The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

Tumor cells require angiogenesis to deliver nutrients and oxygen to support their fast growth and metabolism. The vascular endothelial growth factor (VEGF) pathway plays an important role in promoting angiogenesis, including tumor-induced angiogenesis. Recent clinical trials have demonstrated the benefit of targeting VEGF in the treatment of glioblastoma. However, the prognostic significance of the expression of VEGFA and its receptors VEGFR1 (FLT1) and VEGFR2 (KDR) are still largely elusive. In the present study, we aimed to investigate the prognostic significance of these three factors, alone or in combination, in glioma patients. Gene mRNA expression was extracted from three independent brain tumor cohorts totaling 242 patients and the association between gene expression and survival was tested. We found that when VEGFA, FLT1 and KDR expressions were considered alone, only VEGFA demonstrated a significant association with patient survival. Patients with high expression of both VEGFA and either receptor had significantly worse survival than patients expressing both factors at a low level. Importantly, we found that those patients whose tumors overexpressed all three genes had a significantly shorter survival compared to those patients with a low level expression of these genes. Our results suggest that a high level expression of VEGFA and its receptors, both FLT1 and KDR, may be required for brain tumor progression, and that these three factors should be considered together as a prognostic indicator for brain tumor patients.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.

Perceived difficulty of various steps of manual small incision cataract surgery among trainees in rural China

Background: The perceived difficulty of steps of manual small incision cataract surgery among trainees in rural China was assessed. Design: Cohort study. Participants: Fifty-two trainees at the end of a manual small incision cataract surgery training programme. Methods: Participants rated the difficulty of 14 surgical steps using a 5-point scale, 1 (very easy) to 5 (very difficult). Demographic and professional information was recorded for trainees. Main Outcome Measure: Mean ratings for surgical steps. Results: Questionnaires were completed by 49 trainees (94.2%, median age 38 years, 8 [16.3%] women). Twenty six (53.1%) had performed ≤50 independent cataract surgeries prior to training. Trainees rated cortical aspiration (mean score±standard deviation=3.10±1.14) the most difficult step, followed by wound construction (2.76±1.08), nuclear prolapse into the anterior chamber (2.74±1.23) and lens delivery (2.51±1.08). Draping the surgical field (1.06±0.242), anaesthetic block administration (1.14±0.354) and thermal coagulation (1.18±0.441) were rated easiest. In regression models, the score for cortical aspiration was significantly inversely associated with performing >50 independent manual small incision cataract surgery surgeries during training (P=0.01), but not with age, gender, years of experience in an eye department or total number of cataract surgeries performed prior to training. Conclusions: Cortical aspiration, wound construction and nuclear prolapse pose the greatest challenge for trainees learning manual small incision cataract surgery, and should receive emphasis during training. Number of cases performed is the strongest predictor of perceived difficulty of key steps. © 2013 Royal Australian and New Zealand College of Ophthalmologists.

Visual outcomes and astigmatism after sutureless, manual cataract extraction in rural China: study of cataract outcomes and up-take of services (SCOUTS) in the caring is hip project, report 1.

OBJECTIVE: To study the visual acuity and astigmatism of persons undergoing cataract extraction by local surgeons in rural China. METHODS: Visual acuity, keratometry, and refraction were measured 10 to 14 months postoperatively for all cataract cases during 4 months in Sanrao, China. RESULTS: Among 313 eligible subjects, 242 (77%) could be contacted, of whom 176 (73%) were examined. Of those who were examined, mean +/- SD age was 69.3 +/- 10.5 years, 66.5% were female, 35 had been operated on bilaterally at Sanrao, and 85.2% had a preoperative presenting visual acuity of 6/60 or worse. Presenting and best-corrected postoperative acuity in the eye that was operated on were 6/18 or better in 83.4% and 95.7%, respectively. Among 27 fellow eyes operated on elsewhere, 40.7% had a presenting acuity of 6/18 or better and 40.7% were blind (P < .001). Mean +/- SD postoperative astigmatism did not differ between 211 eyes that were operated on (-1.13 +/- 0.84 diopters) and 109 eyes that were not (-1.13 +/- 1.17 diopters; P = .27). Presence of operative complications (8.5%) and older age were associated with worse vision; bilateral surgery was associated with better vision. CONCLUSIONS: These results confirm the effectiveness of skill transfer in this setting, with superior outcomes to most studies in rural Asia and to eyes in this cohort operated on at other facilities.

Visual function and postoperative care after cataract surgery in rural China: study of cataract outcomes and up-take of services (SCOUTS) in the caring is hip project, report 2.

OBJECTIVE:

To study the postoperative visual function and uptake of refraction and second-eye surgery among persons undergoing cataract surgery in rural China.

METHODS:

Self-reported visual function was measured 10 to 14 months after surgery. Subjects with improvement of 2 or more lines with refraction were offered glasses, and those with significant cataract were offered second-eye surgery.

RESULTS:

Among 313 eligible subjects, 242 (77%) could be contacted; 176 (73%) of those contacted were examined. Interviewed subjects had a mean +/- SD age of 69.9 +/- 10.2 years, and 63.6% were female. The mean +/- SD visual function score was 88.4 +/- 12.3, higher than previously reported for cataract programs in rural China and significantly (P = .03) correlated with presenting vision. Forty-two percent of subjects had spectacles, more than half being reading glasses. Though 87% of subjects' vision improved with refraction, only 35% accepted prescriptions, the most common reason for refusal being lack of perceived need. Second-eye surgery was accepted by a total of 48% (85 of 176) of patients, cost being the biggest reason for refusal.

CONCLUSIONS:

Visual function was high in this cohort. Potential benefit of refraction and second-eye surgery was substantial, but uptake of services was modest. Programs to improve service uptake should focus on reading glasses and cost-reduction strategies such as tiered pricing.

Ocular comorbidities among cataract-operated patients in rural China: the caring is hip Study of Cataract Outcomes and Uptake of Services (SCOUTS), report No. 3.

PURPOSE: To determine the prevalence and impact on vision and visual function of ocular comorbidities in a rural Chinese cataract surgical program, and to devise strategies to reduce their associated burden. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Persons undergoing cataract surgery by one of two recently trained local surgeons at a government-run village-level hospital in rural Guangdong between August 8 and December 31, 2005. INTERVENTIONS: Eligible subjects were invited to return for a comprehensive ocular examination and visual function interview 10 to 14 months after surgery. Prevalent ocular comorbid conditions were identified. MAIN OUTCOME MEASURES: Presenting and best-corrected vision, visual function, and treatability of the comorbidity. RESULTS: Of 313 persons operated within the study window, 242 (77%) could be contacted by telephone; study examinations and interviews were performed on 176 (74%). Examined subjects had a mean age of 69.4+/-10.5 years, 116 (66%) were female, and 149 (85%) had been blind (presenting vision < or = 6/60) in the operative eye before surgery. Among unoperated eyes, 89 of 109 (81.7%) had > or =1 ocular comorbidities, whereas for operated eyes the corresponding proportion was 72 of 211 (34.1%). The leading comorbidity among operated eyes was refractive error (43/72 [59.7%]), followed by glaucoma/glaucoma suspect (14/72 [19.4%]), whereas for unoperated eyes, it was cataract (80/92 [87.0%]), followed by refractive error (12/92 [13.0%]). Among operated eyes with comorbidities, 90.3% (65/72) had > or =1 comorbidities that were treatable. In separate models adjusting for age and gender, persons with > or =1 comorbidities in the operated eye had significantly worse presenting vision (P<0.001) than those without such findings, but visual function (P = 0.197) and satisfaction with surgery (P = 0.796) were unassociated with comorbidities. CONCLUSIONS: Ocular comorbidities are highly prevalent among persons undergoing cataract surgery in this rural Asian setting, and their presence is significantly associated with poorer visual outcomes. The fact that the great majority of comorbidities encountered in this program are treatable suggests that strategies to reduce their impact can be successful.

Distribution and visual impact of postoperative refractive error after cataract surgery in rural China: study of cataract outcomes and up-take of services report 4.

PURPOSE: To model the possible impact of using average-power intraocular lenses (IOLs) and evaluate the postoperative refractive error in patients having cataract surgery in rural China.SETTING: Rural Guangdong, China.METHODS: Patients having cataract surgery by local surgeons were examined and visual function was assessed 10 to 14 months after surgery. Subjective refraction at near and distance was performed bilaterally by an ophthalmologist. Patients had a target refraction of -0.50 diopter (D) based on ocular biometry.RESULTS: Of the 313 eligible patients, 242 (77%) could be contacted and 176 (74% of contacted patients, 56% overall) were examined. Examined patients had a mean age of 69.4 +/- 10.5 years. Of the 211 operated eyes, 73.2% were within +/-1.0 D of the target refraction after surgery. The best presenting distance vision was in patients within +/-1.0 D of plano and the best presenting near vision, in those with mild myopia (<-1.0 D to > or =2.0 D) (P= .005). However, patients with hyperopia (>+1.0 D) reported significantly better adjusted visual function than those with emmetropia or myopia (<-1.0 D). When the predicted use of an average-power IOL (median +21.5 D) was modeled, predicted visual acuity was significantly reduced (P= .001); however, predicted visual function was not significantly altered (P>.3).CONCLUSIONS: Accurate selection of postoperative refractive error was achieved by local surgeons in this rural area. Based on visual function results, aiming for mild postoperative myopia may not be suitable in this setting. Implanting average-power IOLs significantly reduced postoperative presenting vision, but not visual function.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Background: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries.

Methods: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue.
Findings: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women.

Interpretation: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.