Prognostic significance of PI-RADS 5 lesions in patients treated by radical prostatectomy.

PURPOSE: To analyse the pathological features and survival of patients with a PI-RADS 5 lesion on pre-biopsy MRI. METHODS: We extracted from a European multicentre prospectively gathered database the data of patients with a PI-RADS 5 lesion on pre-biopsy MRI, diagnosed using both systematic and targeted biopsies and subsequently treated by radical prostatectomy. The Kaplan-Meier model was used to assess the biochemical-free survival of the whole cohort and univariable and multivariable Cox models were set up to study factors associated with survival. RESULTS: Between 2013 and 2019, 539 consecutive patients with a PI-RADS 5 lesion on pre-biopsy MRI were treated by radical prostatectomy and included in the analysis. Follow-up data were available for 448 patients. Radical prostatectomy and lymph node dissection specimens showed non-organ confined disease in 297/539 (55%), (including 2 patients with a locally staged pT2 lesion and lymph node involvement (LNI)). With a median follow-up of 25 months (12-39), the median biochemical recurrence-free survival was 54% at 2 years (95% CI 45-61) and 28% at 5 years (95% CI 18-39). Among the factors studied, MRI T stage [T3a vs T2 HR 3.57 (95%CI 1.78-7.16); T3b vs T2 HR 6.17 (95% CI 2.99-12.72)] and PSA density (HR 4.47 95% CI 1.55-12.89) were significantly associated with a higher risk of biochemical recurrence in multivariable analysis. CONCLUSION: Patients with a PI-RADS 5 lesion on pre-biopsy MRI have a high risk of early biochemical recurrence after radical prostatectomy. MRI T stage and PSA density can be used to improve patient selection and counselling.

Association of alcohol control policies with adolescent alcohol consumption and with social inequality in adolescent alcohol consumption: A multilevel study in 33 countries and regions.

Background Previous research found inconsistent associations between alcohol control policies and socioeconomic inequality with adolescent drinking outcomes. This study expands the focus beyond individual associations to examine whether a combination of policies is related to socioeconomic inequality in adolescent drinking outcomes and whether this relationship varies across survey years. Methods Multilevel modelling of 4 waves of repeat cross-sectional survey data (2001/02, 2005/06, 2009/10, and 2013/14) from the Health Behaviour in School-aged Children (HBSC) study was carried out. The sample was composed of 671,084 adolescents (51% girls) aged 11, 13, and 15 (mean age=13.58; SD=1.65) from 33 European and North American countries/regions. The dependent variables were lifetime alcohol consumption, weekly alcohol consumption, and lifetime drunkenness. Independent variables were of three types: individual-level variables (age, sex, Family Affluence Scale, and the Perceived Family Wealth), time-level variable (survey year), and context-level variables (minimum legal drinking age, physical availability, advertising restrictions, a total alcohol policy index, and affordability of alcohol). Results The total alcohol policy index showed a negative relationship with both lifetime and weekly consumption. Higher affordability of alcohol was related to higher lifetime and weekly consumption and higher lifetime drunkenness. Family Affluence Scale was positively related to all three alcohol measures and Perceived Family Wealth was negatively related to lifetime drunkenness, with these associations increasing across survey years. The total alcohol policy index buffered the associations of Family Affluence Scale and Perceived Family Wealth with adolescent drinking outcomes. Conclusion A combination of alcohol control policies is more effective in reducing adolescent drinking outcomes than single policy measures. Reducing the affordability of alcohol stood out as the most successful single measure. Socioeconomic inequalities (i.e. higher alcohol consumption and drunkenness in adolescents with higher family affluence and higher drunkenness in adolescents perceiving their families to be poor) have persisted and even increased across survey years. A combined alcohol control policy can help in tackling them.

Monocytes from patients with Primary Ciliary Dyskinesia show enhanced inflammatory properties and produce higher levels of pro-inflammatory cytokines.

