Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.

PURPOSE: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. METHODS: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. RESULTS: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001). CONCLUSIONS: In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.

Tratamiento secuencial en osteoporosis. Nuevas tendencias / Sequential treatment in osteoporosis. New trends

El tratamiento para la osteoporosis suele ser largo en el tiempo, por lo que es necesario en muchas ocasiones recurrir a una estrategia secuencial de tratamiento. El clínico debe saber no solo seleccionar la mejor terapia disponible en cada situación clínica, sino también cómo discontinuar o cambiar de tratamiento en un momento determinado de la evolución de la enfermedad. En este documento presentamos de forma resumida una revisión de los mecanismos de acción y las consecuencias de la discontinuación de cada uno de los fármacos para la osteoporosis, así como qué ocurre en las diferentes secuencias de tratamiento. La discontinuación de denosumab tiene consecuencias claramente negativas para el hueso, y solo los bisfosfonatos, por tener un efecto antirresortivo residual, podrían discontinuarse durante un tiempo limitado (vacaciones terapéuticas). El cambio de un antirresortivo por otro antirresortivo con diferente mecanismo de acción es una opción que puede ser favorable en el manejo de algunos pacientes con osteoporosis. Cambiar un antirresortivo por un osteoformador puede asociarse a una pérdida inicial de densidad mineral ósea que no parece tener consecuencias negativas en la eficacia antifractura. Empezar con un tratamiento osteoformador (teriparatida o romosozumab) y cambiar posteriormente a un antirresortivo constituye la mejor secuencia de tratamiento, por lo que podría ser la opción preferente en pacientes con muy alto riesgo de fractura. (AU)

Treatment for osteoporosis is usually long term, so it is often necessary to implement a sequential treatment strategy. The clinician must know not only how to select the best available therapy in each clinical situation, but also how to discontinue or change treatment at a certain point in the evolution of the disease. Here, we briefly review the mechanisms of action and the consequences of discontinuing each of the drugs for osteoporosis, as well as what happens with the different treatment sequences. Discontinuation of denosumab has clearly negative consequences for the skeleton, and only bisphosphonates, due to its particular remaining antiresorptive effect, could be discontinued for a limited time (drug holidays). Switching from antiresorptive to another antiresorptive with a different mechanism of action is an option that may be favorable in the management of some patients with osteoporosis. Switching from antiresorptive to anabolic may be associated with an initial bone mineral density loss that does not appear to have negative consequences on antifracture efficacy. Starting with anabolic (teriparatide or romosozumab) and subsequently switching to antiresorptive is the best treatment sequence, so it could be the preferred option in patients who present a very high risk of fracture. (AU)

Quality of care in psychiatry is related to research activity.

BACKGROUND: The top biomedical research institutions have traditionally been assumed to provide better medical treatment for their patients. However, this may not necessarily be the case. Low-to-moderate negative associations between research activity and the quality-of-care provided by clinical departments have been described. We aimed to examine this relationship in the psychiatric units of the largest hospitals in Spain. METHODS: Scientific publications for 50 hospitals were retrieved from the Web of Science (2006-2015), and quality of mental healthcare data were gathered from Spanish National Health System records (2008-2014). Spearman-rank correlation analyses (adjusting for number of beds and population) were used to examine the associations between research data and quality-of-care outcomes in psychiatry. Stepwise regression models were built in order to determine the predictive value of research productivity for healthcare outcomes. RESULTS: We found a positive association between research activity indicators (i.e., number of publications, number of citations, cumulative impact factor, and institutional H-index) and better quality-of-care outcomes in psychiatry (i.e., number of readmissions, transfers, and discharges from hospital). In particular, a higher research activity predicted a lower level of readmissions for individuals with psychoses (p = 0.025; R = 0.317), explaining 8.2% of the variance when other factors were accounted for. CONCLUSIONS: Higher research activity is associated with better quality of mental healthcare in psychiatry. Our results can inform decision-making in clinical and research management settings in order to determine the most appropriate quality measures of the impact of research on the prognosis of individuals with psychiatric conditions.

