Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients.

BACKGROUND: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. RESULTS: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. CONCLUSION: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.

Using Iron L-Edge and Nitrogen K-Edge X-ray Absorption Spectroscopy to Improve the Understanding of the Electronic Structure of Iron Carbene Complexes.

Iron-centered N-heterocyclic carbene compounds have attracted much attention in recent years due to their long-lived excited states with charge transfer (CT) character. Understanding the orbital interactions between the metal and ligand orbitals is of great importance for the rational tuning of the transition metal compound properties, e.g., for future photovoltaic and photocatalytic applications. Here, we investigate a series of iron-centered N-heterocyclic carbene complexes with +2, + 3, and +4 oxidation states of the central iron ion using iron L-edge and nitrogen K-edge X-ray absorption spectroscopy (XAS). The experimental Fe L-edge XAS data were simulated and interpreted through restricted-active space (RAS) and multiplet calculations. The experimental N K-edge XAS is simulated and compared with time-dependent density functional theory (TDDFT) calculations. Through the combination of the complementary Fe L-edge and N K-edge XAS, direct probing of the complex interplay of the metal and ligand character orbitals was possible. The σ-donating and π-accepting capabilities of different ligands are compared, evaluated, and discussed. The results show how X-ray spectroscopy, together with advanced modeling, can be a powerful tool for understanding the complex interplay of metal and ligand.

Biomarkers in Contrast-Induced Acute Kidney Injury: Towards A New Perspective.

Contrast-Induced Acute Kidney Injury (CI-AKI) remains a frequent iatrogenic condition since radiological procedures using intra-vascular iodinated contrast media (CM) are being widely administered for diagnostic and therapeutic purposes. Despite the improvement of the medical healthcare system worldwide, CI-AKI is still associated with direct short-term and indirect long-term outcomes including increased morbidity and mortality, especially in patients with underlying pre-existing renal function impairment, cardiovascular disease, or diabetes that could rapidly progress into Chronic Kidney Disease. Although the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease), AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease Improving Global Outcomes) clinical criteria and recommendation guidelines are based on traditional "gold standard" biomarkers known as serum creatinine, glomerular filtration rate, and urinary output, new reliable serum and urinary biomarkers are still needed for an effective unified diagnostic strategy for AKI. Starting from previous and recent publications on the benefits and limitations of validated biomarkers responding to kidney injury, glomerular filtration, and inflammation among others, this review unravels the role of new emerging biomarkers used alone or in combination as reliable tools for early diagnosis and prognosis of CI-AKI, taking into account patients and procedures-risk factors towards a new clinical perspective.

Vision transformer assisting rheumatologists in screening for capillaroscopy changes in systemic sclerosis: an artificial intelligence model.

OBJECTIVES: The first objective of this study was to implement and assess the performance and reliability of a vision transformer (ViT)-based deep-learning model, an 'off-the-shelf' artificial intelligence solution, for identifying distinct signs of microangiopathy in nailfold capilloroscopy (NFC) images of patients with SSc. The second objective was to compare the ViT's analysis performance with that of practising rheumatologists. METHODS: NFC images of patients prospectively enrolled in our European Scleroderma Trials and Research group (EUSTAR) and Very Early Diagnosis of Systemic Sclerosis (VEDOSS) local registries were used. The primary outcome investigated was the ViT's classification performance for identifying disease-associated changes (enlarged capillaries, giant capillaries, capillary loss, microhaemorrhages) and the presence of the scleroderma pattern in these images using a cross-fold validation setting. The secondary outcome involved a comparison of the ViT's performance vs that of rheumatologists on a reliability set, consisting of a subset of 464 NFC images with majority vote-derived ground-truth labels. RESULTS: We analysed 17 126 NFC images derived from 234 EUSTAR and 55 VEDOSS patients. The ViT had good performance in identifying the various microangiopathic changes in capillaries by NFC [area under the curve (AUC) from 81.8% to 84.5%]. In the reliability set, the rheumatologists reached a higher average accuracy, as well as a better trade-off between sensitivity and specificity compared with the ViT. However, the annotators' performance was variable, and one out of four rheumatologists showed equal or lower classification measures compared with the ViT. CONCLUSIONS: The ViT is a modern, well-performing and readily available tool for assessing patterns of microangiopathy on NFC images, and it may assist rheumatologists in generating consistent and high-quality NFC reports; however, the final diagnosis of a scleroderma pattern in any individual case needs the judgement of an experienced observer.

