Decrease of Plasminogen Activator Inhibitor-1 May Contribute to the Anti-Invasive Action of Cannabidiol on Human Lung Cancer Cells

Purpose  

Using human lung cancer cells, we evaluated the involvement of plasminogen activator inhibitor-1 (PAI-1) in the anti-invasive action of cannabidiol, a non-psychoactive cannabinoid.     

Adamantiades-Beh?et's disease. Clinical review]

Beh?et's disease is a chronic relapsing systemic vasculitis of unknown etiology, affecting predominantly oral and genital mucocutaneous tissues and also the eyes. The disease is spread worldwide with a higher prevalence rate in countries along the ancient Silk Route, but it is rare (1-10/100,000) in Central and Northern Europe. Genetic, environmental, immunologic, inflammatory and rheologic factors are involved in the pathogenesis and the course of the disease. Any vascularized organ may be affected. Eye involvement is frequent, and may eventually result in loss of vision. Further important complications are cerebral manifestations, thrombotic syndromes, and arterial aneurysms with a high risk of rupture. Diagnosis and therapy of Beh?et's disease are best managed by an interdisciplinary team. Skin lesions may be controlled by systemic treatment with colchicine, alternatively with dapsone, and in severe cases with thalidomide. Active systemic disease should be treated more aggressively using immunosuppressants. Despite advances in treatment relapses are still frequent, and systemic disease remains associated with an adverse prognosis.     

The impact of postoperative atrial fibrillation on neurocognitive outcome after coronary artery bypass graft surgery.

Neurocognitive decline is a continuing source of morbidity after cardiac surgery. Atrial fibrillation occurs often after cardiac surgery and has been linked to adverse neurologic events. We sought to determine whether postoperative atrial fibrillation was associated with postoperative cognitive dysfunction. Four-hundred-eleven patients were enrolled to receive a battery of neurocognitive tests both preoperatively and 6 wk after elective coronary artery bypass graft surgery. Neurocognitive test scores were separated into four cognitive domains, with a composite cognitive index (the mean of the four domain scores) determined for each patient at every testing period. Multivariable analysis controlling for age, years of education, diabetes mellitus, left ventricular ejection fraction, and preoperative atrial fibrillation compared the presence of postoperative atrial fibrillation with change in cognitive function. Three-hundred-eight patients completed both pre- and postoperative cognitive testing; 69 patients (22%) had postoperative atrial fibrillation. Those who developed atrial fibrillation showed more cognitive decline than those who did not develop postoperative atrial fibrillation (P = 0.036). Atrial fibrillation was associated with poorer cognitive function 6 wk after surgery. Although the mechanism of this association is yet to be determined, prevention of atrial fibrillation may result in improved neurocognitive function. IMPLICATIONS: Neurocognitive dysfunction is common after coronary artery bypass graft surgery. The relationship between atrial fibrillation and neurocognitive dysfunction has not been examined. Our study shows that postoperative atrial fibrillation is associated with neurocognitive decline.     

RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH,primary and metastatic prostate cancer disease

Background

The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level.

Methods

Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples.

Results

The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p < 0.001) as compared to BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (< 7 or ≥ 7, p = 0.028) or PSA level (< 10 or ≥ 10 µg/l, p = 0.004). RANKL and OPG mRNA expression was higher in tumour tissue from patients with metastatic compared to local disease. The RANKL/OPG ratio was low in normal prostate tissue and high tumours with bone metastases (p < 0.05). Expression of all three cytokines was high in BPH tissue but did not exceed as much as in the tumour tissue.

Conclusion

We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.

     

Multicenter evaluation of guideline adherence for pelvic lymph node dissection in patients undergoing open retropubic vs. laparoscopic or robot assisted radical prostatectomy according to the recent German S3 guideline on prostate cancer

Purpose

Pelvic lymph node dissection (PLND) is recommended for patients with prostate cancer (PCa) and significant risk for nodal metastases. This study aimed to assess guideline adherence regarding PLND according to the German S3 guideline as example for a national but highly used guideline on prostate cancer and to compare the rate of complications different approaches for radical prostatectomy (RP).