Multidisciplinary expert consensus on secondary fracture prevention in Spain.

The study aimed to achieve expert consensus to optimize secondary fracture prevention in Spain. Relevant gaps in current patient management were identified. However, some aspects were considered difficult to apply. Future efforts should focus on those items with greatest divergences between importance and feasibility. PURPOSE: To establish a Spanish multidisciplinary expert consensus on secondary fracture prevention. METHODS: A two-round Delphi consensus was conducted, guided by a Scientific Committee. The 43-item study questionnaire was designed from a literature review and a subsequent multidisciplinary expert group (n = 12) discussion. The first-round questionnaire, using a 7-point Likert scale, assessed the experts' opinion of the current situation, their wish for items to happen, and their prognosis that items would be implemented within 5 years. Items for which consensus was not achieved were included in the second round. Consensus was defined as ≥ 75% agreement or ≥ 75% disagreement. A total of 102 experts from 14 scientific societies were invited to participate. RESULTS: A total of 75 (response rate 73.5%) and 69 (92.0%) experts answered the first and second Delphi rounds, respectively. Participants mean age was 51.8 years [standard deviation (SD): 10.1 years]; being 24.0% rheumatologists, 21.3% primary care physicians, 14.7% geriatricians, 8.0% internal medicine specialists, 8.0% rehabilitation physicians, and 8.0% gynecologists. Consensus was achieved for 79.1% of items (wish, 100%; prognosis, 58.1%). Effective secondary prevention strategies identified as requiring improvement included: clinical report standardization, effective hospital primary care communication (telephone/mail and case managers), health-related quality of life (HRQoL) questionnaires use, and treatment compliance monitoring (prognosis agreement 33.3%, 47.8%, 18.8%, and 55.1%, respectively). CONCLUSION: A consensus was reached by health professionals in their wish to implement strategies to optimize secondary fracture prevention; however, they considered some difficult to apply. Efforts should focus on those items with currently low application and those with greatest divergence between wish and prognosis.

Is a treat-to-target strategy in osteoporosis applicable in clinical practice? Consensus among a panel of European experts.

A panel of European experts was convened to establish consensus on a treat-to-target strategy in osteoporosis. Panellists agreed that the ultimate goals of treating osteoporosis are recovering pre-fracture functional level and reducing subsequent fracture risk; there was consensus that total hip bone mineral density is currently the most appropriate treatment target in clinical practice. INTRODUCTION: A modified Delphi approach was convened to establish consensus among European experts on best practice management for patients with fragility fractures and whether a treat-to-target (T2T) strategy is applicable in osteoporosis. METHODS: A panel of 12 clinical experts (from eight European countries) voted on 13 final statements relating to a T2T strategy for osteoporosis across three rounds of blinded, remotely conducted electronic surveys (Likert scale: 'strongly disagree', 'disagree', 'unable to answer', 'agree', 'strongly agree'). When panellists disagreed, they were asked how the statement could be adjusted to allow for a positive response, which was used to refine the statement for the following round. Consensus was defined as ≥ 75% agreement with a statement. Panellists were selected by UCB Pharma, which provided financial and logistical support. RESULTS: Consensus was reached for 13/13 statements. Panellists agreed that the most important goals for fragility fracture patients are recovery of pre-fracture functional level and reduction of subsequent fracture risk. There was also consensus that a T2T strategy is applicable to osteoporosis and that bone mineral density (BMD) is currently the most clinically appropriate target. With regard to the definition of a specific BMD treatment target and timeframes applicable to T2T in osteoporosis, no clear consensus was reached; panellists emphasised that these would need to be individually determined. CONCLUSIONS: According to a panel of European experts, the main goals of fracture management are to recover pre-fracture functional level and reduce fracture risk. Total hip BMD seems to be the most clinically appropriate treatment target within a T2T strategy.

Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures: results of the VERO clinical trial.

FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. INTRODUCTION: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. METHODS: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 µg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. RESULTS: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. CONCLUSION: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Enteritis inducida por quimioterapia: experiencia institucional y revisión bibliográfica / Chemotherapy-induced enteritis: Institutional experience and review of the literature

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Spanish consensus on treat to target for osteoporosis.

