Developing Cardio-Oncology Programs in the New Era: Beyond Ventricular Dysfunction Due to Cancer Treatments.

Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but could also be secondary to the anticancer treatments. With the goal of offering a multidisciplinary approach to guaranteeing optimal cancer therapy and the early detection of related cardiac diseases, and in light of the recent ESC Cardio-Oncology Guideline recommendations, we developed a Cardio-Oncology unit devoted to the prevention and management of these specific complications. This document brings together important aspects to consider for the development and organization of a Cardio-Oncology program through our own experience and the current evidence.

Development of IFNß-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis.

IFNß (recombinant interferon Beta) has been widely used for the treatment of Multiple sclerosis for the last four decades. Despite the human origin of the IFNß sequence, IFNß is immunogenic, and unwanted immune responses in IFNß-treated patients may compromise its efficacy and safety in the clinic. In this study, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of IFNß-1a. Two de-immunized versions of IFNß-1a were produced in CHO cells and designated as IFNß-1a(VAR1) and IFNß-1a(VAR2). First, the secondary and tertiary protein structures were analyzed by circular dichroism spectroscopy. Then, the variants were also tested for functionality. While IFNß-1a(VAR2) showed similar in vitro antiviral activity to the original protein, IFNß-1a(VAR1) exhibited 40% more biological potency. Finally, in vivo assays using HLA-DR transgenic mice revealed that the de-immunized variants showed a markedly reduced immunogenicity when compared to the originator.

Apraxia severa por atrapamiento del nervio radial en el brazo: "síndrome de Lotem". Presentación de un caso / Severe apraxia due to entrapment of the radial nerve in the arm: "Lotem syndrome". Case report

Se presenta el caso de un hombre de 57 años que consulta por parálisis alta del nervio radial, con dolor y prueba de Tinel positiva en la cara lateral del brazo dominante, de inicio súbito, luego de grandes esfuerzos musculares repetitivos, sin mejoría clínica al tercer mes de evolución. Se realizó un tratamiento quirúrgico descompresivo. El paciente tuvo una rápida recuperación a partir del séptimo día, y remisión completa a los 25 días de la cirugía. Conclusión: El atrapamiento del nervio radial en el brazo es un cuadro poco frecuente. Según los estudios publicados, la evolución clínica es variada, pero si no hay remisión o la evolución de la parálisis no es favorable en 3 meses, creemos que la cirugía es el tratamiento de elección. Nivel de Evidencia: IV

We present the case of a 57-year-old male patient who consulted for high radial nerve palsy, with pain and positive Tinel test on the lateral side of the dominant arm, of sudden onset after great repetitive muscular efforts, without clinical improvement after three months of evolution. A decompressive surgical treatment was performed, presenting a rapid recovery since the 7th day and full recovery after 25 postoperative days. Conclusion: The entrapment of the radial nerve in the arm is a rare pathology and its clinical presentation may vary. We consider that in the face of no remission or favorable evolution of paralysis within the first three months of conservative treatment, surgery should be performed. Level of Evidence: IV

Clinical Profile and Prognosis of a Real-World Cohort of Patients With Moderate or Severe Cancer Therapy-Induced Cardiac Dysfunction.

Introduction and Objectives: Cancer therapy-related cardiac dysfunction (CTRCD) is a common cause of cancer treatment withdrawal, related to the poor outcomes. The cardiac-specific treatment could recover the left ventricular ejection fraction (LVEF). We analyzed the clinical profile and prognosis of patients with CTRCD in a real-world scenario. Methods: A retrospective study that include all the cancer patients diagnosed with CTRCD, defined as LVEF < 50%. We analyzed the cardiac and oncologic treatments, the predictors of mortality and LVEF recovery, hospital admission, and the causes of mortality (cardiovascular (CV), non-CV, and cancer-related). Results: We included 113 patients (82.3% women, age 49.2 ± 12.1 years). Breast cancer (72.6%) and anthracyclines (72.6%) were the most frequent cancer and treatment. Meantime to CTRCD was 8 months, with mean LVEF of 39.4 ± 9.2%. At diagnosis, 27.4% of the patients were asymptomatic. Cardiac-specific treatment was started in 66.4% of patients, with LVEF recovery-rate of 54.8%. Higher LVEF at the time of CTRCD, shorter time from cancer treatment to diagnosis of CTRCD, and younger age were the predictors of LVEF recovery. The hospitalization rate was 20.4% (8.8% linked to heart failure). Treatment with trastuzumab and lower LVEF at diagnosis of CTRCD were the predictors of mortality. Thirty point nine percent of patients died during the 26 months follow-up. The non-CV causes and cancer-related were more frequent than CV ones. Conclusions: Cardiac-specific treatment achieves LVEF recovery in more than half of the patients. LVEF at the diagnosis of CTRCD, age, and time from the cancer treatment initiation to CTRCD were the predictors of LVEF recovery. The CV-related deaths were less frequent than the non-CV ones. Trastuzumab treatment and LVEF at the time of CTRCD were the predictors of mortality.

