Microbiopsy a first-level diagnostic test to rule out oral dysplasia or carcinoma in general dental practice.

OBJECTIVES: Diagnostic delay in oral oncology could be improved if general dentists had a reliable and easy-to-use first-level diagnostic test to rule out the presence of oral dysplasia or carcinoma. Microbiopsy has been proved to have high sensitivity and high negative predictive value in a clinical setting characterized by high prevalence of disease. Moreover, it has been proved to be easily performed by general dentists. This study aimed to determine the negative predictive value of microbiopsy in routine dental practice: a clinical setting characterized by low prevalence of disease. METHODS: Within the frame of a previous study, general dentists from the Metropolitan Area of Turin performed microbiopsy for each oral mucosal lesion detected during their practice. The clinical outcome of 129 lesions negative at microbiopsy was checked by a query performed through the database of the Piedmont Cancer Registry, covering the population of the Metropolitan Area of Turin, with particular reference to cancer involving the mouth (ICD-10:C03-06). This allowed us to define "true negative" cases and to calculate the negative predictive value of microbiopsy. RESULTS: In a mean follow-up of 7.5 years (range 7-9 years), with a dropout rate of 7.7%, no case of tumour involving the mouth was observed, thus revealing a negative predictive value approaching 100%. CONCLUSIONS: Microbiopsy represents an easy-to-use and reliable first-level test able to aid general dentists to select patients requiring an oral medicine assessment in a short time and definitely to avoid diagnostic delay in oncologically relevant oral mucosal lesions.

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort.

BACKGROUND: Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors. PATIENTS AND METHODS: Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects. RESULTS: Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor. CONCLUSION: Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.

Reliability of heart rate measures during walking before and after running maximal efforts.

Previous studies on HR recovery (HRR) measures have utilized the supine and the seated postures. However, the most common recovery mode in sport and clinical settings after running exercise is active walking. The aim of the current study was to examine the reliability of HR measures during walking (4 km · h(-1)) before and following a maximal test. Twelve endurance athletes performed an incremental running test on 2 days separated by 48 h. Absolute (coefficient of variation, CV, %) and relative [Intraclass correlation coefficient, (ICC)] reliability of time domain and non-linear measures of HR variability (HRV) from 3 min recordings, and HRR parameters over 5 min were assessed. Moderate to very high reliability was identified for most HRV indices with short-term components of time domain and non-linear HRV measures demonstrating the greatest reliability before (CV: 12-22%; ICC: 0.73-0.92) and after exercise (CV: 14-32%; ICC: 0.78-0.91). Most HRR indices and parameters of HRR kinetics demonstrated high to very high reliability with HR values at a given point and the asymptotic value of HR being the most reliable (CV: 2.5-10.6%; ICC: 0.81-0.97). These findings demonstrate these measures as reliable tools for the assessment of autonomic control of HR during walking before and after maximal efforts.

Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.

Testicular cancer in Europe and the USA: survival still rising among older patients.

BACKGROUND: Despite high curability, some testicular cancer (TC) patient groups may have increased mortality. We provide a detailed age- and histology-specific comparison of population-based relative survival of TC patients in Europe and the USA. Design Using data from 12 European cancer registries and the USA Surveillance, Epidemiology and End Results 9 database, we report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993-1997 and 2003-2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA adjusting for differences in age and histology. RESULTS: In 2003-2007, the 5-year relative survival of patients with testicular seminoma was at least 98% among those aged <50 years, survival of patients with nonseminoma remained 3%-6% units lower. Despite improvements in the relative survival of nonseminoma patients aged ≥ 50 years by 13%-18% units, survival remained markedly lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients. CONCLUSIONS: There remains little room for survival improvement among testicular seminoma patients, especially for those aged <50 years. Older TC patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients.

Weather conditions and daylight-mediated photodynamic therapy: protoporphyrin IX-weighted daylight doses measured in six geographical locations.