Ultrasound measurement of optic nerve sheath diameter in a healthy adult Colombian population.

BACKGROUND: Measurement of the optic nerve sheath diameter (ONSD) provides a rapid, safe, and easy method for detecting increased intracranial pressure (ICP). However, the normal mean and upper limit values may vary according to sex, age, ethnicity, and ultrasound technique. AIM: We aimed to obtain the mean ONSD in a healthy Colombian adult population and to correlate it with demographic and anthropometric measures. METHODS: In a prospective study using a 10-13 MHz linear ultrasound probe, eye transverse diameter (ETD) and ONSD in the transverse (ONSD-TP) and sagittal planes (ONSD-SP) were measured in healthy adult volunteers in Bogota, Colombia. RESULTS: A total of 100 healthy subjects were included, with a mean age of 26,7 ± 8,3 years and 62 women. The mean ETD, ONSD-TP and ONSD-SP was 23.11 mm (95% confidence interval (CI): 22.90 mm-23.32 mm), 3.96 mm (95% CI: 3.85 mm-4.07 mm) and 4.0 mm (95% CI: 3.90 mm-4.11 mm), respectively. The ONSD in both planes ranged from 2.35 mm to 5.20 mm. There was a significant correlation between ONSD-SP and ONSD-TP (p < 0.0001) but no correlation between the ocular measures and demographic or anthropometric variables (p > 0.05). The intraclass correlation between the eyes was statistically significant. CONCLUSION: Our study shows that ultrasound-measured ONSD in healthy adults in Colombia is similar to that found worldwide. An ONSD of 5.5 mm may be considered the upper limit for healthy adults in Colombia. ONSD can be measured in either plane; there is a good correlation between the two eyes; and ONSD is not modified by demographic or anthropometric characteristics.

Obese adolescents have higher risk for severe lower extremity fractures after falling.

INTRODUCTION: Reports vary on the impact of obesity on the incidence of lower extremity fractures after a fall. We hypothesized that obese adolescents (OA) presenting after a fall have a higher risk of any and severe lower extremity fractures compared to non-OAs. METHODS: A national database was queried for adolescents (12-17 years old) after a fall. Primary outcome included lower extremity fracture. Adolescents with a body mass index (BMI) ≥ 30 (OA) were compared to adolescents with a BMI < 30 (non-OA). RESULTS: From 20,264 falls, 2523 (12.5%) included OAs. Compared to non-OAs, the rate of any lower extremity fracture was higher for OAs (51.5% vs. 30.7%, p < 0.001). This remained true for lower extremity fractures at all locations (all p < 0.05). After adjusting for sex and age, associated risk for any lower extremity fracture (OR 2.41, CI 2.22-2.63, p < 0.001) and severe lower extremity fracture (OR 1.31, CI 1.15-1.49, p < 0.001) was higher for OAs. This remained true in subset analyses of ground level falls (GLF) and falls from height (FFH) (all p < 0.05). CONCLUSIONS: Obesity significantly impacts adolescents' risk of all types of lower extremity fractures after FFH or GLF. Hence, providers should have heightened awareness for possible lower extremity fractures in OAs. LEVEL OF EVIDENCE: IV.

Risk Factors for Death and Severe Neurological Sequelae in Childhood Bacterial Meningitis.

INTRODUCTION: Acute bacterial meningitis (ABM) continues to be a challenge from a diagnostic and therapeutic point of view. Identifying severity risk factors and predictive scores may guide interventions to reduce poor outcome. METHODS: Data from a retrospective study for ABM in children admitted to the Institute of Tropical Medicine in Paraguay was analyzed. ABM was defined as positive cerebrospinal fluid culture, positive latex agglutination, or identification of microorganism by real time-polymerase chain reaction. Univariate and multivariate analyses of risk factors at hospital admission that predicted major morbidity or death during hospitalization were performed. A point-based scoring system that included variables, which were clearly different among those who passed away, was constructed. RESULTS: One hundred fourteen children hospitalized with ABM were eligible for the study. The mean age was 46 ± 57 months (range, 1-192 months). The observed mortality was 33% (38/114 patients). When a point-based scoring system was used, for score of 0 (n = 29) and 1 (n = 12), no death was observed. Among patients with a score of 2 (n = 14), 3 (n = 10 patients), 4 (n = 12 patients), and 5 (n = 13 patients), the mortality rate was 14.3%, 40%, 50%, and 53.8%, respectively. When the score was 6 or higher, the mortality rate was at least 63.6%. CONCLUSIONS: The present score accurately discriminated the probability of death in children hospitalized with ABM, and it could be a useful tool to select candidates for admission to the intensive care unit and for adjunctive therapy in clinical trials.