Methods

Patients undergoing open (RRP), laparoscopic (LARP) or robot-assisted (RARP) RP in six centers in Germany and Austria were included. The primary endpoint was the total number of removed lymph nodes (LN) between the different surgical approaches according to recent guideline recommendations. Secondary endpoints were the number of patients undergoing a sufficient PLND, defined as a removal of at least 10 LN and associated complication rates.

Results

2634 patients undergoing RP were included (RRP: 66%, RARP/LARP: 34%). PLND was performed in 88% (RRP: 88.5%, RARP/LARP: 86.8%, p = 0.208). In intermediateor high risk PCa, PLND was performed in 97.2% (RRP: 97.7%, RARP/LARP: 96.2, p = 0.048). Of those, the mean number of LN was 19 (RRP: 19 vs. RARP/LARP: 17, p < 0.005) and sufficient PLND was observed in 84.6% of RRP compared to 77.2% of RARP/LARP (p < 0.005). Symptomatic lymphoceles requiring surgical treatment occurred more often in RRP than in RARP/LARP (4.0% vs. 1.6%, p = 0.001).

Conclusions

The general guideline adherence regarding performing PNLD and the LN yield is high, regardless of the surgical approach. As expected, lymph node yield was higher when very experienced surgeons conducted the procedure. This should be considered in patients’ counseling.

     

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis related to or comparable with mechanisms seen in inflammatory pathways? Part II: angiogenesis- and inflammation-related molecular pathways,tumor-associated macrophages,and possible therapeutic implications: a comprehensive review

Phacomatoses are a special group of familial hamartomatous syndromes with unique neurocutaneous manifestations as well as characteristic tumors. Neurofibromatosis type 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. A vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with these syndromes, related to NF2 and TSC, respectively. These tumors can present with an obstructive hydrocephalus due to their location adjacent to or in the ventricles. Remarkably, both tumors are also known to have a unique association with elevated protein concentrations in the cerebrospinal fluid (CSF), sometimes in association with a non-obstructive (communicating) hydrocephalus. Of the two, SGCT has been shown to be associated with a predisposition to CSF clotting, causing a debilitating recurrent shunt obstruction. However, the exact relationship between high protein levels and clotting of CSF remains unclear, nor do we understand the precise mechanism of CSF clotting observed in SGCT. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood–brain barrier. The two presumed underlying pathophysiological processes for that in the context of tumorigenesis are angiogenesis and inflammation. Both these processes are correlated to the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin pathway which is tumorigenesis related in many neoplasms and nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation pathways on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I described the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating hydrocephalus. Part II hereafter describes the different cellular and molecular pathways involved in angiogenesis and inflammation observed in both tumors and explores the existing metabolic overlap between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both tumors, inflammatory processes seem significantly more prominent in SGCT. Both SGCT and VS are characterized by different subgroups of tumor-associated macrophages (TAMs): the pro-inflammatory M1 type is predominating in SGCTs, while the pro-angiogenetic M2 type is predominating in VSs. We suggest that a lack of NF2 protein in VS and a lack of TSC1/TSC2 proteins in SGCT significantly influence this fundamental difference between the two tumor types by changing the dominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, the pro-inflammatory state of SGCT may also explain the associated tendency for CSF clotting. The underlying cellular and molecular differences observed can potentially serve as an access point for direct therapeutic interventions for tumors that are specific to certain phacomatoses or others that also carry such genetic changes.     