BACKGROUND: Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated methyl aminolaevulinate PDT (daylight-PDT) is a simple and painless treatment procedure for PDT. All daylight-PDT studies have been performed in the Nordic countries. To be able to apply these results in other parts of the world we have to compare the daily protoporphyrin IX (PpIX) light dose in other countries with the PpIX light doses found in Nordic countries. OBJECTIVES: To calculate where and when daylight-PDT of AKs was possible in six different geographical locations using ground stations measuring PpIX-weighted daylight doses. METHODS: PpIX-weighted daylight doses were measured using a dosimeter with a customer-specific photodiode with a detector sensitivity that mimics the PpIX absorption spectrum and measures in 'PpIX doses'. The dosimeters were built into ground stations that were placed in six geographical locations measuring from July to December 2008. Temperature data for each location were obtained from the internet. The maximal ultraviolet (UV) index for Copenhagen was obtained for the measuring period of the dosimeters. RESULTS: If the PpIX light dose should be above 8Jcm(-2) and the maximum temperature of the day at least 10°C, it was possible to treat patients on nearly all days until the middle of September in Reykjavik and Oslo, until the last week of October in Copenhagen and Regensburg, until the middle of November in Turin and all year in Israel. CONCLUSIONS: Where and when to perform daylight-PDT depends on the PpIX light dose and outdoor temperature. The PpIX light dose was influenced by the geographical location (latitude), weather condition and time of year. The UV index was not more suitable than temperature and weather to predict if the intensity of daylight would be sufficient for daylight-PDT.

Changes in incidence, survival and mortality of prostate cancer in Europe and the United States in the PSA era: additional diagnoses and avoided deaths.

BACKGROUND: We describe changes in prostate cancer incidence, survival and mortality and the resulting impact in additional diagnoses and avoided deaths in European areas and the United States. METHODS: Using data from 12 European cancer registries and the Surveillance, Epidemiology and End Results program, we describe changes in prostate cancer epidemiology between the beginning of the PSA era (USA: 1985-1989, Europe: 1990-1994) and 2002-2006 among patients aged 40-64, 65-74, and 75+. Additionally, we examine changes in yearly numbers of diagnoses and deaths and variation in male life expectancy. RESULTS: Incidence and survival, particularly among patients aged <75, increased dramatically, yet both remain (with few exceptions in incidence) lower in Europe than in the United States. Mortality reductions, ongoing since the mid/late 1990 s, were more consistent in the United States, had a distressingly small absolute impact among patients aged 40-64 and the largest absolute impact among those aged 75+. Overall ratios of additional diagnoses/avoided deaths varied between 3.6 and 27.6, suggesting large differences in the actual impact of prostate cancer incidence and mortality changes. Ten years of remaining life expectancy was reached between 68 and 76 years. CONCLUSION: Policies reflecting variation in population life expectancy, testing preferences, decision aids and guidelines for surveillance-based management are urgently needed.

[Nosocomial urinary tract infection in critical pediatric patients]. / Infección nosocomial del tracto urinario en niños críticos.

OBJECTIVE: To determine the incidence, etiology and risk factors of nosocomial urinary tract infections (nUTI) in a second level Pediatric Intensive Care Unit (PICU). PATIENTS AND METHODS: A prospective study of 104 patients admitted to the PICU with a length of stay of more than 48 hours was carried out over a one year period (January to December 2009) to study the incidence and risk factors of nUTI. Urine samples were collected and cultured in all patients admitted for more than 48 hours to our PICU. Those needing indwelling urinary catheters had urine samples collected upon admission and every 24 hours until catheter retrieval, while those who did not need catheters had samples collected upon admission and every 48 hours until discharge from the PICU. RESULTS: Six patients (5.8% of those admitted) were diagnosed of nUTI, with an incidence density of 5/1000 patients/day and 12.2/1000 catheterization days. Four of these were caused by E. coli (including a multiresistant strain), and two by C. albicans. Patients suffering nUTIs had significantly more relevant medical antecedents and a longer period of admittance than patients without nUTI. A statistically nonsignificant tendency towards increased infection risk was also found in younger patients and in those who needed an indwelling catheter for longer periods. CONCLUSIONS: We found a higher incidence density of catheter associated nUTI than in other reports. This at least partially could be due to the characteristics of our patients, and to the exhaustive methodology used for detection.

Mammographic breast density and characteristics of invasive breast cancer.

INTRODUCTION: Inconclusive data exist on the association between breast density and breast cancer characteristics. MATERIALS AND METHODS: We conducted a case-only study on 667 invasive breast cancers, using data from the Piedmont Cancer Registry. We applied a multivariate logistic regression model to estimate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of high breast density (Breast Imaging Reporting and Data System, BI-RADS 3-4) versus low (BI-RADS 1-2) in relation to histologic grade, pathological tumour size and lymph node status, histotype, estrogen and progesterone receptor, HER2 and Ki67 status. Histopathological data were assessed according to the American Joint Committee on Cancer (AJCC) Staging Manual guidelines. The model includes terms for age at diagnosis, education level, body mass index, reproductive factors, family history of breast cancer, smoking and diabetes. RESULTS: As regards histologic grade, compared to well differentiated tumours, the OR of high (versus low) breast density cases was 0.61 (95% CI 0.38-0.98) for moderately-poorly differentiated tumours. No other associations with hormonal and histopathological characteristics were observed. DISCUSSION: Our results indicate that low breast density is associated with moderately-poorly differentiated breast tumours.