Role of Glucocorticoid Signaling and HDAC4 Activation in Diaphragm and Gastrocnemius Proteolytic Activity in Septic Rats.

Sepsis increases glucocorticoid and decreases IGF-1, leading to skeletal muscle wasting and cachexia. Muscle atrophy mainly takes place in locomotor muscles rather than in respiratory ones. Our study aimed to elucidate the mechanism responsible for this difference in muscle proteolysis, focusing on local inflammation and IGF-1 as well as on their glucocorticoid response and HDAC4-myogenin activation. Sepsis was induced in adult male rats by lipopolysaccharide (LPS) injection (10 mg/kg), and 24 h afterwards, rats were euthanized. LPS increased TNFα and IL-10 expression in both muscles studied, the diaphragm and gastrocnemius, whereas IL-6 and SOCS3 mRNA increased only in diaphragm. In comparison with gastrocnemius, diaphragm showed a lower increase in proteolytic marker expression (atrogin-1 and LC3b) and in LC3b protein lipidation after LPS administration. LPS increased the expression of glucocorticoid induced factors, KLF15 and REDD1, and decreased that of IGF-1 in gastrocnemius but not in the diaphragm. In addition, an increase in HDAC4 and myogenin expression was induced by LPS in gastrocnemius, but not in the diaphragm. In conclusion, the lower activation of both glucocorticoid signaling and HDAC4-myogenin pathways by sepsis can be one of the causes of lower sepsis-induced proteolysis in the diaphragm compared to gastrocnemius.

AttentionDDI: Siamese attention-based deep learning method for drug-drug interaction predictions.

BACKGROUND: Drug-drug interactions (DDIs) refer to processes triggered by the administration of two or more drugs leading to side effects beyond those observed when drugs are administered by themselves. Due to the massive number of possible drug pairs, it is nearly impossible to experimentally test all combinations and discover previously unobserved side effects. Therefore, machine learning based methods are being used to address this issue. METHODS: We propose a Siamese self-attention multi-modal neural network for DDI prediction that integrates multiple drug similarity measures that have been derived from a comparison of drug characteristics including drug targets, pathways and gene expression profiles. RESULTS: Our proposed DDI prediction model provides multiple advantages: (1) It is trained end-to-end, overcoming limitations of models composed of multiple separate steps, (2) it offers model explainability via an Attention mechanism for identifying salient input features and (3) it achieves similar or better prediction performance (AUPR scores ranging from 0.77 to 0.92) compared to state-of-the-art DDI models when tested on various benchmark datasets. Novel DDI predictions are further validated using independent data resources. CONCLUSIONS: We find that a Siamese multi-modal neural network is able to accurately predict DDIs and that an Attention mechanism, typically used in the Natural Language Processing domain, can be beneficially applied to aid in DDI model explainability.

Cryopreservation of llama semen using a combination of permeable cryoprotectants.

Semen cryopreservation is not available for massive use in South American Camelids (SACs) due to the lack of an efficient protocol and the low pregnancy rates obtained with artificial insemination (AI). The use of a single cryoprotectant (CP) is commonly used in SACs frozen semen. The objective of the study was to evaluate the combined cryoprotective capacity of two permeable CPs at different stages of the cryopreservation protocol in llama semen. Sixteen ejaculates from 4 llama males were analysed, and sperm quality was assayed in raw semen, at 5°C, after equilibration of samples with the CPs and when samples were thawed. The following CPs and combination were used: 6% glycerol (GL), 6% dimethylformamide (DMF) and the combination of both CPs: 3% GL and 3% DMF. A Kruskal-Wallis test and an experimental factorial design, considering one factor with four levels (raw semen, 6% GL, 6% DMF and GL/DMF), were used. Total sperm motility and live sperm with intact acrosomes remained unchanged after equilibration of samples (p > .05). A significant decrease in the percentage of functional membrane, motile and live sperm with intact acrosomes was observed when samples were thawed (GL, DMF and GL/DMF). Nevertheless, the cryopreservation protocols used preserved sperm DNA quality; thus, sperm chromatin condensation and DNA fragmentation were unaffected (p > .05) when GL, DMF and GL/DMF were used. To conclude, no superiority was found between the use of a single or a combination of permeable cryoprotectants to freeze llama semen.

