2-years retrospective observational case-control study on survival and marginal bone loss of implants in patients with hereditary coagulopathies.

BACKGROUND: Evaluating 2-years implant loss and marginal bone loss in patients with hereditary coagulopathies, comparing with a healthy control group. MATERIAL AND METHODS: 37 implants in 13 patients (17 haemophilia A, 20 Von-Willebrand disease) versus 26 implants in 13 healthy patients. Data measured through Lagervall-Jansson index (after surgery, at prosthetic loading, at 2 years). STATISTICS: Chi-square, Haberman's, ANOVA, Mann-Whitney-U. Significance p<0.05. RESULTS: Haemorrhagic accidents in 2 coagulopathies patients (non-statistical differences). Hereditary coagulopathies patients suffered more hepatitis (p<0.05), HIV (p<0.05) and less previous periodontitis (p<0.01). Non-statistical differences in marginal bone loss among groups. 2 implants were lost in the hereditary coagulopathies and none in the control group (non-statistical differences). Hereditary coagulopathies patients had longer (p<0.001), and narrower implants (p<0.05) placed. 43.2% external prosthetic connection in hereditary coagulopathies patients (p<0.001); change of prosthetic platform more frequent in control group (p<0.05). 2 implants lost: external connection (p<0.05). Survival rate 96.8% (hereditary coagulopathies 94.6%, control group 100%). CONCLUSIONS: Implant and marginal bone loss at 2 years is similar in patients with hereditary coagulopathies and control group. Precautions should be taken on the treatment for hereditary coagulopathies patients, through prior haematological protocol. Implant loss only occurred in in a patient with Von-Willebrand´s disease.

Reproducibilidad de parámetros radiográficos para determinar el éxito quirúrgico de fracturas de radio distal / Reliability of radiographic parameters to determine the surgical success in distal radius fractures

Resumen: Introducción: las fracturas del radio distal son las más comunes en extremidades superiores. Estandarizar las mediciones radiográficas para su abordaje quirúrgico es importante. Este estudio midió la reproducibilidad intra/interobservador de parámetros radiográficos asociados al éxito quirúrgico en estas fracturas. Material y métodos: diseño transversal retrospectivo con datos secundarios de expedientes clínicos. Se evaluaron radiografías de 112 fracturas en planos posteroanterior y lateral por dos traumatólogos estandarizados en toma de mediciones para calcular cinco parámetros indicativos de éxito postquirúrgico: altura radial, inclinación radial, inclinación volar, varianza cubital y escalón articular. La reproducibilidad de distancias y ángulos se evaluó con el método de Bland-Altman calculando: diferencia media entre mediciones, rango a ± 2 DE y proporción de mediciones fuera de ± 2 DE. El éxito postquirúrgico se comparó en pacientes con/sin obesidad según la media de las dos mediciones de cada evaluador. Resultados: el evaluador 1 tuvo la mayor diferencia intraobservador en altura radial (0.16 mm) y la mayor proporción fuera de ± 2 DE en varianza cubital (8.1%); el evaluador 2 tuvo la mayor diferencia en inclinación volar (1.92o) y la mayor proporción en inclinación radial (10.7%). La mayor diferencia interobservador fue en varianza cubital (1.02 mm) y la mayor proporción fuera de ± 2 DE en altura radial (5.4%). La inclinación radial tuvo la mayor diferencia (1.41o) con 4.5% de mediciones fuera de ± 2 DE. La varianza cubital y la inclinación volar tuvieron la mayor diferencia de éxito postquirúrgico entre evaluadores, sobre todo en pacientes con obesidad. Conclusión: mejorar la calidad radiográfica y estandarizar las mediciones resulta en indicadores más reproducibles.