Resultados funcionales y radiográficos de la prótesis reversa y la reinserción del troquíter en pacientes con fracturas de húmero proximal / Functional and radiologic outcomes of reverse shoulder arthroplasty and greater tuberosity reattachment in proximal humerus fractures

Objetivo: Comunicar los resultados funcionales y radiográficos de pacientes tratados con prótesis reversa por fracturas complejas. El objetivo secundario fue determinar la relación entre rangos de movilidad y puntaje ASES con la evolución radiográfica del troquíter. Materiales y Métodos: Se incluyeron 16 pacientes >65 años, tratados con prótesis reversa y reinserción del troquíter, entre 2013 y 2017, operados antes de las 4 semanas del trauma y con un seguimiento mínimo de 2 años. Se consignaron el puntaje ASES y el rango de movilidad activa. En las radiografías, se evaluaron la posición y la consolidación del troquíter, y se registraron las complicaciones y su tratamiento. Resultados: La media de la edad fue 74.5 años (RIC 66-78.5), 11 (69%) eran mujeres. Once fracturas (69%) eran a 4 fragmentos y 5, luxofracturas a 4 fragmentos. La media entre el trauma y la cirugía fue 9.4 días y el seguimiento, 29.5 meses. En 9 casos (56%), el troquíter presentó consolidación. Rotación interna: 5 pacientes alcanzaron la región glútea con el pulgar; 4, la vértebra T12; 4, la vértebra L3; 3, la T7. Las medianas de rotación externa y flexión anterior fueron 30° (RIC 17,5-40) y 100° (RIC 87,5-160). El puntaje ASES promedio fue 78,3 (RIC 63,3-87,4). No hubo una asociación estadísticamente significativa entre la evolución del troquíter y la flexión anterior y el puntaje (p = 0,24 y 0,52, respectivamente). Conclusión: La prótesis reversa en fracturas agudas con reinserción de las tuberosidades puede llevar a buenos resultados funcionales. No se encontró relación entre la consolidación del troquíter y el puntaje ASES. Nivel de Evidencia: IV

Objective: To report functional and radiologic outcomes of reverse shoulder arthroplasty (RSA) in patients with complex proximal humeral fractures. A second objective was to assess the relation between the greater tuberosity healing and the range of motion (ROM) and the American Shoulder and Elbow Surgeons (ASES) score. Materials and Methods: Sixteen patients treated between 2013 and 2017, older than 65 years old, operated before 4 weeks after the trauma, and with a minimum of 2-year follow-up were included. ASES scores and active ROMs were recorded. Greater tuberosity and the prosthesis position and healing were radiologically evaluated, and the complications and treatment were recorded. Results: The median age was of 74.5 years (IQR 66-78.5), 11 patients were females (69%). According to Neer classification, 11 cases were four-part fractures and 5 were four-part fracture-dislocations. The average time between trauma and surgery was 9.4 days, and the average follow-up was of 29.5 months. The greater tuberosity was healed in 9 cases (56%). Internal rotation: 5 patients (31.25%) were able to reach up with their thumbs to gluteal level, 4 (25%) to T12, 3 (18.75%) to T7, and 4 (25%) to L3. The medians for external rotation and forward flexion were 30° (IQR 17.5°-40°) and 100° (IQR 87.5°-160°). The average ASES score was of 78.3 (IQR 63.3-87.4). There was no significant statistical relation between greater tuberosity healing and forward flexion or ASES score (P=0.24 and P=0.52, respectively). Conclusion: The use of reverse prostheses for complex fractures with greater tuberosity reattachment could lead to good functional outcomes, low complication rates and reoperations. There was no significant statistical relation between ASES score and greater tuberosity healing or failure to heal. Level of Evidence: IV

Iron Deficiency: Impact on Functional Capacity and Quality of Life in Heart Failure with Preserved Ejection Fraction.