Evidence for the involvement of KIF4 in the anterograde transport of L1-containing vesicles.

In this study we present evidence about the cellular functions of KIF4. Using subcellular fractionation techniques and immunoisolation, we have now identified a type of vesicle that associates with KIF4, an NH(2)-terminal globular motor domain kinesin-like protein. This vesicle is highly concentrated in growth cones and contains L1, a cell adhesion molecule implicated in axonal elongation. It lacks synaptic vesicle markers, receptors for neurotrophins, and membrane proteins involved in growth cone guidance. In cultured neurons, KIF4 and L1 predominantly localize to the axonal shaft and its growth cone. Suppression of KIF4 with antisense oligonucleotides results in the accumulation of L1 within the cell body and in its complete disappearance from axonal tips. In addition, KIF4 suppression prevents L1-enhanced axonal elongation. Taken collectively, our results suggest an important role for KIF4 during neuronal development, a phenomenon which may be related to the anterograde transport of L1-containing vesicles.

Life expectancy of women with lupus nephritis now approaches that of the general population.

Immunosuppressive treatment has changed the prognosis of Lupus nephritis over time, but improvement in prognosis is difficult to analyze in different historical periods, and should be better demonstrated in comparison with life expectancy of sex-and age-matched people. Long-term patient and renal survival of 90 patients diagnosed with Lupus nephritis at our center from 1968 to 2001 with a follow-up time of 14+/-8 years was retrospectively evaluated. Patient and kidney survival significantly increased over time. Multivariate analyses show that risks of patient and renal death decreased by 8% at each year of follow-up, and increased by more than 5 time in patients aged > 30 years at diagnosis. As only 14 patients were men, relative survival as compared to that of the sex- and age-matched general population of the Piedmont Region was calculated for the 76 women. Improvement in the survival of the cohort of women was seen at any time of follow-up: in particular, it was sharply lower in the first period (relative survival at 5, 10 and 15 years = 0.784, 0.665, and 0.620, respectively) and increased in the second (relative survival at 5, 10 and 15 years = 0.939, 0.921, and 0.850, respectively) nearly approaching that expected for the general population, i.e. 0.993, 0.983 and 0.967, respectively. Taken together, our data allow us to draw the conclusion that life expectancy in women with Lupus nephritis has improved over time, paralleling an improved awareness of the disease and a significant increase in steroid pulse therapy as induction/remission phase. Improvement in survival is for the first time demonstrated to cover the gap with life expectancy of the general population for women with Lupus nephritis.

Finite element simulation of the braiding process.

Braiding is one of the most common technique employed for the manufacture of fabrics and ropes. It is also commonly used to produce near-net shaped preforms for advanced fibre reinforced composites. This paper presents an explicit finite element approach to create and simulate the braiding process for the virtual manufacture of 2D braids. The process starts from the definition of an analytical function which describes the movement of the carriers on a braiding track plate. Models of idealised Maypole-type braiding machines are built and used to shape virtual yarns into braids. This procedure can be used in a parameter control fashion, to optimise or to create virtual braided structures, which can serve as input for other structural analyses. It is emphasised that multiple cylinders are required for the modelling of a multifilament yarn to achieve better correlation with the experimental results. A parametric study is presented to investigate the effect of the number of virtual cylinders to represent a real yarn and the shape of the final braid. Excellent correlation was found between the virtual models and the experimental results when comparing the braid angle and yarn width.

Improvement in relative survival of patients with vasculitis: study of 101 cases compared to the general population.

Immunosuppressive treatment has changed the prognosis of renal vasculitis over time, but improvement in prognosis is difficult to analyze in different historical periods, and can be better demonstrated by comparison with life expectancy of sex- and age-matched people. Long-term survival of 101 patients diagnosed with systemic vasculitis at our center from 1975 to 2002 was retrospectively evaluated in comparison with that of the Region's age- and sex-matched population. Patient and kidney survival significantly increased over time. Multivariate analyses showed that risks of patient and renal death decreased by 10% and 7%, respectively, at each year of follow-up, and increased by 6.3% and 5.2% for each year of age. Relative survival significantly improved over time, approaching that of the general population for cases diagnosed after 1993, mainly in women < 60 years (from 0.671 at 5-years in the first period to 0.916 in the last period), while 5-year-relative-survival was still 0.530 and 0.682 in men and women greater than 60 years, respectively. Poisson-based multinomial analyses confirmed the significant risk of the first periods of diagnosis and of dialysis in worsening of the relative survival of patients compared to that of the general population. Life expectancy in patients with renal vasculitis has improved over time, paralleling a significant increase in steroid pulse/cyclophosphamide association therapy and an earlier diagnosis due to the introduction of the ANCA test. Relative survival has considerably improved, and now approaches that expected in the general population for women, but not for men.

