cells using flow cytometry, immunofluorescence, and Western blotting. The role of CD15 was investigated using an adhesion assay under static and physiological flow live-cell conditions. Human tissue sections were examined using immunohistochemistry.

Results

CD15, which was weakly expressed on hCMEC/D3 human brain endothelial cells, was expressed at high levels on metastatic NSCLC cells (NCI-H1299, SEBTA-001, and SEBTA-005) and at lower levels on primary NSCLC (COR-L105 and A549) cells (P < .001). The highest expression of CD62E was observed on hCMEC/D3 cells activated with TNF-α, with lower levels on metastatic NSCLC cells followed by primary NSCLC cells. Metastatic NSCLC cells adhered most strongly to hCMEC/D3 compared with primary NSCLC cells. CD15 immunoblocking decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (P < .0001), confirming a correlation between CD15 and cerebral metastasis. Both CD15 and CD62E expression were detected in lung metastatic brain biopsies.

Conclusion

This study enhances the understanding of cancer cell-brain endothelial adhesion and confirms that CD15 plays a crucial role in adhesion in concert with TNF-α activation of its binding partner, CD62E.

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