Endometrial cancer (EC) is the sixth deadliest cancer in women. The depth of myometrial invasion is one of the most important prognostic factors, being directly associated with tumor recurrence and ...mortality. In this study, ALCAM, a previously described marker of EC recurrence, was studied by immunohistochemistry at the superficial and the invasive tumor areas from 116 EC patients with different degree of myometrial invasion and related to a set of relevant epithelial and mesenchymal markers. ALCAM expression presented a heterogeneous functionality depending on its localization, it correlated with epithelial markers (E-cadherin/β-catenin) at the superficial area, and with mesenchymal markers at the invasive front (COX-2, SNAIL, ETV5, and MMP-9). At the invasive front, ALCAM-negativity was an independent marker of myometrial invasion. This negativity, together with an increase of soluble ALCAM in uterine aspirates from patients with an invasive EC, and its positive correlation with MMP-9 levels, suggested that ALCAM shedding by MMP-9 occurs at the invasive front.
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models of invasive EC were generated by ETV5-overexpression. In those, we demonstrated that ALCAM shedding was related to a more invasive pattern and that full-ALCAM recovery reverted most of the ETV5-cells mesenchymal abilities, partially through a p-ERK dependent-manner.
Chronic kidney disease (CKD) is known to be associated with several co-occurring conditions. We aimed at exploring multimorbidity patterns associated with CKD, as well as the impact of physical ...performance and CKD severity on them in a population of older outpatients.
Our series consisted of 2252 patients enrolled in the Screening of CKD among Older People across Europe multicenter observational study. Hypertension, stroke, transient ischemic attack, cancer, hip fracture, osteoporosis, Parkinson's disease, asthma, chronic obstructive pulmonary disease, congestive heart failure, angina, myocardial infarction, atrial fibrillation, anemia, CKD (defined as GFR < 60, < 45 or < 30 ml/min/1.73 m
), cognitive impairment, depression, hearing impairment and vision impairment were included in the analyses. Physical performance was assessed by the Short Physical Performance Battery (SPPB) and used as stratification variable. Pairs of co-occurring diseases were analyzed by logistic regression. Patterns of multimorbidity were investigated by hierarchical cluster analysis.
CKD was among the most frequently observed conditions and it was rarely observed without any other co-occurring disease. CKD was significantly associated with hypertension, anemia, heart failure, atrial fibrillation, myocardial infarction and hip fracture. When stratifying by SPPB, CKD was also significantly associated with vision impairment in SPPB = 5-8 group, and hearing impairment in SPPB = 0-4 group. Cluster analysis individuated two main clusters, one including CKD, hypertension and sensory impairments, and the second including all other conditions. Stratifying by SPPB, CKD contribute to a cluster including diabetes, anemia, osteoporosis, hypertension and sensory impairments in the SPPB = 0-4 group. When defining CKD as eGFR< 45 or 30 ml/min/1.73 m
, the strength of the association of CKD with hypertension, sensory impairments, osteoporosis, anemia and CHF increased together with CKD severity in pairs analysis. Severe CKD (eGFR< 30 ml/min/1.73 m
) contributed to a wide cluster including cardiovascular, respiratory and neurologic diseases, as well as osteoporosis, hip fracture and cancer.
CKD and its severity may contribute significantly to specific multimorbidity patterns, at least based on the cluster analysis. Physical performance as assessed by SPPB may be associated with not negligible changes in both co-occurring pairs and multimorbidity clusters.
The SCOPE study is registered at clinicaltrials.gov ( NCT02691546 ).
Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, ...HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.
•There is a significant overlap between the clinical characteristics and molecular profiles of CNL and aCML.•CNL and aCML can be classified as a single entity.
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Chronic neutrophilic ...leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio HR = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.
The aim of the HISPANIAS (HyperperfusIon Syndrome Post-carotid ANgIoplasty And Stenting) study was to define CHS rates and develop a clinical predictive model for cerebral hyperperfusion syndrome ...(CHS) after carotid artery stenting (CAS).
CHS is a severe complication following CAS. The presence of clinical manifestations is estimated on the basis of retrospective reviews and is still uncertain.
The HISPANIAS study was a national prospective multicenter study with 14 recruiting hospitals. CHS was classified as mild (headache only) and moderate-severe (seizure, impaired level of consciousness, or development of focal neurological signs).
A total of 757 CAS procedures were performed. CHS occurred in 22 (2.9%) patients, in which 16 (2.1%) had moderate-severe CHS and 6 (0.8%) had mild CHS (only headache). The rate of hemorrhages was 0.7% and was associated with high mortality (20%). Pre-operative predictors of moderate-severe CHS in multivariate analysis were female sex (odds ratio OR: 3.24; 95% confidence interval CI: 1.11 to 9.47; p = 0.03), older patients (OR: 1.09; 95% CI: 1.01 to 1.17; p = 0.02), left carotid artery treated (OR: 4.13; 95% CI: 1.11 to 15.40; p = 0.03), and chronic renal failure (OR: 6.29; 95% CI: 1.75 to 22.57; p = 0.005). The area under the curve of this clinical and radiological model was 0.86 (95% CI: 0.81 to 0.92; p = 0.001).
