Vedat O. Yildiz

CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway

Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44high GBM but not from CD44low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44high GBM, but not in CD44low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKTpathway.

Postmenopausal weight change and incidence of fracture: post hoc findings from Women’s Health Initiative Observational Study and Clinical Trials

Objectives To determine associations between postmenopausal change in body weight and incidence of fracture and associations between voluntary and involuntary weight loss and risk of fracture. Design Post hoc analysis of data from the Women’s Health Initiative Observational Study and Clinical Trials. Setting 40 clinical centers in the United States. Participants 120 566 postmenopausal women, aged 50-79 at baseline (1993-98), followed through 2013 (mean fracture follow-up duration 11 years from baseline). Exposures Annualized percentage change in measured body weight from baseline to year 3, classified as stable (<5% change), weight loss (≥5%), or weight gain (≥5%). Self assessment of whether weight loss was intentional or unintentional. Cox proportional hazards regression models were adjusted for age, race/ethnicity, baseline body mass index (BMI), smoking, alcohol intake, level of physical activity, energy expenditure, calcium and vitamin D intake, physical function score, oophorectomy, hysterectomy, previous fracture, comorbidity score, and drug use. Main outcomes Incident self reported fractures of the upper limbs, lower limbs, and central body; hip fractures confirmed by medical records. Results Mean participant age was 63.3. Mean annualized percent weight change was 0.30% (95% confidence interval 0.28 to 0.32). Overall, 79 279 (65.6%) had stable weight; 18 266 (15.2%) lost weight; and 23 021 (19.0%) gained weight. Compared with stable weight, weight loss was associated with a 65% higher incidence rates of fracture in hip (adjusted hazard ratio 1.65, 95% confidence interval 1.49 to 1.82), upper limb (1.09, 1.03 to 1.16), and central body (1.30, 1.20 to 1.39); weight gain was associated with higher incidence rates of fracture in upper limb (1.10, 1.05 to 1.18) and lower limb (1.18, 1.12 to 1.25). Compared with stable weight, unintentional weight loss was associated with a 33% higher incidence rates of hip fracture (1.33, 1.19 to 1.47) and increased incidence rates of vertebral fracture (1.16, 1.06 to 1.26); intentional weight loss was associated with increased incidence rates of lower limb fracture (1.11, 1.05 to 1.17) and decreased incidence of hip fracture (0.85, 0.76 to 0.95). Conclusions Weight gain, weight loss, and intentional weight loss are associated with increased incidence of fracture, but associations differ by fracture location. Clinicians should be aware of fracture patterns after weight gain and weight loss.

CT Gray-Level Texture Analysis as a Quantitative Imaging Biomarker of Epidermal Growth Factor Receptor Mutation Status in Adenocarcinoma of the Lung

OBJECTIVE The purpose of this study was to investigate the radiogenomic correlation between CT gray-level texture features and epidermal growth factor receptor (EGFR) mutation status in adenocarcinoma of the lung. MATERIALS AND METHODS This retrospective study included 25 patients with exon 19 short inframe deletion (exon 19) and 21 patients with exon 21 L858R point (exon 21) EGFR mutations among 125 patients with EGFR mutant adenocarcinoma of the lung. The randomly formed control group consisted of 20 patients selected from 126 patients with EGFR mutation-negative (wild-type) adenocarcinomas. Five gray-level texture features (contrast, correlation, inverse difference moment, angular second moment, and entropy) were analyzed. RESULTS Contrast differentiated both exon 19 (p = 0.00027) and exon 21 (p = 0.00001) mutants from the wild type. Wild-type adenocarcinomas had high scores for contrast (mean, 1598.547) compared with EGFR mutants (mean, 679.463). Correlation differentiated both exon 19 (p = 0.017) and exon 21 (p = 0.0015) mutants from wild-type adenocarcinomas. Inverse difference moment differentiated exon 19 mutants from exon 21 mutants (p = 0.019) and both exon 19 (p = 0.044) and exon 21 (p = 0.00001) mutants from wild-type adenocarcinomas. Angular second moment and entropy were not associated with statistically significant differences between mutation statuses. CONCLUSION Contrast, correlation, and inverse difference moment texture features correlate with EGFR mutation status in adenocarcinoma of the lung. Further investigation with larger prospective studies is needed to validate the role of CT gray-level texture analysis as a quantitative imaging biomarker.

Choroid plexus carcinoma in children: the Head Start experience.

Choroid plexus carcinoma (CPC) is a rare aggressive intracranial neoplasm with a predilection for young children and a historically poor outcome. Currently, no defined optimal therapeutic strategy exists. The Head Start (HS) regimens have included irradiation‐avoiding strategies in young children with malignant brain tumors using high dose chemotherapy to improve survival and minimize neurocognitive sequelae.

Choroid plexus carcinoma in children

Choroid plexus carcinoma (CPC) is a rare aggressive intracranial neoplasm with a predilection for young children and a historically poor outcome. Currently, no defined optimal therapeutic strategy exists. The Head Start (HS) regimens have included irradiation‐avoiding strategies in young children with malignant brain tumors using high dose chemotherapy to improve survival and minimize neurocognitive sequelae.