Cost-effectiveness analysis of different screening procedures for type 2 diabetes: the KORA Survey 2000

OBJECTIVE: To compare the cost-effectiveness of different type 2 diabetes screening strategies using population-based data (KORA Survey; Augsburg, Germany; subjects aged 55-74 years), including participation data. RESEARCH DESIGN AND METHODS: The decision analytic model, which had a time horizon of 1 year, used the following screening strategies: fasting glucose testing, the oral glucose tolerance test (OGTT) following fasting glucose testing in impaired fasting glucose (IFG) (fasting glucose + OGTT), OGTT only, and OGTT if HbA(1c) was >5.6% (HbA(1c) + OGTT), all with or without first-step preselection (p). The main outcome measures were costs (in Euros), true-positive type 2 diabetic cases, incremental cost-effectiveness ratios (ICERs), third-party payers, and societal perspectives. RESULTS: After dominated strategies were excluded, the OGTT and HbA(1c) + OGTT from the perspective of the statutory health insurance remained, as did fasting glucose + OGTT and HbA(1c) + OGTT from the societal perspective. OGTTs (4.90 per patient) yielded the lowest costs from the perspective of the statutory health insurance and fasting glucose + OGTT (10.85) from the societal perspective. HbA(1c) + OGTT was the most expensive (21.44 and 31.77) but also the most effective (54% detected cases). ICERs, compared with the next less effective strategies, were 771 from the statutory health insurance and 831 from the societal perspective. In the Monte Carlo analysis, dominance relations remained unchanged in 100 and 68% (statutory health insurance and societal perspective, respectively) of simulated populations. CONCLUSIONS: The most effective screening strategy was HbA(1c) combined with OGTT because of high participation. However, costs were lower when screening with fasting glucose tests combined with OGTT or OGTT alone. The decision regarding which is the most favorable strategy depends on whether the goal is to identify a high number of cases or to incur lower costs at reasonable effectiveness.     

Tibial torsion measurement by surface curvature

BACKGROUND: Tibial torsion is the angle between the transverse axes of the proximal and distal tibial articular surfaces. It measures the degree of twisting of the tibia around its own longitudinal axis. The accurate measurement on the magnitude of tibial torsion is of great use in monitoring derangements. It is also useful as a baseline in the event of surgical intervention. Various methods have been developed but none of them have gained wide acceptance. Even the CT scan technique, which is considered the "gold standard", produces varying results when executed by different researchers. A quick, objective and non-invasive method is thus very much needed for the effective monitoring of tibial torsion in clinical environments. METHODS: Eighteen adult men's lower legs were scanned by a laser scanner to give the surface coordinates of the leg surfaces. By calculating curvature maps of legs from the 3D coordinates, stable anatomical landmarks such as the lateral and medial malleoli can be located. The angle indicating the degree of tibial torsion can then be derived from these landmarks. FINDINGS: The objective determination of the various anatomical landmarks results in a reproducible measure of tibial torsion. The results obtained in this study are generally in agreement with the measurements reported previously. INTERPRETATION: The reproducibility of the results allows for the objective observation, monitoring and comparison of tibial torsion over time and across subjects. It allows also for the development of a system of measurement that is fast, convenient, accurate and radiation-free.     

Chemotherapy-induced nausea and vomiting in routine practice: a European perspective

Goals of work The aim of this study was to evaluate the occurrence of chemotherapy-induced nausea and vomiting (CINV) and its effect on patients ability to carry out daily life activities following moderately to highly emetogenic, first-cycle chemotherapy in routine practice in cancer centers of four different European countries.Patients and methods This was a prospective, cross-sectional, nonrandomized, self-assessment study in 249 patients enrolled from cancer centers in Spain, Austria, Germany, and Switzerland. The study population consisted of 78% women, with a mean age of 54. Breast, lung, and ovarian cancers made up 75% of all cancers in the study. Patients received a mean of 2.0 chemotherapy agents and 2.5 antiemetic drugs.Main results A total of 450 emetic episodes experienced by 243 patients was recorded over 5 days following chemotherapy, with an average of 1.8 episodes per patient (range: 0–28). A higher percentage of patients (38%) suffered from delayed compared to acute emesis (13%). Between 42% and 52% of all patients suffered from nausea (visual analogue scale 5 mm) on any one day, peaking at day 3. Using the Functional Living Index for Emesis (FLIE) questionnaire, 75% of patients with nausea and 50% with vomiting reported a negative impact of these conditions on performance of daily living.Conclusions CINV remains a significant problem in routine practice, particularly in the delayed phase posttreatment. Overall, CINV had a negative impact on patients daily life.