Patients with Primary Ciliary Dyskinesia (PCD) suffer from recurrent upper and lower airway infections due to defects in the cilia present on the respiratory epithelium. Since chronic inflammatory conditions can cause changes in innate immune responses, we investigated whether monocytes isolated from the peripheral blood of pediatric PCD patients respond differently to inflammatory stimuli, compared to monocytes from healthy children and adults. The receptor for C5a (C5aR) was upregulated in PCD, whereas expression levels of the leukocyte chemoattractant receptors CCR1, CCR2, CCR5, BLT1 and FPR1 on PCD monocytes were similar to those on monocytes from healthy individuals. Also in vitro migration of PCD monocytes towards the ligands of those receptors (CCL2, fMLP, C5a and LTB4) was normal. Compared to healthy children, PCD patients had a higher percentage of the non-classic monocyte subset (CD14+CD16++) in circulation. Finally, PCD monocytes produced higher levels of pro-inflammatory cytokines (IL-1ß and TNF-α) and chemokines (CCL3, CCL5, CCL18 and CCL22) in response to LPS, peptidoglycan and/or dsRNA stimulation. These data suggest that monocytes might exacerbate inflammatory reactions in PCD patients and might maintain a positive feedback-loop feeding the inflammatory process.

Platelet-rich fibrin (PRF): an autologous packing material for middle ear microsurgery.

OBJECTIVES: To assess the use of PRF prepared using an optimised protocol in middle ear surgery as a substitute for conventional packing products of animal origin such as collagen derived from porcine skin. METHODOLOGY: A retrospective study of 108 patients in whom optimised PRF was used exclusively to pack the external auditory canal or middle ear. The effectiveness or harmlessness of the PRF was evaluated by assessing a range of parameters. A morphological comparison was also made of PRF produced using the Choukroun procedure and our procedure. RESULTS: The success rate of the repair of the tympanic membrane one year after the surgery was 45/48 patients. In 5 of 63 patients in whom a retro-auricular approach and wall-up technique were used, granuloma was observed along the incision in the ear canal. Granuloma was not seen in any of the 23 patients undergoing a procedure with an endaural approach. CONCLUSION: The use of a material prepared from patients themselves and not of animal origin has numerous advantages in terms of biocompatibility and safety, without any adverse effect on the success rate for general middle ear procedures. The protocol is simple and does not prolong the time spent by the patient in the operating theatre. The Choukroun technique should be modified to prevent excessive failure rates in PRF processing.

Social motives for drinking in students should not be neglected in efforts to decrease problematic drinking.

High heavy drinking prevalence persists in students. Recently, drinking motivation received a lot of attention as an important determinant. Enhancement and coping motives are mostly positively related and conformity motives are mostly negatively related with heavy drinking. Relations are less clear for social motives. This study aimed at gaining more insight in the role of drinking motives in heavy drinking students. Overall, 15 897 Belgian university and college students (mean age: 20.7, SD = 2.6) anonymously participated in an online survey. Logistic regressions tested relationships between motives and problematic drinking (>weekly drinking, ≥monthly binge drinking and being at risk for problematic drinking by the Alcohol Use Disorders Identification Test [AUDIT]). Social motives had the highest prevalence, followed by enhancement, coping and conformity motives. Men engaged more in problematic drinking and reported more motives, except for coping. Enhancement, coping and social-motivated students have higher chances for problematic drinking, while the opposite is true for conformity-motivated students. Although this study found a similar ranking of motives as in other studies, a relationship between problematic drinking and all motives, including social motives, was revealed. This might indicate the different functions of social motives in heavy drinking in different cultures/sub-populations and countries. This finding is relevant for the development of interventions.

Autocrine CCL2, CXCL4, CXCL9 and CXCL10 signal in retinal endothelial cells and are enhanced in diabetic retinopathy.