To reach a Spanish expert consensus on a treat-to-target strategy in osteoporosis, a Delphi Consensus Study has been developed. Most of the experts (59.8%) were rheumatologist with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items. Therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been defined. INTRODUCTION: The paper aims to achieve a Spanish expert consensus on a treat-to-target (T2T) strategy in osteoporosis. METHODS: A scientific committee led the project and was involved in expert panel identification and Delphi questionnaire development. Two Delphi rounds were completed. The first-round questionnaire included 24 items and assessed, using a seven-point Likert scale, the experts' wish (W) and prognosis (P) in 5 years for each topic (applicability, therapeutic objectives, patient follow-up, and possible treatment to be prescribed). Items for which there was no consensus in the first round were included in the second round. Consensus was defined as ≥75% agreement (somewhat/mostly/entirely agree) or disagreement (somewhat/mostly/entirely disagree) responses. RESULTS: Of the experts, 112 and 106 completed the first and second rounds, respectively. 59.8% were rheumatologists with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items, and was established regarding the utility of a T2T strategy to define therapeutic objectives, optimal follow-up, and therapeutic algorithm. Participants agreed on the utility of the bone mineral density (BMD) value (T-score >-2.5 SD for spine and >-2.5/-2.0 SD for femoral neck), lack of fractures, and fracture risk (FRAX) as therapeutic objectives. For measuring BMD changes, consensus was achieved on the suitability of hip and femoral neck locations. Experts agreed to consider treatment failure as when a significant BMD gain could not be achieved, or when a new fracture occurs within 2-3 years. There was consensus that all proposed therapies should achieve a therapeutic target through T2T strategy (treatments with the highest consensus scores were denosumab and teriparatide). CONCLUSION: The therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been established by a panel of experts. Some aspects nevertheless still require further analysis.

Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

Comparison of total, free and bioavailable 25-OH vitamin D determinations to evaluate its biological activity in healthy adults: the LabOscat study.

Determination of different forms of 25-OHD (total, free and bioavailable) in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency. INTRODUCTION: Determination of 25-OH vitamin D serum levels (25-OHD) constitutes the method of choice for evaluating vitamin D deficiency. However, vitamin D-binding protein (DBP) may modulate its bioavailability thereby affecting correct evaluation of 25-OHD status. We analysed the impact of the determination of 25-OHD (total, free and bioavailable) on the evaluation its biologic activity (estimated by serum PTH determination) in healthy young women. METHODS: 173 premenopausal women (aged 35-45 yrs.) were included. We analysed serum values of total 25-OHD (25-OHDT), DBP, albumin, PTH and bone formation (PINP,OC) and resorption (NTx,CTx) markers. Free(25-OHDF) and bioavailable (25-OHDB) serum 25-OHD levels were estimated by DBP and albumin determinations and also directly by ELISA (25-OHDF-2). We analysed threshold PTH values for the different forms of 25-OHD and the correlations and differences according to 25-OHDT levels <20 ng/ml. RESULTS: 62% of subjects had 25-OHD values <20 ng/ml and also had significantly lower 25-OHDF and 25-OHDB values, with no significant differences in bone markers and PTH values. The PTH threshold value was similar for all forms of 25-OHD (∼70 pg/ml). Women with PTH values >70 had lower 25-OHDT (15.4 ± 1.4 vs. 18.3 ± 2.7, p < 0.05) and 25OHDB values (1.7 ± 0.2 vs. 2.2 ± 0.09, p < 0.05). The different forms of 25OHD were significantly intercorrelated, with marginal correlations between PTH and 25-OHDT (r = -0.136, p = 0.082). CONCLUSIONS: Determination of different forms of 25-OHD in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency.