Left ventricular longitudinal strain and strain rate measurements in paediatric patients in long-term treatment for Chagas disease.

INTRODUCTION: Previous echocardiographic studies failed to show residual alterations of heart function in paediatric patients that have received treatment for Chagas disease. While the echocardiogram is the fundamental front-line tool for evaluating heart function, the appearance of new techniques allows a more detailed analysis. We aimed to evaluate systolic and diastolic function with new techniques in a paediatric population with Chagas disease several years after treatment completion. MATERIAL AND METHODS: Echocardiograms were obtained from 84 Chagas disease patients (48 female) and 27 healthy controls. All patients had received treatment concluding on average 10 years prior to the study. The prospective analysis considered cardiac dimensions and cardiac function using two-dimensional, M-mode, Doppler and tissue Doppler imaging with emphasis on measuring longitudinal strain in the left ventricle by speckle tracking. Ejection fraction was measured with three-dimensional echocardiography. RESULTS: Patients had an age of 14.2 ± 5.7 years (6-33) at the time of evaluation. Global and segmental motility of the left ventricle was normal in all patients. Ejection fraction was 59.2 ± 6.5 and 57.4 ± 6.5% (p = 0.31) in patients and controls respectively. Left ventricular global longitudinal systolic strain was -19 ± 2.4% in patients and -19 ± 3.6% (p = 0.91) in controls. No significant differences were found in remaining systolic and diastolic function measurements. CONCLUSIONS: Paediatric patients that have received treatment for Chagas disease, evaluated with either conventional techniques or new tools, do not show significant long-term alterations of ventricular function.

Effect of Cilastatin on Cisplatin-Induced Nephrotoxicity in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy.

Cisplatin is one of the most widely used chemotherapeutic agents in oncology, although its nephrotoxicity limits application and dosage. We present the results of a clinical study on prophylaxis of cisplatin-induced nephrotoxicity in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC-cisplatin). Prophylaxis was with imipenem/cilastatin. Cilastatin is a selective inhibitor of renal dehydropeptidase I in the proximal renal tubule cells that can reduce the nephrotoxicity of cisplatin. Unfortunately, cilastatin is not currently marketed alone, and can only be administered in combination with imipenem. The study has a retrospective part that serves as a control (n = 99 patients receiving standard surgical prophylaxis) and a prospective part with imipenem/cilastatin prophylaxis corresponding to the study group (n = 85 patients). In both groups, we collected specific data on preoperative risk factors of renal damage, fluid management, hemodynamic control, and urine volume during surgery (including the hyperthermic chemotherapy perfusion), as well as data on hemodynamic and renal function during the first seven days after surgery. The main finding of the study is that cilastatin may exert a nephroprotective effect in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal cisplatin perfusion. Creatinine values remained lower than in the control group (ANOVA test, p = 0.037). This translates into easier management of these patients in the postoperative period, with significantly shorter intensive care unit (ICU) and hospital stay.

Interleukin-35 inhibits alveolar bone resorption by modulating the Th17/Treg imbalance during periodontitis.