This study aimed at examining the presence and role of chemokines (angiogenic CCL2/MCP-1 and angiostatic CXCL4/PF-4, CXCL9/Mig, CXCL10/IP-10) in proliferative diabetic retinopathy (PDR). Regulated chemokine production in human retinal microvascular cells (HRMEC) and chemokine levels in vitreous samples from 40 PDR and 29 non-diabetic patients were analyzed. MCP-1, PF-4, Mig, IP-10 and VEGF levels in vitreous fluid from PDR patients were significantly higher than in controls. Except for IP-10, cytokine levels were significantly higher in PDR with active neovascularization and PDR without traction retinal detachment (TRD) than those in inactive PDR, PDR with TRD and control subjects. Exploratory regression analysis identified associations between higher levels of IP-10 and inactive PDR and PDR with TRD. VEGF levels correlated positively with MCP-1 and IP-10. Significant positive correlations were observed between MCP-1 and IP-10 levels. In line with these clinical findings Western blot analysis revealed increased PF-4 expression in diabetic rat retinas. HRMEC produced MCP-1, Mig and IP-10 after stimulation with IFN-γ, IL-1ß or lipopolysaccharide. IFN-γ synergistically enhanced Mig and IP-10 production in response to IL-1ß or lipopolysaccharide. MCP-1 was produced by HRMEC in response to VEGF treatment and activated HRMEC via the ERK and Akt/PKB pathway. On the other hand, phosphorylation of ERK induced by VEGF and MCP-1 was inhibited by PF-4, Mig and IP-10. In accordance with inhibition of angiogenic signal transduction pathways, PF-4 inhibited in vitro migration of HRMEC. Thus, regulatory roles for chemokines in PDR were demonstrated. In particular, IP-10 might be associated with the resolution of active PDR and the development of TRD.

Malaria: host-pathogen interactions, immunopathological complications and therapy.

Malaria is a global tropical disease causing more than 1 million deaths and 300 million clinical cases every year. It is caused by parasites from the genus Plasmodium and is transmitted by Anopheles mosquitoes. Approximately 3 billion people live in malaria-endemic regions and a majority of them are infected. In this review, we discuss the life cycle of the parasite, the complex interactions with the human host and the ensuing immune reactions and complications. The immune system plays a dual role in malaria, by providing life-saving immunity against the parasite, but also by causing often lethal complications in a number of patients. Cytokines, chemokines and proteases are key players in the immunopathological complications, and we propose immunomodulation with dexamethasone as a promising strategy for the therapy of malaria-associated acute respiratory distress syndrome.

Cardiovascular determinants and prognostic significance of CC Chemokine Ligand-18 (CCL18/PARC) in patients with stable coronary artery disease.

Chemokines are important mediators of angiogenesis, hematopoiesis and leucocyte trafficking. CC Chemokine Ligand-18 (CCL18)/ pulmonary and activation-regulated chemokine (PARC) is a circulating chemokine that plays a role in injury healing, physiological homing of mononuclear blood cells and inflammatory responses. CCL18/PARC is also expressed in atherosclerotic plaques. We prospectively evaluated CCL18/PARC levels and their cardiovascular and biological determinants in a large cohort of 285 patients with stable coronary heart disease who were subsequently followed for 3 years for hard cardiac events. It was found that CCL18/PARC levels were associated with decreased cardiac function, decreased exercise capacity and increased inflammatory parameters including interleukin-6 (IL-6) and hs-CRP. More importantly high CCL18/PARC levels were an independent predictor of future cardiovascular events. Therefore, CCL18/PARC is a potential diagnostic and prognostic parameter in patients with stable coronary artery disease.

Prognostic factors and assessment of staging systems for head and neck soft tissue sarcomas in adults.