Abstract: Introduction: distal radius fractures are the most common in upper extremities. Therefore, it is important to standardize radiographic measures for their surgical approach. This study assessed the intra/interobserver reproducibility of radiographic parameters associated with surgical success of distal radius fractures. Material and methods: retrospective cross-sectional design of secondary data extracted from clinical records. Posteroanterior and lateral X-rays of 112 distal radius fractures were assessed by two trauma specialists standardized in the measurements required to compute five parameters indicative of postoperative success: radial height, radial inclination, volar tilt, ulnar variance, and articular stepoff. The reproducibility of distances and angles was evaluated using the Bland-Altman method, calculating the mean of the difference between measurements, the range at ± 2 SD, and the proportion of measurements outside ± 2 SD. Postoperative success was also compared between patients with and without obesity according to the mean of the two measures made by each evaluator. Results: evaluator 1 had the largest intra-observer difference in radial height (0.16 mm) and the largest proportion outside ± 2 SD in ulnar variance (8.1%); evaluator 2 had the largest difference in volar tilt (1.92o) and the highest proportion in radial inclination (10.7%). The largest inter-observer difference was for ulnar variance (1.02 mm) and the largest proportion outside ± 2 SD. for radial height (5.4%). Radial tilt had the largest difference (1.41o) with 4.5% of measurements outside ± 2 SD. Ulnar variance and volar tilt had the largest difference in postoperative success between evaluators, especially in patients with obesity. Conclusion: improving the radiographic quality and standardizing the measurements results in more reproducible indicators.

[Reliability of radiographic parameters to determine the surgical success in distal radius fractures]. / Reproducibilidad de parámetros radiográficos para determinar el éxito quirúrgico de fracturas de radio distal.

INTRODUCTION: distal radius fractures are the most common in upper extremities. Therefore, it is important to standardize radiographic measures for their surgical approach. This study assessed the intra/interobserver reproducibility of radiographic parameters associated with surgical success of distal radius fractures. MATERIAL AND METHODS: retrospective cross-sectional design of secondary data extracted from clinical records. Posteroanterior and lateral X-rays of 112 distal radius fractures were assessed by two trauma specialists standardized in the measurements required to compute five parameters indicative of postoperative success: radial height, radial inclination, volar tilt, ulnar variance, and articular stepoff. The reproducibility of distances and angles was evaluated using the Bland-Altman method, calculating the mean of the difference between measurements, the range at ± 2 SD, and the proportion of measurements outside ± 2 SD. Postoperative success was also compared between patients with and without obesity according to the mean of the two measures made by each evaluator. RESULTS: evaluator 1 had the largest intra-observer difference in radial height (0.16 mm) and the largest proportion outside ± 2 SD in ulnar variance (8.1%); evaluator 2 had the largest difference in volar tilt (1.92o) and the highest proportion in radial inclination (10.7%). The largest inter-observer difference was for ulnar variance (1.02 mm) and the largest proportion outside ± 2 SD. for radial height (5.4%). Radial tilt had the largest difference (1.41o) with 4.5% of measurements outside ± 2 SD. Ulnar variance and volar tilt had the largest difference in postoperative success between evaluators, especially in patients with obesity. CONCLUSION: improving the radiographic quality and standardizing the measurements results in more reproducible indicators.

INTRODUCCIÓN: las fracturas del radio distal son las más comunes en extremidades superiores. Estandarizar las mediciones radiográficas para su abordaje quirúrgico es importante. Este estudio midió la reproducibilidad intra/interobservador de parámetros radiográficos asociados al éxito quirúrgico en estas fracturas. MATERIAL Y MÉTODOS: diseño transversal retrospectivo con datos secundarios de expedientes clínicos. Se evaluaron radiografías de 112 fracturas en planos posteroanterior y lateral por dos traumatólogos estandarizados en toma de mediciones para calcular cinco parámetros indicativos de éxito postquirúrgico: altura radial, inclinación radial, inclinación volar, varianza cubital y escalón articular. La reproducibilidad de distancias y ángulos se evaluó con el método de Bland-Altman calculando: diferencia media entre mediciones, rango a ± 2 DE y proporción de mediciones fuera de ± 2 DE. El éxito postquirúrgico se comparó en pacientes con/sin obesidad según la media de las dos mediciones de cada evaluador. RESULTADOS: el evaluador 1 tuvo la mayor diferencia intraobservador en altura radial (0.16 mm) y la mayor proporción fuera de ± 2 DE en varianza cubital (8.1%); el evaluador 2 tuvo la mayor diferencia en inclinación volar (1.92o) y la mayor proporción en inclinación radial (10.7%). La mayor diferencia interobservador fue en varianza cubital (1.02 mm) y la mayor proporción fuera de ± 2 DE en altura radial (5.4%). La inclinación radial tuvo la mayor diferencia (1.41o) con 4.5% de mediciones fuera de ± 2 DE. La varianza cubital y la inclinación volar tuvieron la mayor diferencia de éxito postquirúrgico entre evaluadores, sobre todo en pacientes con obesidad. CONCLUSIÓN: mejorar la calidad radiográfica y estandarizar las mediciones resulta en indicadores más reproducibles.

Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

E-Cadherin gene expression in oral cancer: Clinical and prospective data.

BACKGROUND: Low protein expression of E-cadherin in oral squamous cell carcinoma (OSCC) has been associated with clinical and histopathological traits such as metastases, recurrence, low survival and poor tumor differentiation, and it is considered a high-risk marker of malignancy. However, it is still unknown whether low expression of E-cadherin is also present at the mRNA level in OSCC cases. OBJECTIVE: The aim of this study was to compare E-cadherin mRNA expression in OSCC patients and controls and to correlate the expression with clinical and prospective characteristics. MATERIAL AND METHODS: Forty patients and 40 controls were enrolled. E-cadherin mRNA expression was evaluated by quantitative real-time polymerase chain reaction using TaqMan probes. RESULTS: E-cadherin mRNA expression was significantly decreased in OSCC patients compared to that of controls (p<0.001). Whereas no significant association between clinical parameters and E-cadherin expression levels was observed, we noted lower E-cadherin expression levels in patients with positive lymph node metastasis. CONCLUSIONS: E-cadherin mRNA expression was markedly diminished in OSCC, in agreement with previous results that examined E-cadherin expression at the protein level. E-cadherin is downregulated in the early clinical stages of OSCC, and its mRNA levels do not change significantly in the advanced stages, suggesting that there is limited usefulness of this parameter for predicting disease progression.

Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients.

BACKGROUND: Chronic spontaneous urticaria (CSU) is defined as spontaneous occurrence of wheals and/or angioedema for ≥6 weeks. Omalizumab is a monoclonal anti-IgE antibody effective in refractory CSU, but its mechanism of action and markers predictive of response remain not completely defined. OBJECTIVES: To correlate baseline levels of two proposed biomarkers, total IgE (bIgE) and d-dimer (bd-dimer), and clinical parameters to omalizumab response and to relapses after drug withdrawal. METHODS: In this retrospective Italian multicentre study, clinical data were collected in 470 CSU patients, and bIgE and bd-dimer were measured in 340 and 342 patients, respectively. Disease activity was determined by Urticaria Activity Score 7 (UAS7) at week 1 and 12 after omalizumab starting. Relapses were evaluated during a 2- and 3-month interval after a first and a second course of treatment, respectively. RESULTS: bIgE correlated to a good response to omalizumab since levels were significantly higher in responders than non-responders (P = 0.0002). Conversely, bd-dimer did not correlate to response. There was no correlation between both bIgE and d-dimer and either first or second relapse. Disease duration was significantly longer in patients who experienced either first or second relapse (P < 0.0001 and P = 0.0105, respectively), while baseline UAS7 correlated only to first relapse (P = 0.0023). CONCLUSIONS: Our study confirms bIgE as a reliable biomarker predicting response to omalizumab in CSU, while it does not support the usefulness of bd-dimer unlike previous findings. CSU duration before omalizumab and baseline UAS7 may be clinical markers of relapse risk.

Current model systems for the study of preeclampsia.

Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the values of blood pressure, urine protein concentrations, symptomatology, and onset of disease there is a wide range of phenotypes, from mild forms developing predominantly at the end of pregnancy to severe forms developing in the early stage of pregnancy. In the worst cases severe forms of PE could lead to systemic endothelial dysfunction, eclampsia, and maternal and/or fetal death. Worldwide the fetal morbidity and mortality related to PE is calculated to be around 8% of the total pregnancies. PE still being an enigma regarding its etiology and pathophysiology, in general a deficient trophoblast invasion during placentation at first stage of pregnancy, in combination with maternal conditions are accepted as a cause of endothelial dysfunction, inflammatory alterations and appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in vivo, and in silico models have been used to evaluate the PE pathophysiology as well as to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This review focuses on the most common models used for the study of PE, including those related to placental development, abnormal trophoblast invasion, uteroplacental ischemia, angiogenesis, oxygen deregulation, and immune response to maternal-fetal interactions. The advances in mathematical and computational modeling of metabolic network behavior, gene prioritization, the protein-protein interaction network, the genetics of PE, and the PE prediction/classification are discussed. Finally, the potential of these models to enable understanding of PE pathogenesis and to evaluate new preventative and therapeutic approaches in the management of PE are also highlighted. Impact statement This review is important to the field of preeclampsia (PE), because it provides a description of the principal in vitro, in vivo, and in silico models developed for the study of its principal aspects, and to test emerging therapies or biomarkers predicting the syndrome before their evaluation in clinical trials. Despite the current advance, the field still lacking of new methods and original modeling approaches that leads to new knowledge about pathophysiology. The part of in silico models described in this review has not been considered in the previous reports.