AIM: T lymphocytes play a central role during the pathogenesis of periodontitis, and the imbalance between the pathogenic T-helper type 17 (Th17) and protective T-regulatory (Treg) lymphocytes determines the tooth-supporting alveolar bone resorption. Interleukin (IL)-35 is a novel anti-inflammatory cytokine with therapeutic properties in diseases whose pathogenesis is associated with the Th17/Treg imbalance; however, its role during periodontitis has not been established yet. This study aimed to elucidate whether IL-35 inhibits the alveolar bone resorption during periodontitis by modulating the Th17/Treg imbalance. MATERIALS AND METHODS: Mice with ligature-induced periodontitis were treated with locally or systemically administrated IL-35. As controls, periodontitis-affected mice without IL-35 treatment and non-ligated mice were used. Alveolar bone resorption was measured by micro-computed tomography and scanning electron microscopy. The Th17/Treg pattern of the immune response was analysed by qPCR, ELISA, and flow cytometry. RESULTS: IL-35 inhibited alveolar bone resorption in periodontitis mice. Besides, IL-35 induced less detection of Th17 lymphocytes and production of Th17-related cytokines, together with higher detection of Treg lymphocytes and production of Treg-related cytokines in periodontitis-affected tissues. CONCLUSION: IL-35 is beneficial in the regulation of periodontitis; particularly, IL-35 inhibited alveolar bone resorption and this inhibition was closely associated with modulation of the periodontal Th17/Treg imbalance.

Predicting the outcome of initial non-surgical endodontic procedures by periapical status and quality of root canal filling: a cohort study.

To assess the previous periapical status and the quality of root canal filling as predictors of the outcome in initial non-surgical endodontic procedures. A retrospective cohort study was designed in which the presence of a previous periapical lesion was determined radiographically. The quality of the root filling was evaluated in terms of homogeneity, taper, and apical extension. The response variable was dichotomized to success and failure. Bivariate analyzes and a mixed generalized linear model interpreted the association between the explanatory variables and the outcome of the initial non-surgical endodontic procedures. A total of 349 roots were evaluated, and a failure rate of 13.18% was established. Poor filling quality was determined in 8.3% of the roots. As a main result, the presence of a preoperative periapical lesion did not determine a significant risk to the failure of the initial treatment. Unlike, a poor quality of the obturation determined association with an unfavorable outcome like this: (1) homogeneity (OR 2.32; p = 0.0181); (2) taper (OR 5.8; p = 0.0); and, (3) extension (OR 3.41; p = 0.0). Therefore, a significant association between inadequate quality of the root filling and failure of the primary non-surgical endodontic procedures was found. Short length of filling was highly associated with failure. The presence of previous periapical lesion was not found to be a significant predictor for treatment outcomes.

Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity.

Autoimmune diseases (ADs) are a chronic and clinically heterogeneous group of diseases characterized by share common immunopathogenic mechanisms and risk factors (i.e., the autoimmune tautology), which explain the fact that one AD may coexist with others (i.e., polyautoimmunity - PolyA). In the present exploratory study, a mixed-cluster analysis of the most common autoimmune rheumatic diseases (ARDs) was done. A total of 187 consecutive women with established systemic lupus erythematosus (n = 70), rheumatoid arthritis (n = 51), systemic sclerosis (n = 35) and Sjögren's syndrome (n = 31) were included. A comprehensive clinical, autoantibody and cytokine assessment was simultaneously done. Total PolyA was registered in 142 (75.9%) patients. Six clusters were obtained, built mainly on autoantibodies: PolyA-I to -VI. The PolyA-III cluster showed the highest frequency of overt PolyA (p = 0.01), and the PolyA-I, -III, and -IV clusters exhibited the highest positivity for IL-12/23p40 (p = 0.015). These results provide new insights into the pathophysiology of PolyA and warrant prospective validation to enable development of a more accurate taxonomy of ARDs.

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease.

BACKGROUND: Parkinson's disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patient stratification. Mitochondrial function, which is impaired in and central to PD pathogenesis, may represent one such surrogate indicator. METHODS: Mitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n = 47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine-learning-based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. The effects of mitochondrial respiration on α-synuclein stress were assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions. RESULTS: Bioenergetic properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients, and the correlation is stronger with predominantly nondopaminergic signs. Bioenergetic analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients' fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors α-synuclein stress in different cellular experimental systems. Machine-learning-based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration. CONCLUSION: The suppression of mitochondrial activity in PD may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures in fibroblasts are potential peripheral biomarkers to follow disease progression. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Can we predict recurrence in WHO G1-G2 pancreatic neuroendocrine neoplasms? Results from a multi-institutional Spanish study.