OBJECTIVES: The primary objectives of this study were to analyse the outcome of patients diagnosed with head and neck soft tissue sarcomas (HNSTS) and to identify relevant prognostic factors. As well as this, we compared the prognostic value of two staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Memorial Sloan-Kettering Cancer Center (MSKCC). METHODS: From 07/1988 to 01/2008, the charts of 42 adult patients were retrospectively reviewed. Potential prognostic factors were analysed according to overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: At 5 years, OS was 57%, DFS 47% and DSS 72%. On univariate analysis, statistically significant prognostic factors were for OS, distant or lymph node metastasis at diagnosis (p=0.032), for DFS, margins after surgery (p=0.007), for DSS, regional or distant metastasis at diagnosis (p=0.002), initial AJCC and MSKCC stage (p=0.018 and p=0.048) and margins after surgery (p=0.042). On multivariate analysis, margins remained statistically significant for DFS (p=0.039) when there was a trend with the initial AJCC stage (p=0.054) for OS. The AJCC staging system was of more prognostic value than the MSKCC staging system. CONCLUSIONS: Achieving clear margins after surgery is vital for improved local control and the best chance of survival. Adjuvant chemotherapy and radiotherapy were not shown to provide additional benefit. To better identify prognostic factors, it seems essential to set up national and international databases allowing multicenter registration for those patients.

Comparison between new and old generation RetroX auditory implants.

OBJECTIVE: To compare post aural soft tissues tolerance of the old and new titanium RetroX (Auric GmbH, Rheine, Germany) tube, and to compare the hearing improvements between the old (DSP-pro) and the new (Concertino) hearing aid units of the RetroX. METHODOLOGY: Retrospective case review of 46 patients with high-frequency sensorineural hearing loss, fitted with DSP-pro or Concertino, and who received 51 implantations (with the old or new generation titanium tube) in a tertiary referral center at a university hospital. The RetroX consists of an electronic unit situated in the postaural sulcus connected to a titanium tube implanted under the auricle between the sulcus and the external auditory meatus. Implanting requires minor surgery (10 minutes under local anaesthesia). Three months after their implantation, patients were asked to fill out a questionnaire to evaluate acoustic feedback annoyance and to undergo 3 audiometric tests: pure-tone audiometry in silence, speech audiometry in silence, and speech audiometry in noise. RESULTS: The new tube is more reliable (12 explantations from patients who received 26 older tubes compared with 1 explantation in 25 who received new tubes) even if the size must be adjusted more often (2/26 for the old model and 5/25 for the new one). Concertino allows a higher amplification before feedback appears, which improves hearing gain. CONCLUSIONS: The new RetroX is better tolerated than the older one, and improves hearing ability.

Microbial interactions influence inflammatory host cell responses.

The inflammatory response plays an important role in the tissue destruction associated with periodontitis. Bacterial species can regulate the inflammatory responses of host cells, triggered by pathogens. It was hypothesized that, in the field of oral microbiology/immunology, such effects of bacterial interactions on inflammatory host cell responses might also be present. In this study, the effects of beneficial, commensal, and pathogenic species on Aggregatibacter actinomycetemcomitans-induced interleukin-8 (IL-8) production by human cells were investigated. The beneficial species, Streptococcus mitis, Streptococcus salivarius, and Streptococcus sanguinis, were able to lower the IL-8 production triggered by A. actinomycetemcomitans. The inhibitory effect was also achieved by the application of streptococcal supernatants. In contrast, the commensal Streptococcus gordonii caused no reduction, and the pathogen Fusobacterium nucleatum increased IL-8 production by the host cells. These results show that bacterial species can influence the inflammatory responses of host cells triggered by infection with A. actinomycetemcomitans.

TNF-alpha and the IFN-gamma-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma.

Interferon-gamma-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-alpha (TNF-alpha) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-alpha into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10- or TNF-alpha-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10- and TNF-alpha-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy.

Mechanistic insight into taxol-induced cell death.

We analysed the involvement of proteases during taxol-mediated cell death of human A549 non-small-cell lung carcinoma cells using a proteomics approach that specifically targets protein N termini and further detects newly formed N termini that are the result of protein processing. Our analysis revealed 27 protease-mediated cleavages, which we divided in sites C-terminal to aspartic acid (Asp) and sites C-terminal to non-Asp residues, as the result of caspase and non-caspase protease activities, respectively. Remarkably, some of the former were insensitive to potent pancaspase inhibitors, and we therefore suggest that previous inhibitor-based studies that report on the caspase-independent nature of taxol-induced cell death should be judged with care. Furthermore, many of the sites C-terminal to non-Asp residues were also uniquely observed in a model of cytotoxic granule-mediated cell death and/or found by in vitro cataloging human mu-calpain substrates using a similar proteomics technique. This thus raises the hypothesis that killing tumor cells by chemotherapy or by immune cells holds similar non-Asp-specific proteolytic components with strong indications to calpain activity.

Circulating fibrocytes contribute to the myofibroblast population in proliferative vitreoretinopathy epiretinal membranes.

BACKGROUND/AIMS: Fibrocytes, circulating cells that co-express markers of haematopoietic stem cells, leucocytes and fibroblast products, traffic to sites of tissue injury, differentiate into myofibroblasts and contribute to wound healing and fibrosis. We investigated the presence of fibrocytes and the expression of their chemotactic pathways CCL21/CCR7 and CXCL12/CXCR4 in proliferative vitreoretinopathy (PVR) epiretinal membranes. METHODS: Sixteen membranes were studied by immunohistochemical techniques. RESULTS: Cells expressing alpha-smooth-muscle actin (alpha-SMA), a marker of differentiation of fibrocytes into myofibroblasts, were present in all membranes. Cells expressing the haematopoietic stem-cell antigen CD34, the leucocyte common antigen CD45, CCR7, CXCR4, CCL21 and CXCL12 were noted in 50%, 75%, 68.8%, 100%, 80% and 93.8% of the membranes, respectively. Double immunohistochemistry indicated that all cells expressing CD34, CD45, CCR7, CXCR4, CCL21 and CXCL12 co-expressed alpha-SMA. The number of cells expressing CD34 correlated significantly with the numbers of cells expressing CXCL12 (r(s) = 0.567; p = 0.022) and CCL21 (r(s) = 0.534; p = 0.04). CONCLUSIONS: Circulating fibrocytes may function as precursors of myofibroblasts in PVR membranes.

[The role of plasma chemokines in cancer]. / Rol van plasma-chemokinen bij kanker.

Chemokines have diverse roles in tumor biology. Monocyte chemotactic protein-(MCP-1)/CCL2 was the first chemokine described to elicit influx of monocyte/macrophages into tumors. Application of chemokines as anti-tumoral therapy to attract immunocompetent cells and to mediate the mounting of an efficient anti-tumoral response has been tested as a method to combat cancer for some years now. However, these chemokine-related therapy has not yet been approved for clinical application, although it has been tested succesfully in animal models for years now. A different kind of approach for chemokine anti-cancer therapy involves angiostatic chemokines. These chemokines inhibit pro-angiogenic tumoral factors, thereby limiting tumor growth and metastasis. Recently, we described a most potent new angiostatic chemokine, namely a variant of platelet factor 4, designated PF-4var/CXCL4L1. With regard to hematological tumors we described a new plasma chemokine, PARC/CCL18, that can be used to distinguish between pediatric patients with acute lymfoid leukemia or acute myeloid leukemia. Whether this elevated plasma concentration of PARC/CCL18 is the cause of the pathology or the consequence of a disturbed cytokine balance is not clear at the moment.

Expression of chemokines and gelatinase B in sympathetic ophthalmia.