Favourable prognostic role of histological regression in stage III positive sentinel lymph node melanoma patients.

BACKGROUND: Sentinel lymph node (SLN)-positive melanoma patients are a heterogeneous group of patients with survival rates ranging from ∼20 to over 80%. No data are reported concerning the role of histological regression on survival in stage III melanoma. METHODS: The study included 365 patients with positive SLN from two distinct hospitals. The model was developed on patients from 'AOU Città della Salute e della Scienza di Torino', and externally validated on patients from IRCCS of Candiolo. Survival analyses were carried out according to the presence of regression and adjusted for all other prognostic factors. RESULTS: Among patients followed at 'AOU Città della Salute e della Scienza di Torino' (n=264), the median follow-up time to death or censoring (whatever two events occurred earlier) was 2.7 years since diagnosis (interquartile range: 1.3-5.8). In all, 79 patients died from melanoma and 11 from other causes. Histological regression (n=43) was associated with a better prognosis (sub-HR=0.34, CI 0.12-0.92), whereas the other factors above showed an inverse association. In the external validation, the concordance index was 0.97 at 1 year and decreased to 0.66 at 3 years and to 0.59 at 5 years. Adding histological regression in the prognostic model increased the discriminative ability to 0.75 at 3 years and to 0.62 at 5 years. Finally, using a cutoff of 20% for the risk of death led to a net re-classification improvement of 15 and 11% at 3 and 5 years after diagnosis, respectively. CONCLUSIONS: Histological regression could lead to an improvement in prognostic prediction in patients with stage III-positive SLN melanoma.

Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis.

The prognostic significance of histological regression in primary melanoma has been debated for many years. We aim to review the evidence to see how histological regression may affect prognosis. A systematic review was performed by searching in MEDLINE, Scopus and the Cochrane Library from 1 January 1966 to 1 August 2015. All studies reporting hazard ratios or data on survival and histological regression were included. Primary random-effects meta-analyses were used to summarize outcome measures. Heterogeneity was assessed using the χ2 -test and I2 -statistic. To assess the potential bias of small studies we used funnel plots and the Begg and Mazumdar adjusted rank correlation method. Summaries of survival outcomes were measured as hazard ratios or relative risk of death at 5 years according to the presence of histological regression of primary melanoma. In total, 183 articles were reviewed out of 1876 retrieved. Ten studies comprising 8557 patients were included. Patients with histological regression had a lower relative risk of death (0·77, 95% confidence interval 0·61-0·97) than those without. Examination of the funnel plot did not provide evidence of publication bias. The results showed that histological regression is a protective factor for survival.

Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution.

PURPOSE: Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. METHODS: 52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment. RESULTS: During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 ± 28 months. Thyroid disorders occurred 45.1 ± 20.8 and 151 ± 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. CONCLUSIONS: Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.

Patients with advanced oral squamous cell carcinoma have high levels of soluble E-cadherin in the saliva.

BACKGROUND: The objective of this study was to assess the potential clinical value of the concentration of soluble salivary E-cadherin (sE-cadherin) compared with the clinical value of the presence of membranous E-cadherin (mE-cadherin) in oral squamous cell carcinoma tumor tissues. MATERIAL AND METHODS: Data regarding patient demographics, clinical stage, saliva and tumor tissue samples were collected. The saliva was analyzed for sE-cadherin protein levels and was compared to the mE-cadherin immunohistochemical expression levels in tumor tissues, which were assessed via the HercepTest® method. Patients without cancer were included in the study as a control group for comparisons of the sE-cadherin levels. RESULTS: sE-cadherin levels in the saliva of patients without cancer were lower than those in patients with cancer, and the difference was statistically significant (p=0.031). Low mE-cadherin expression was statistically significantly associated with lymph node positivity (p=0.015) and advanced clinical stage (p=0.001). The inverse relationship between mE-cadherin and sE-cadherin was significant in terms of lymph node positivity (p=0.014) and advanced clinical stage (p=0.037). CONCLUSIONS: The results suggest that sE-cadherin levels are significantly increased in patients with oral cancer and that its low expression within the membrane as well as the progression of the disease appear to be inversely associated with levels of sE-cadherin in the saliva.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.