The rate of CHS in the HISPANIAS study was 2.9%, with moderate-severe CHS of 2.1%. CHS was independently associated with female sex, older age, history of chronic kidney disease, and a treated left carotid artery. Although further investigations are needed, the authors propose a model to identify high-risk patients and develop strategies to decrease CHS morbidity and mortality in the future.
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There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR ...expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1–2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1–30%. Sensitivity was highest for the cutoff values of 80–90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0–10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9–83.3%); 20–80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0–93.9%); and 90–100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8–100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0–10%), intermediate-risk (20–80%), and low-risk (90–100%) group.
•Estrogen receptors (ERs) and progesterone receptor (PRs) are prognosticators in endometrial cancer.•However, the optimal cutoff for ER and PR expression is unclear.•Three ER/PR subgroups with distinct clinical outcome were identified.•Cases with 0–10% of ER/PR expression had adverse outcomes, and cases with 90–100% of ER/PR expression had favorable outcomes.•We propose classification as per the 0–10%, 20–80%, and 90–100% subgroups.
Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a ...strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas.
The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated.
In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs.
The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.
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•Cemiplimab monotherapy was evaluated in pretreated patients with advanced NSCLC.•Cemiplimab showed substantial antitumor activity, with durable responses observed.•The majority of ...TEAEs observed with cemiplimab treatment were Grades 1–2.•No unexpected safety signals were observed.•Cemiplimab is a promising therapy option for patients with pretreated advanced NSCLC.
Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort.
Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab.
Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50–82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1–4). Median duration of follow-up was 7.0 months (range: 1.0–18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7–49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2–72.8 %).
Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.
Objective
To describe health‐related quality of life (HRQOL) and physical function in patients with early axial spondyloarthritis (SpA) and to assess their associations with disease activity and ...radiographic damage.
Methods
This was a cross‐sectional study drawing upon baseline data of axial SpA patients (Assessment of SpondyloArthritis international Society criteria) from the ESPERANZA cohort. Linear regression analyses were used to evaluate the associations between disease activity and radiographic damage (spine and sacroiliac joints) with HRQOL, physical function, and spinal mobility.
Results
In total, 259 patients were included. The mean ± SD age was 32.2 ± 6.9 years, disease duration was 13.3 ± 6.8 months, Ankylosing Spondylitis Quality of Life score was 5.9 ± 4.8, Bath Ankylosing Spondylitis Functional Index score was 2.4 ± 2.3, Bath Ankylosing Spondylitis Metrology Index score was 1.4 ± 1.3, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was 3.8 ± 2.3, C‐reactive protein (CRP) level was 9.7 ± 13.2 mg/liter, and Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI‐s) score was 1.7 ± 1.6. HRQOL was mainly associated with disease activity on univariate analysis (β values for BASDAI 0.646, patient global visual analog scale VAS 0.641, night back pain VAS 0.598, physician VAS 0.560, and CRP level 0.275; P < 0.01 for all), whereas the association with radiographic damage was weaker (standardized β for BASRI‐s 0.142; P < 0.05). On multivariate models, HRQOL only remained significantly associated with disease activity (standardized β for BASDAI 0.330; P < 0.01, and physician VAS 0.205 and night back pain VAS 0.210; P = 0.01). Similarly, physical function was associated with disease activity and radiographic damage on univariate analysis, but only with disease activity (BASDAI β 0.466; P < 0.01) on multivariate analysis. However, spinal mobility was associated with radiographic damage in both univariate and multivariate analyses.
Conclusion
Patients with axial SpA already have impaired quality of life and physical function, albeit mildly, at the beginning of their disease course. Both outcomes are mainly associated with disease activity in these patients.
► Preferential Action Plan stands out among the measures implemented in Spain to reduce occupational injuries. ► Preferential Action Plans have been effective in the prevention of occupational ...injuries. ► This is an important opportunity for the worldwide sharing of good practices in prevention of occupational injuries.
The objective was to evaluate the effectiveness of an occupational injury prevention program, known as the Preferential Action Plan (PAP), focused on companies with high incidence rates of occupational injuries. We studied 1189 companies in the industrial, construction and services sectors between 1999 and 2007 in the Valencia region (Spain). Our sample included 507,262 workers, among whom 44,250 non-fatal occupational injuries with at least a workday lost were registered. Companies included in a PAP program were divided into three intervention groups, according to the year that each company entered into a PAP (2000, 2001, and 2002). We calculated annual percentage change in incidence rates of occupational injuries for companies with a PAP and for those without a PAP (comparison group), and trends in the incidence rates of occupational injuries were compared between each intervention group and the comparison group. The results showed that the trend in the occupational injury rate declined 12%, 14% and 11% annually for the 2000, 2001, and 2002 intervention groups respectively, and around 5% for the comparison group. The differences in intervention and comparison group trends were found to be statistically significant. This pattern is observed by company size and activity sector, length of sick leave, and type of injury. According to these results, the use of PAPs in companies with high incidence rates of occupational injuries seems to be effective in the prevention of occupational injuries.
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