PURPOSE: To examine the expression of gelatinase B (matrix metalloproteinase-9) and the chemokines monocyte chemotactic protein-1 (CCL2/MCP-1) and stromal cell-derived factor-1 (CXCL12/SDF-1) in sympathetic ophthalmia (SO). METHODS: Five enucleated exciting eyes with a clinical diagnosis and typical histopathological findings of SO were studied by immunohistochemical techniques using a panel of monoclonal antibodies directed against gelatinase B, MCP-1, and SDF-1. In addition, a panel of monoclonal and polyclonal antibodies was used to characterize the composition of the inflammatory infiltrate. RESULTS: In all cases, the extensive uveal inflammatory infiltrate was organized as a diffuse infiltrate and as large granulomas consisting of epithelioid cells and multinucleated giant cells. CD20(+) B lymphocytes predominated in the diffuse infiltrate and CD3(+) T lymphocytes were few. The monocyte/macrophage marker CD68 was expressed in scattered inflammatory mononuclear cells and within granulomas and Dalen-Fuchs nodules. Most of the inflammatory cells were HLA-DR(+). Immunoreactivity for gelatinase B, MCP-1, and SDF-1 was observed in cells within granulomas and in scattered epithelioid cells. Immunoreactivity for MCP-1 was noted in retinal pigment epithelial cells. Endothelial cells of choriocapillaries showed weak immunoreactivity for SDF-1. CONCLUSIONS: Gelatinase B, MCP-1, and SDF-1 might have a pathogenic role in the recruitment of leucocytes into the eye in SO.

Natural post-translational modifications of chemokines.

Chemokines, adhesion molecules, cytokines and proteases regulate the extravasation of leucocytes during acute and chronic inflammation and leucocyte homing. Chemokines are produced after transcriptional activation by inflammatory mediators such as cytokines or microbial Toll-like receptor ligands and their effect depends on the expression of chemokine receptors on specific cell types. More and more evidence points towards a role for post-translational modifications in the fine-tuning of chemokine activity. Although both glycosylation and proteolytic processing of the C- and/or N-terminus of chemokines has been reported, mainly proteolytic processing of the N-terminus appears to affect the receptor specificity, chemotactic property and signalling potency of these low-molecular-mass proteins. N-terminal processing of chemokines by aminopeptidases or endoproteases may alter the receptor specificity and may result in up- or down-regulation of their chemotactic, antiviral or angiogenic activity.

Endonasal endoscopic resection of an ethmoidal solitary fibrous tumor.

Solitary fibrous tumor (SFT) is an uncommon spindle cell tumor that typically arises at the level of the pleura in adults. However, SFT has also been reported in various extrapleural sites including orbit, meninges, liver, lung, salivary glands, retroperitoneum, mediastinum. In the head and neck region, SFT has been documented in the external auditory canal, larynx, thyroid, sublingual gland, tongue, parapharyngeal space and the infratemporal fossa. The nose and the paranasal sinuses are a rare site for SFT with only 14 publications in the world literature. We present an additional case of a SFT arising at the level of the right ethmoid sinus successfully removed in one piece endoscopically and review the corresponding literature.

Chemokines in gastrointestinal disorders.

The intestine is constantly challenged by food antigens and pathogens and is therefore in need of a good working innate and adaptive immune response. Chemokines are important modulators as they assure the directed movement of immune cells within the body. In addition, chemokines play an important role in hematopoiesis, angiogenesis and tumor metastasis. This review focuses on chemokines and gastrointestinal disorders, more particularly on inflammatory bowel diseases and gastrointestinal tumors. In a first part, the current knowledge on chemokine expression in inflammatory bowel diseases is summarized. Idiopathic inflammatory bowel diseases are characterized by an uncontrolled immune response. The resulting chronic inflammation of the intestine involves massive infiltration of immune cells, causing intestinal damage by the release of cytokines and proteolytic enzymes. Chemokines are believed to be key mediators in this process of aberrant leukocyte recruitment. Chemokine expression in inflammatory bowel disease strongly correlates with the grade of disease activity. The potential therapeutic use of chemokines in gastrointestinal tumors by the use of gene therapy is also reviewed. Chemokines have therapeutic potential in anti-tumor therapy by their angiostatic effect. On the other hand, chemokines can augment the cell-mediated adaptive immune response and thereby exert anti-tumor activity. However, chemokines can passively favor escape of tumor cells by stimulating the release of tissue degrading matrix metalloproteinases and can actively promote metastasis of chemokine receptor-expressing tumor cells.