Dietary Inflammatory Index, Bone Mineral Density, and Risk of Fracture in Postmenopausal Women: Results From the Women's Health Initiative

Previous studies suggest that bone loss and fracture risk are associated with higher inflammatory milieu, potentially modifiable by diet. The primary objective of this analysis was to evaluate the association of the dietary inflammatory index (DII), a measure of the inflammatory potential of diet, with risk of hip, lower‐arm, and total fracture using longitudinal data from the Womens Health Initiative Observational Study and Clinical Trials. Secondarily, we evaluated changes in bone mineral density (BMD) and DII scores. DII scores were calculated from baseline food frequency questionnaires (FFQs) completed by 160,191 participants (mean age 63 years) without history of hip fracture at enrollment. Year 3 FFQs were used to calculate a DII change score. Fractures were reported at least annually; hip fractures were confirmed by medical records. Hazard ratios for fractures were computed using multivariable‐adjusted Cox proportional hazard models, further stratified by age and race/ethnicity. Pairwise comparisons of changes in hip BMD, measured by dual‐energy X‐ray absorptiometry from baseline, year 3, and year 6 were analyzed by quartile (Q1 = least inflammatory diet) of baseline DII scores in a subgroup of women (n = 10,290). Mean DII score improved significantly over 3 years (p < 0.01), but change was not associated with fracture risk. Baseline DII score was only associated with hip fracture risk in younger white women (HR Q4,1.48; 95% CI, 1.09 to 2.01; p = 0.01). There were no significant associations among white women older than 63 years or other races/ethnicities. Women with the least inflammatory DII scores had less loss of hip BMD (p = 0.01) by year 6, despite lower baseline hip BMD, versus women with the most inflammatory DII scores. In conclusion, a less inflammatory dietary pattern was associated with less BMD loss in postmenopausal women. A more inflammatory diet was associated with increased hip fracture risk only in white women younger than 63 years.

Impact of the Addition of Digital Breast Tomosynthesis (DBT) to Standard 2D Digital Screening Mammography on the Rates of Patient Recall, Cancer Detection, and Recommendations for Short-term Follow-up

RATIONALE AND OBJECTIVES The addition of digital breast tomosynthesis (DBT) to digital screening mammography (DM) has been shown to decrease recall rates and improve cancer detection rates, but there is a lack of data regarding the impact of DBT on rates of short-term follow-up. We assessed possible changes in performance measures with the introduction of DBT at our facility. MATERIALS AND METHODS In our observational study, databases were used to compare rates of recall, short-term follow-up, biopsy, and cancer detection between women undergoing DM without (n = 10,477) and women undergoing DM with (n = 2304) the addition of DBT. Regression analysis was performed to determine associations with patient age, breast density, and availability of comparison examinations. RESULTS The addition of DBT resulted in significantly lower recall rates (16%-14%, P = .017), higher rates of biopsy (12.7%-19.1%, P < .01), and increased detection of ductal carcinoma in situ, with a difference of 2.3 cases per 1000 screens (P = .044). A 33% increase in cancer detection rates was observed with DBT, which did not reach statistical significance. Short-term follow-up of probably benign findings was 80% higher in the DBT group (odds ratio = 1.80, 95% confidence interval = 1.38-2.36, P < .001). CONCLUSIONS To our knowledge, we are the first to study the impact of DBT on rates of short-term follow-up, and observed an 80% increase over the DM group. Further research is needed to determine the malignancy rate of Breast Imaging Reporting and Data System 3 lesions detected with DBT, and establish appropriate follow-up to maximize cancer detection while minimizing expense and patient anxiety.

Antioxidant micronutrients and the risk of renal cell carcinoma in the Women's Health Initiative cohort

Renal cell carcinoma (RCC) is the eighth leading cancer among women in incidence and commonly is diagnosed at a more advanced stage. Oxidative stress has been considered to play an important role in the pathogenesis of RCC. Various dietary micronutrients have antioxidant properties, including carotenoids and vitamins C and E; thus, diets rich in these nutrients have been evaluated in relation to RCC prevention. The objective of this study was to explore the correlation between antioxidant micronutrients and the risk of RCC.

Outcomes of benign breast papillomas diagnosed at image-guided vacuum-assisted core needle biopsy

PURPOSE To determine the upgrade rate of benign papillomas diagnosed at image-guided vacuum-assisted core needle biopsy (VACNB) and to compare our results with the summarized literature. MATERIALS AND METHODS A database search was performed to identify patients older than 18 years of age with benign papillomas diagnosed at VACNB between 2004 and 2013. A total of 199 papillomas in 184 patients were identified. Clinical, imaging, and pathological features for each were analyzed. Patients who were subsequently diagnosed with malignancy at the site of papilloma, either at surgical excision or upon imaging follow-up, were compared with those not upgraded. Upgrade was defined as a diagnosis of invasive carcinoma or ductal carcinoma in situ (DCIS). RESULTS Of 199 papillomas, 110 (55.3%) were diagnosed at ultrasound-guided VACNB, 78 (39.2%) were diagnosed at stereotactic-guided VACNB, and 11 (5.5%) were diagnosed at magnetic resonance imaging-guided VACNB. Surgical excision was performed for 89 (44.7%), and the remaining 110 (55.3%) underwent imaging follow-up. Two patients were subsequently diagnosed with invasive carcinoma and 4 were found with DCIS. The upgrade rate across both groups was 3% (6 of 199). Masses with calcifications (P=.001) and smaller needle gauge at VACNB (P=.02) had a significant association with upgrade. CONCLUSION Benign papillomas diagnosed with VACNB demonstrated a 3% upgrade rate to malignancy, which is similar to the 2.9% upgrade rate calculated by compiling applicable published literature. Conservative management with imaging follow-up as opposed to surgical excision may be appropriate in cases where an initial diagnosis of benign papilloma is made with VACNB. Benign papillomas associated with calcifications on imaging should be considered for surgical excision given their increased association with malignancy.

Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice

Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF.