Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL

To identify microRNAs regulated by oncogenic Notch signaling, we performed microarray-based miRNA profiling of T-cell acute lymphoblastic leukemia (T-ALL) cells before and after treatment with γ-secretase inhibitor (GSI) to block Notch signaling. We show miR-223 levels increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We also demonstrate that insulin-like growth factor-1 receptor (IGF1R) is regulated by miR-223 in this context, but observe no apparent effects on cell growth by overexpression or knock-down of miR-223 alone. We conclude that miR-223 contributes to IGF1R regulation, but may act in concert with other genes and/or microRNAs to alter T-ALL biology.     

ALCAM (CD166) expression and serum levels are markers for poor survival of esophageal cancer patients

The expression of the activated leukocyte cell adhesion molecule (ALCAM and CD166) is increased in various types of cancer. We aimed to evaluate its role as a prognostic marker for esophageal cancer (EC). We retrospectively analyzed ALCAM expression in 299 primary lesions, 147 lymph node and 46 distant metastases from EC patients, on a tissue microarray using immunohistochemistry. Bone marrow samples from representative cancer patients (n = 16), taken before primary surgery, were stained by double-immunofluorescence for ALCAM and cytokeratins (CK). Blood serum samples from 236 cancer patients and 127 controls were analyzed for serum ALCAM (s-ALCAM) by ELISA. The immunohistochemical analysis showed increased ALCAM expression in the majority of lesions (primary tumor 71%, lymph node 76% and distant metastases 80%). ALCAM expression was not associated with histopathological parameters except for tumor grading (p = 0.015). ALCAM-positive patients had significantly worse recurrence-free and overall survival (OS; p = 0.002). Disseminated tumor cells (DTC) in bone marrow showed two phenotypes, ALCAM+/CK+ (36%) and ALCAM-/CK+ (64%). Multivariate analysis revealed that ALCAM expression and elevated s-ALCAM serum values are powerful prognostic variables for OS in patients with EC (hazard ratio [HR] 3.987, 95% confidence interval [95%CI] 1.906-8.340, p < 0.001 and HR 1.915, 95%CI 1.021-3.592, p = 0.043). The results of our study provide preliminary evidence for the potential clinical utility of ALCAM as a prognostic biomarker for EC, which might be a basis for future clinical application. In addition, ALCAM expression in a subset of DTC of the bone marrow indicates a potential function in the metastatic cascade of EC.     

Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group

A multidisciplinary approach is mandatory for patients with gastric cancer. Patients should be managed by an experienced team of physicians. The outcome of patients is related to the experience of the multidisciplinary team. Surgery is the cornerstone of the management of patients with resectable gastric cancer. The standard recommendations for resectable gastric adenocarcinoma are free-margin surgery with at least D1 resection combined to removal of a minimum of 15 lymph nodes. It has been shown that the outcome of patients with resectable gastric cancer can be improved by a strategy of perioperative (pre- and postoperative) chemotherapy or by postoperative chemoradiotherapy. The evidence comes from large randomised phase 3 studies. In the treatment of unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, no chemotherapy combination was accepted as the gold standard. Cisplatin/5-FU (CF) and ECF (epirubicin plus CF) regimens have been investigated widely in clinical studies and were until recently presented as the reference regimens. Despite a relative chemosensitivity of gastric cancer, a low rate of complete response was obtained, the response duration was short and patients' outcomes remained poor. Recently, new options have been introduced in the management of advanced gastric cancer. It has been shown that capecitabine is at least as good as 5-FU and that oxaliplatin at least as good as cisplatin in these combinations. It has also been demonstrated that the addition of docetaxel to CF resulted in statistically significant improved efficacy endpoints (including patient's quality of life), but also in an increased toxicity. The DCF regimen (docetaxel, cisplatin and 5-FU) has become, therefore, a new active option in advanced gastric cancer in selected patients in good condition. Further randomised trials are therefore to be designed to further improve chemotherapy by modifying and optimising the chemotherapy regimens, and investigating novel treatment combinations. The addition of biological agents to the optimal chemotherapy regimen may achieve further improvements in efficacy.     

Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients

PURPOSE: To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ). PATIENTS AND METHODS: Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5x2 Gy/wk. Thirty-five patients received concomitant TMZ at 50 mg/m2, and in 8 patients 75 mg/m2 of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only. RESULTS: Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient. CONCLUSIONS: Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.     

Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib

The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early‐PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia‐free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.     

Contrast-enhancement in supratentorial low-grade gliomas: a classic prognostic factor in the molecular age

Background

Contrast enhancement (CE) is found in 10–60% of low-grade gliomas. Its prognostic significance is controversial, and its correlation with IDH mutations and 1p/19q codeletion is elusive. The aim of this study is to investigate whether CE is associated with molecular characteristics of low-grade gliomas and uncover its prognostic value.

Materials and methods

All confirmed histological cases of low-grade gliomas diagnosed at our institution between years 2000–2016 were reviewed (n?=?102). Spinal and brainstem localization, only-biopsied tumours with ring-like enhancement and incomplete medical records were excluded.

Results

Mean age was 42 years (?±?13.9 years), and 63.6% were male. The median follow-up time was 79.8 months. CE was present on 25% of preoperative MRI, and 25% of patients were considered high-risk according to Pignatti score. Most were astrocytomas (67%) and 87.2% were surgically removed. IDH mutation was found in 64.6% of tumour samples, and 18.8% had a 1p/19q codeletion. No subgroup differences were observed according to CE except for presurgical performance status and postoperative chemotherapy. IDH status and 1p/19q codeletion were evenly distributed. On univariate analysis, age, size?>?6 cm, CE, extent of resection, Pignatti score, IDH mutation and 1p/19q codeletion were significantly associated to OS. On multivariate analysis, only CE and IDH status were independently associated to OS. CE remained a significant prognostic factor in IDH-mutant non-codeleted tumours when analysed by tumour subtype.

Conclusion

CE in low-grade gliomas provides prognostic information in IDH-mutant non-codeleted tumours, although its meaning remains uncertain in IDH-wildtype gliomas.

     

Preoperative motor mapping by navigated transcranial magnetic brain stimulation improves outcome for motor eloquent lesions

Background

Navigated transcranial magnetic stimulation (nTMS) has been proven to influence surgical indication and planning. Yet there is still no clear evidence how these additional preoperative functional data influence the clinical course and outcome. Thus, this study aimed to compare patients with motor eloquently located supratentorial lesions investigated with or without preoperative nTMS in terms of clinical outcome parameters.

Methods

A prospectively enrolled cohort of 100 patients with supratentorial lesions located in motor eloquent areas was investigated by preoperative nTMS (2010–2013) and matched with a control of 100 patients who were operated on without nTMS data (2006–2010) by a matched pair analysis.

Results

Patients in the nTMS group showed a significantly lower rate of residual tumor on postoperative MRI (OR 0.3828; 95% CI 0.2062–0.7107). Twelve percent of patients in the nTMS and 1% of patients in the non-nTMS group improved while 75% and 81% of the nTMS and non-nTMS groups, respectively, remained unchanged and 13% and 18% of patients in the nTMS and non-nTMS groups, respectively, deteriorated in postoperative motor function on long-term follow-up (P = .0057). Moreover, the nTMS group showed smaller craniotomies (nTMS 22.4 ± 8.3 cm²; non-nTMS 26.7 ± 11.3 cm²; P = .0023).

Conclusions

This work increases the level of evidence for preoperative motor mapping by nTMS for rolandic lesions in a group comparison study. We therefore strongly advocate nTMS to become increasingly used for these lesions. However, a randomized trial on the comparison with the gold standard of intraoperative mapping seems mandatory.     

Appropriateness of colorectal cancer screening: appraisal of evidence by experts.

OBJECTIVE: . To evaluate how the level of evidence perceived by an international panel of experts was concordant with the level of evidence found in the literature, to compare experts perceived level of evidence to their appropriateness scores, and to compare appropriateness criteria for colonoscopy between experts and an evidence-based approach. DESIGN: Comparison of expert panel opinions and systematic literature review regarding the level of evidence and appropriateness of colonoscopy indications. PARTICIPANTS: European Panel on the Appropriateness of Gastrointestinal Endoscopy multidisciplinary experts from 14 European countries. MAIN OUTCOME MEASURES: Concordance and weighted kappa coefficient between level of evidence as perceived by the experts' and that found in the literature, and between panel- and literature-based appropriateness categories. RESULTS: Experts overestimated the level of published evidence of 57 indications. Concordance between the level of evidence perceived by the experts and the actual level of evidence found in the literature was 36% (weighted kappa 0.18). Indications for colonoscopy were reported to be appropriate, uncertain, and inappropriate by the experts in 54, 19, and 27% of the cases, and by the literature in 37, 46, and 17% of the cases. A 46% agreement (weighted kappa 0.29) was found between literature-based and experts' appropriateness criteria. CONCLUSIONS: Experts often overestimated the level of evidence on which they based their decisions. However, rarely did the experts' judgement completely disagree with the literature, although concordance between panel- and literature-based appropriateness was only fair. A more explicit discussion of existing evidence should be undertaken with the experts before they evaluate appropriateness criteria.     

Obesity in South Africa: the South African demographic and health survey

OBJECTIVES: To ascertain the anthropometric profile and determinants of obesity in South Africans who participated in the Demographic and Health Survey in 1998. RESEARCH METHODS AND PROCEDURES: A sample of 13,089 men and women (age, > or =15 years) were randomly selected and then stratified by province and urban and nonurban areas. Height, weight, mid-upper arm circumference, and waist and hip circumference were measured. Body mass index (BMI) was used as an indicator of obesity, and the waist/hip ratio (WHR) was used as an indicator of abdominal obesity. Multivariate regression identified sociodemographic predictors of BMI and waist circumference in the data. RESULTS: Mean BMI values for men and women were 22.9 kg/m(2) and 27.1 kg/m(2), respectively. For men, 29.2% were overweight or obese (> or =25 kg/m(2)) and 9.2% had abdominal obesity (WHR > or =1.0), whereas 56.6% of women were overweight or obese and 42% had abdominal obesity (WHR >0.85). Underweight (BMI <18.5 kg/m(2)) was found in 12.2% of men and 5.6% of women. For men, 19% of the variation of BMI and 34% of the variation in waist circumference could be explained by age, level of education, population group, and area of residence. For women, these variables explained 16% of the variation of BMI and 24% of the variation in waist circumference. Obesity increased with age, and higher levels of obesity were found in urban African women. DISCUSSION: Overnutrition is prevalent among adult South Africans, particularly women. Determinants of overnutrition include age, level of education, ethnicity, and area of residence.     

Biological activity of the essential oil of Kadsura longipedunculata (Schisandraceae) and its major components

Objectives The aim was to determine the chemical composition of the essential oil of Kadsura longipedunculata and the biological activity of the oil and its major components. Methods The essential oil from stem bark of Kadsura longipedunculata was analysed by capillary gas chromatography (GLC/FID) and gas chromatography–mass spectrometry (GLC/MS). The ability of the oil to reduce diphenylpicrylhydrazine (DPPH^?) was used to evaluate the antioxidant activity. Inhibition of both lipoxygenase and prostaglandin E₂ was used to assess the anti‐inflammatory activity. Antimicrobial activity was studied in vitro against a range of bacteria and fungi using diffusion and microdilution methods. Inhibition of trypanosome proliferation was assessed using resazurin as vital stain. The in‐vitro cytotoxicity of the essential oil on six human cancer cell lines (HepG2, MIA PaCa‐2, HeLa, HL‐60, MDA‐MB‐231 and SW‐480) was examined using the MTT assay. Key findings Fifty compounds, representing 97.63% of total oil, were identified. δ‐Cadinene (21.79%), camphene (7.27%), borneol (6.05%), cubenol (5.12%) and δ‐cadinol (5.11%) were found to be the major components of the oil. The oil exerted a good antimicrobial activity against all Gram‐positive bacteria tested, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecalis. Streptococcus pyogenes and S. agalactiae were the most sensitive bacteria with a minimal inhibitory concentration (MIC) of 60 µg/ml oil. The essential oil showed a moderate fungicidal activity against yeasts, but it did not show any activity against Gram‐negative bacteria. The essential oil showed a good trypanocidal activity in Trypanosoma b. brucei with an IC50 value of 50.52 ± 0.029 µg/ml. Radical scavenging activity had an IC50 value of 3.06 ± 0.79 mg/ml. 5‐Lipoxygenase inhibition (IC50 = 38.58 µg/ml) and prostaglandin E₂ production inhibition (28.82% at 25 µg/ml) accounted for anti‐inflammatory activity of the oil. The oil exhibited some degree of cytotoxic activity against MIA PaCa‐2, HepG‐2 and SW‐480 cell lines with IC50 values of 133.53, 136.96 and 136.62 µg/ml, respectively. The oil increased caspase 3/7 activity (an indicator of apoptosis) 2.5–4 fold in MIA Paca‐2 cells. Camphene and borneol did not show antioxidant activity. However, both compounds exhibited some degree of antimicrobial, trypanocidal, anti‐inflammatory and cytotoxic activity. Conclusions This investigation provided evidence for, and confirmed the efficacy of, K. longipedunculata, a traditionally used Chinese medicinal plant for the treatment of inflammation and infection.