INTRODUCTION: Pancreatic neuroendocrine neoplasms (PNEN) are rare tumours and well differentiated PNEN are associated with relatively indolent physiological behaviour. For this reason, only few studies have investigated those factors associated with recurrence in this group of patients. The aim of this study is to analyse whether it is possible to predict tumour recurrence in World Health Organization (WHO) 2017 G1-G2 PNEN patients. METHODS: This is a retrospective multi-institutional study. Patients submitted to pancreatic resection from 7 Spanish centres were reviewed. Only patients with WHO G1-G2 PNEN were included. Demographic and clinicopathological variables were analysed. RESULTS: Data from 137 patients were reviewed. Median age was 59.2 (25-84) years. Recurrence of disease occurred in 19 (13.9%) patients. Median DFS was 55 months. At multivariate analysis, tumour size >20 mm, lymphnode metastasis and a new tumour grade 2 incorporating Ki-67 labelling index (LI) > 5% and mitotic index (MI) > 2 were independently associated with recurrence. We developed a risk score model with these three factors. High-risk patients had a significantly lower 5-year disease-specific survival compared to low-risk patients (70% vs 100%). CONCLUSION: We propose a novel risk score for recurrence based on lymphnode metastasis, tumour size > 20 mm and a new grade 2 based on Ki-67 LI >5% and MI > 2. If 2 factors are present, patients have a higher risk for recurrence and a significantly poorer DSS, and therefore they should be closely monitored during follow-up. The role of adjuvant chemotherapy in these patients needs to be evaluated in clinical trials.

Cytokine imbalance in patients with systemic sclerosis and resilience: the key role of interleukin-6.

OBJECTIVES: Resilience, the ability to respond positively to adverse events, may be influenced by long-term stressors and autoimmune/inflammatory conditions such as systemic sclerosis (SSc). Since the immune system plays a role in the development of resilience, we aimed to evaluate the relationship between a panel of cytokines and resilience in patients with SSc. METHODS: Thirty-five consecutive women with established SSc were involved in this exploratory study. Clinical characteristics, including severity of symptoms and resilience, a panel of 15 serum cytokines and 17 autoantibodies were assessed simultaneously. Multivariate methods were used to analyse the data. RESULTS: Interleukin-6 (IL-6) levels were associated with severity of symptoms (ß=1.8395, p=0.04), and low resilience scores (ß= -0.581120, p=0.02). Furthermore, resilience was not associated with clinical manifestations nor polyautoimmunity. Cytokine levels did not significantly differ between groups based on regular physical activity. CONCLUSIONS: The results highlight the importance of IL-6 as a key mediator in the altered cytokine network of SSc.

Multirefractory primary immune thrombocytopenia; targeting the decreased sialic acid content.

Patients with multirefractory immune thrombocytopenia (ITP) have limited treatment options. Recent data suggest that specific anti-platelet antibodies may cause destruction of platelets by favoring platelet loss of sialic acid. In this multicenter study 35 patients with ITP, including 16 with multirefractory disease, were analyzed for antiplatelet-antibodies, thrombopoietin (TPO) levels, and platelet desialylation. In selected cases, responses to a novel treatment strategy using oseltamivir were tested. We found that antibodies against GPIbα were overrepresented in multirefractory patients compared to responders (n = 19). In contrast to conventional ITP patients, multirefractory patients exhibited a significant increased platelet activation state (granule secretion) and desialylation (RCA-1 binding) (p < 0.05), and a trend toward higher plasma TPO concentrations. The decreased sialic acid content seemed to be restricted to platelet glycoproteins, since other plasma proteins were not hypoglycosylated. A total of 10 patients with multirefractory ITP having remarkable loss of platelet terminal sialic acids were given oseltamivir phosphate. When the antiviral drug was combined with TPO receptor agonists (TPO-RAs) or with immunosuppressant drugs, platelet responses were observed in 66.7% of patients. All responding patients presented with antibodies reactive only against GPIbα. These findings suggest that desialylation may play a key pathogenic role in some multirefractory ITP patients, and provide diagnostic tools for the identification of such patients. Furthermore, we show that sialidase inhibitor treatment in combination with therapies that help to increase platelet production can induce sustained platelet responses in some patients with anti-GPIbα -mediated thrombocytopenia that have failed previous therapies.