To accelerate cancer prevention in Europe: Challenges for cancer registries.

The availability of population-based cancer registry (CR) data is paramount in the development of modern oncology. Major contributions consisted in accurately measuring cancer burden (incidence, survival and prevalence, beside mortality), identifying and quantifying risk factors (case control and cohort studies that, in the last two decades, included gene variant assessment) and evaluating outcomes of treatments and preventive interventions, including mass screening. Cancer registration coverage of European populations progressed slowly since 1940 and is now almost 50%. Areas lacking high-quality national population-based cancer registration still exist within large countries such as France, Italy, Romania and Spain, Germany and Poland having national plans and legislation to reach complete coverage. Depending on programme ownership, history and institutional organisation, European CRs showed huge variations in the scope (research domain), size, available resources and finally exploitation of collected data. This reflects their heterogeneous origins stemming from different professional backgrounds and healthcare systems. This review discusses not only the potential for contributing to acceleration of prevention but also the coverage expansion by and innovation of CR organizations. The latter can be attained not only by more standardisation in institutional organisation and operative methodologies but also by intensification of scientific production and risk communication. The CR's agenda should focus on cancers caused by identifiable risk factor(s) that are amenable to preventive actions, including early detection; short-term priorities usually are with tobacco, and medium-term priorities are with alcohol, occupational exposures, infection-related cancers and ultraviolet-related skin cancers, while obesity-related cancers are likely to increase gradually further in the long term.

Trends in incidence of thick, thin and in situ melanoma in Europe.

BACKGROUND: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness. MATERIAL AND METHODS: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. RESULTS: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. DISCUSSION: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Theory of the deformation of aligned polyethylene.

Solitons are proposed as the agents of plastic and viscoelastic deformation in aligned polyethylene. Interactions between straight, parallel molecules are mapped rigorously onto the Frenkel-Kontorova model. It is shown that these molecular interactions distribute an applied load between molecules, with a characteristic transfer length equal to the soliton width. Load transfer leads to the introduction of tensile and compressive solitons at the chain ends to mark the onset of plasticity at a well-defined yield stress, which is much less than the theoretical pull-out stress. Interaction energies between solitons and an equation of motion for solitons are derived. The equation of motion is based on Langevin dynamics and the fluctuation-dissipation theorem and it leads to the rigorous definition of an effective mass for solitons. It forms the basis of a soliton dynamics in direct analogy to dislocation dynamics. Close parallels are drawn between solitons in aligned polymers and dislocations in crystals, including the configurational force on a soliton. The origins of the strain rate and temperature dependencies of the viscoelastic behaviour are discussed in terms of the formation energy of solitons. A failure mechanism is proposed involving soliton condensation under a tensile load.

Uses of cancer registries for public health and clinical research in Europe: Results of the European Network of Cancer Registries survey among 161 population-based cancer registries during 2010-2012.

AIM: To provide insight into cancer registration coverage, data access and use in Europe. This contributes to data and infrastructure harmonisation and will foster a more prominent role of cancer registries (CRs) within public health, clinical policy and cancer research, whether within or outside the European Research Area. METHODS: During 2010-12 an extensive survey of cancer registration practices and data use was conducted among 161 population-based CRs across Europe. Responding registries (66%) operated in 33 countries, including 23 with national coverage. RESULTS: Population-based oncological surveillance started during the 1940-50s in the northwest of Europe and from the 1970s to 1990s in other regions. The European Union (EU) protection regulations affected data access, especially in Germany and France, but less in the Netherlands or Belgium. Regular reports were produced by CRs on incidence rates (95%), survival (60%) and stage for selected tumours (80%). Evaluation of cancer control and quality of care remained modest except in a few dedicated CRs. Variables evaluated were support of clinical audits, monitoring adherence to clinical guidelines, improvement of cancer care and evaluation of mass cancer screening. Evaluation of diagnostic imaging tools was only occasional. CONCLUSION: Most population-based CRs are well equipped for strengthening cancer surveillance across Europe. Data quality and intensity of use depend on the role the cancer registry plays in the politico, oncomedical and public health setting within the country. Standard registration methodology could therefore not be translated to equivalent advances in cancer prevention and mass screening, quality of care, translational research of prognosis and survivorship across Europe. Further European collaboration remains essential to ensure access to data and comparability of the results.