Percepción de los profesionales médicos respecto la adherencia terapéutica de los pacientes con osteoporosis / Medical professionals’ perceptions regarding therapeutic adherence in patients with osteoporosis

Introducción: La adherencia al tratamiento oral del paciente con osteoporosis es baja, con un alto porcentaje de abandonos durante el primer año. La consecuencia más notable es la falta de respuesta terapéutica. Objetivo: Conocer la percepción de los facultativos involucrados en el abordaje del paciente osteoporótico en relación a la adherencia terapéutica de estos pacientes. Material y métodos: Estudio descriptivo transversal realizado mediante una encuesta de opinión dirigida a médicos de Atención Primaria y Atención Especializada involucrados en el tratamiento de la osteoporosis. Los participantes fueron seleccionados mediante muestreo intencionado. Resultados: El cuestionario fue contestado por 235 especialistas de Reumatología (54,5%), Traumatología (10,6%) y Atención Primaria (18,7%). En opinión del 43,8% de los encuestados, más de un 25% de los pacientes olvida alguna vez tomar el tratamiento. Según el 34,9%, más de 75% de los pacientes están concienciados con el tratamiento. Los efectos secundarios y la complejidad de la administración son las razones mayoritarias que propician un cambio de medicación, con una importancia media de 7,94±2,06 y 6±2,01 puntos respectivamente en una escala 0-10. Conclusiones: Los facultativos percibieron baja adherencia terapéutica asociada fundamentalmente a los efectos secundarios, a la polimedicación y a la falta de comunicación entre profesionales. Espaciar la dosificación y el uso de formas galénicas solubles podrían ser opciones para facilitar la adherencia del paciente al tratamiento con bisfosfonatos orales. Mejorar la educación sobre la importancia de la enfermedad o aumentar el seguimiento del paciente serían algunos de los aspectos que podrían favorecer la adherencia terapéutica (AU)

Introduction: Adherence to oral treatment of patients with osteoporosis is low, with a high dropout rate in the first year. The most noteworthy result is the lack of therapeutic response. Objective: To ascertain the perception of physicians working with osteoporotic patients regarding adherence of these patients. Methods: Cross-sectional study conducted by opinion survey aimed at primary care physicians and specialists involved in osteoporosis treatment. Participants were selected by purposive sampling. Results: The questionnaire was answered by 235 specialists encompassing rheumatology (54.5%), orthopedics (10.6%) and primary care (18.7%). In 43.8% of participants, more than 25% of patients sometimes forget to take their treatment. According to 34.9%, more than 75% of patients are aware of treatment. Side effects and management complexity are the majority reasons that lead to a change in medication, mean value of 7.94±2.06 6±2.01 points respectively on a 0-10 scale. Conclusions: Overall, medical specialists attributed low adherence to side effects, polypharmacy and lack of communication between professionals. Dosage and space use of soluble dosage forms may be options to facilitate patient adherence to treatment with oral bisphosphonates. Improved education concerning the importance of the disease or increased patient monitoring could foster adherence (AU)

Lung cancer and other second neoplasms after treatment of Hodgkin lymphoma

Purpose. To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors. Methods. We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012. Results. 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4-20.7, p < 0.001). Radiotherapy (RT) doses applied were higher in the SN group with an increased risk of LC (HR: 4.0 95 % CI 1.1-11.6, p = 0.010) and other SN (HR: 3.3 95 % CI 1.6-6.7 p = 0.001) with doses higher than 42 Gy. No association was found between alkylating agents and development of SN. In LC, the most frequent histology was adenocarcinoma with an elapsed time after HL of 13.2 years in early stages and 21.3 in advanced (p = 0.02). Median OS after a diagnosis of LC was 12.6 months ranging from 5.9 (in cases presenting due to symptoms) to 49.1 (incidentally diagnosed cases) (p = 0.005). Conclusions. RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up (AU)

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Lung cancer and other second neoplasms after treatment of Hodgkin lymphoma.

PURPOSE: To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors. METHODS: We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012. RESULTS: 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4-20.7, p < 0.001). Radiotherapy (RT) doses applied were higher in the SN group with an increased risk of LC (HR: 4.0 95 % CI 1.1-11.6, p = 0.010) and other SN (HR: 3.3 95 % CI 1.6-6.7 p = 0.001) with doses higher than 42 Gy. No association was found between alkylating agents and development of SN. In LC, the most frequent histology was adenocarcinoma with an elapsed time after HL of 13.2 years in early stages and 21.3 in advanced (p = 0.02). Median OS after a diagnosis of LC was 12.6 months ranging from 5.9 (in cases presenting due to symptoms) to 49.1 (incidentally diagnosed cases) (p = 0.005). CONCLUSIONS: RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up.

Fracture experience among participants from the FROCAT study: what thresholding is appropriate using the FRAX tool?

OBJECTIVE: To perform an external validation of FRAX algorithm thresholds for reporting level of risk of fracture in Spanish women (low < 5%; intermediate ≥ 5% and < 7.5%; high ≥ 7.5%) taken from a prospective cohort "FRIDEX". METHODS: A retrospective study of 1090 women aged ≥ 40 and ≤ 90 years old obtained from the general population (FROCAT cohort). FRAX was calculated with data registered in 2002. All fractures were validated in 2012. Sensitivity analysis was performed. RESULTS: When analyzing the cohort (884) excluding current or past anti osteoporotic medication (AOM), using our nominated thresholds, among the 621 (70.2%) women at low risk of fracture, 5.2% [CI95%: 3.4-7.6] sustained a fragility fracture; among the 99 at intermediate risk, 12.1% [6.4-20.2]; and among the 164 defined as high risk, 15.9% [10.6-24.2]. Sensitivity analysis against model risk stratification FRIDEX of FRAX Spain shows no significant difference. By including 206 women with AOM, the sensitivity analysis shows no difference in the group of intermediate and high risk and minimal differences in the low risk group. CONCLUSIONS: Our findings support and validate the use of FRIDEX thresholds of FRAX when discussing the risk of fracture and the initiation of therapy with patients.

Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity?

Background: Treatment of metastatic colorectal cancer (mCRC) is generally based on genetic testing performed in primary tumor biopsies, but whether the genomic status of primary tumors is identical to that of metastases is not well known. We compared the gene expression profiles of formalin-fixed paraffin-embedded (FFPE) biopsies of colorectal primary tumors and matched liver metastases. Patients and methods: We compared the expression of 18 genes in FFPE CRC tumors and their matched liver metastases from 32 patients. The expression of each gene in CRC primary tumors and their matched liver metastases was tested using Student’s t test for paired samples. Pairwise correlations of each gene in the primary tumors and matched liver metastases were evaluated by Pearson’s correlation coefficient. Results: The expression of six genes was significantly different in primary tumors compared with their matched liver metastases [CXCR4 (p < 0.001), THBS1 (p = 0.007), MMP 9 (p = 0.048), GST Pi (p = 0.050), TYMP(p = 0.042) and DPYD (p < 0.001)]. For the remaining genes, where no significant differences were observed, only SMAD4 (r s = 0.447, p = 0.010), ERCC1 (r s = 0.423, p = 0.016) and VEGF A (r s = 0.453, p = 0.009) showed significant correlation in expression between the two tissues. Therefore, we only detected similar gene expression levels between the tumor and the metastases in these three markers. Conclusions: We only found similar gene expression levels between the tumor and the metastases in three genes (SMAD4, ERCC1, and VEGF A). However, our study could not assess whether the differences in gene expression were secondary to tumoral heterogeneity or to molecular changes induced by previous chemotherapy (AU)

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SMAD4 and TS expression might predict the risk of recurrence after resection of colorectal liver metastases

Purpose. Colorectal liver metastases (CLM) have significant molecular heterogeneity, which contributes to the risk of recurrence following surgery. Most of the traditional scores intended to predict recurrence is based on clinicopathological variables and it is unclear whether incorporating molecular biomarkers might improve our assessment of the risk of recurrence. Our aim was to determine if molecular biomarkers might be associated with the risk of recurrence after surgery of CLM. Patients and methods. A total of 121 patients diagnosed with colorectal cancer (CRC) with resected liver metastases were included. The role of several clinicopathological variables to predict patient’s outcome after resection of liver metastases was analyzed. Eighteen genes related to CRC pathogenesis were also included in the analyses. Univariate and multivariate stepwise Cox regression analyses were performed to identify factors associated with recurrence and the risk of death. Results. Eight prognostic factors for progression-free survival and nine factors for overall survival were identified in the univariate analyses. After adjusting for other risk factors, only the expression of two molecular factors was associated with the risk of recurrence: TS (HR 0.631, 95 % CI 0.422–0.944) and SMAD4 (HR 1.680, 95 % CI 1.047–2.695). None of the variables was significantly associated with the risk of death in the multivariate analyses. Conclusions. The prognostic significance of most traditional clinicopathological variables might be insufficient to define patients at risk for recurrence after liver metastases resection. Molecular biomarkers might improve the identification of patients with higher risk of recurrence (AU)

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Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity?

BACKGROUND: Treatment of metastatic colorectal cancer (mCRC) is generally based on genetic testing performed in primary tumor biopsies, but whether the genomic status of primary tumors is identical to that of metastases is not well known. We compared the gene expression profiles of formalin-fixed paraffin-embedded (FFPE) biopsies of colorectal primary tumors and matched liver metastases. PATIENTS AND METHODS: We compared the expression of 18 genes in FFPE CRC tumors and their matched liver metastases from 32 patients. The expression of each gene in CRC primary tumors and their matched liver metastases was tested using Student's t test for paired samples. Pairwise correlations of each gene in the primary tumors and matched liver metastases were evaluated by Pearson's correlation coefficient. RESULTS: The expression of six genes was significantly different in primary tumors compared with their matched liver metastases [CXCR4 (p < 0.001), THBS1 (p = 0.007), MMP 9 (p = 0.048), GST Pi (p = 0.050), TYMP (p = 0.042) and DPYD (p < 0.001)]. For the remaining genes, where no significant differences were observed, only SMAD4 (r s = 0.447, p = 0.010), ERCC1 (r s = 0.423, p = 0.016) and VEGF A (r s = 0.453, p = 0.009) showed significant correlation in expression between the two tissues. Therefore, we only detected similar gene expression levels between the tumor and the metastases in these three markers. CONCLUSIONS: We only found similar gene expression levels between the tumor and the metastases in three genes (SMAD4, ERCC1, and VEGF A). However, our study could not assess whether the differences in gene expression were secondary to tumoral heterogeneity or to molecular changes induced by previous chemotherapy.

SMAD4 and TS expression might predict the risk of recurrence after resection of colorectal liver metastases.

PURPOSE: Colorectal liver metastases (CLM) have significant molecular heterogeneity, which contributes to the risk of recurrence following surgery. Most of the traditional scores intended to predict recurrence is based on clinicopathological variables and it is unclear whether incorporating molecular biomarkers might improve our assessment of the risk of recurrence. Our aim was to determine if molecular biomarkers might be associated with the risk of recurrence after surgery of CLM. PATIENTS AND METHODS: A total of 121 patients diagnosed with colorectal cancer (CRC) with resected liver metastases were included. The role of several clinicopathological variables to predict patient's outcome after resection of liver metastases was analyzed. Eighteen genes related to CRC pathogenesis were also included in the analyses. Univariate and multivariate stepwise Cox regression analyses were performed to identify factors associated with recurrence and the risk of death. RESULTS: Eight prognostic factors for progression-free survival and nine factors for overall survival were identified in the univariate analyses. After adjusting for other risk factors, only the expression of two molecular factors was associated with the risk of recurrence: TS (HR 0.631, 95 % CI 0.422-0.944) and SMAD4 (HR 1.680, 95 % CI 1.047-2.695). None of the variables was significantly associated with the risk of death in the multivariate analyses. CONCLUSIONS: The prognostic significance of most traditional clinicopathological variables might be insufficient to define patients at risk for recurrence after liver metastases resection. Molecular biomarkers might improve the identification of patients with higher risk of recurrence.