The effects of iron deficiency (ID) have been widely studied in heart failure (HF) with reduced ejection fraction. On the other hand, studies in HF with preserved ejection fraction (HFpEF) are few and have included small numbers of participants. The aim of this study was to assess the role that ID plays in functional capacity and quality of life (QoL) in HFpEF while comparing several iron-related biomarkers to be used as potential predictors. ID was defined as ferritin <100 ng/mL or transferrin saturation <20%. Submaximal exercise capacity, measured by the 6-min walking test (6MWT), and QoL, assessed by the Minnesotta Living with Heart Failure Questionnaire (MLHFQ), were compared between iron deficient patients and patients with normal iron status. A total of 447 HFpEF patients were included in the present cross-sectional study, and ID prevalence was 73%. Patients with ID performed worse in the 6MWT compared to patients with normal iron status (ID 271 ± 94 m vs. non-ID 310 ± 108 m, p < 0.01). They also scored higher in the MLHFQ, denoting worse QoL (ID 49 ± 22 vs. non-ID 43 ± 23, p = 0.01). Regarding iron metabolism biomarkers, serum soluble transferrin receptor (sTfR) was the strongest independent predictor of functional capacity (ß = -63, p < 0.0001, R2 0.39) and QoL (ß = 7.95, p < 0.0001, R2 0.14) in multivariate models. This study postulates that ID is associated with worse functional capacity and QoL in HFpEF as well, and that sTfR is the best iron-related biomarker to predict both. Our study also suggests that the effects of ID could differ among HFpEF patients by left ventricular ejection fraction.

P2Y12 inhibitors in acute coronary syndrome patients with renal dysfunction: an analysis from the RENAMI and BleeMACS projects.

AIMS: The aim of the present study was to establish the safety and efficacy profile of prasugrel and ticagrelor in real-life acute coronary syndrome (ACS) patients with renal dysfunction. METHODS AND RESULTS: All consecutive patients from RENAMI (REgistry of New Antiplatelets in patients with Myocardial Infarction) and BLEEMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registries were stratified according to estimated glomerular filtration rate (eGFR) lower or greater than 60 mL/min/1.73 m2. Death and myocardial infarction (MI) were the primary efficacy endpoints. Major bleedings (MBs), defined as Bleeding Academic Research Consortium bleeding types 3 to 5, constituted the safety endpoint. A total of 19 255 patients were enrolled. Mean age was 63 ± 12; 14 892 (77.3%) were males. A total of 2490 (12.9%) patients had chronic kidney disease (CKD), defined as eGFR <60 mL/min/1.73 m2. Mean follow-up was 13 ± 5 months. Mortality was significantly higher in CKD patients (9.4% vs. 2.6%, P < 0.0001), as well as the incidence of reinfarction (5.8% vs. 2.9%, P < 0.0001) and MB (5.7% vs. 3%, P < 0.0001). At Cox multivariable analysis, potent P2Y12 inhibitors significantly reduced the mortality rate [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.54-0.96; P = 0.006] and the risk of reinfarction (HR 0.53, 95% CI 0.30-0.95; P = 0.033) in CKD patients as compared to clopidogrel. The reduction of risk of reinfarction was confirmed in patients with preserved renal function. Potent P2Y12 inhibitors did not increase the risk of MB in CKD patients (HR 1.00, 95% CI 0.59-1.68; P = 0.985). CONCLUSION: In ACS patients with CKD, prasugrel and ticagrelor are associated with lower risk of death and recurrent MI without increasing the risk of MB.

Avance tendinoso no convencional para lesiones en las zonas I y II de Verdan. Nueva técnica quirúrgica / Non-conventional tendon advancement for injuries in Verdan zones I and II. A new surgical technique

Objetivo: Presentar una nueva técnica quirúrgica y los resultados clínicos comparativos de pacientes con roturas de tenorrafia primaria o lesiones crónicas del flexor profundo en las zonas I y II de Verdan, tratados con avance tendinoso no convencional. Ma-teriales y Métodos: Se incluyó a pacientes >18 años, con antecedente de lesiones en las zonas I y II de Verdan y un seguimiento mínimo de 36 meses. La serie estaba formada por 13 pacientes (edad promedio 29 años) que fueron divididos en dos grupos según el tipo de lesión (7 con roturas de tenorrafia primaria y 6 con lesiones crónicas del flexor profundo) y la técnica quirúrgica utilizada (alargamiento en Z más sutura término-terminal y sutura lateral del tendón alargado a un flexor vecino indemne en la zona V, respectivamente). Se empleó la Clasificación de Strickland para la evaluación. Resultados: El seguimiento promedio fue de 51 meses. El intervalo promedio entre la lesión y la cirugía fue de 11.7 semanas. Según la Clasificación de Strickland, 8 pa-cientes tuvieron resultados excelentes; 4, buenos y uno, pobre. El avance tendinoso promedio fue de 20,5 mm en ambos grupos.Conclusiones: El avance tendinoso no convencional para lesiones en las zonas I y II de Verdan, sea en roturas de tenorrafia primaria o lesiones crónicas del flexor profundo, resultó un tratamiento reproducible y eficaz. Nivel de Evidencia: III

Objective: To report a new surgical technique and the comparative clinical outcomes in patients with primary tenorrhaphy rupture or chronic flexor digitorum profundus (FDP) injuries in Verdan zones I and II, treated with non-conventional tendon advancement. Materials and Methods: The study population consisted of 13 patients over 18 years (averaging 29 years) who had had injuries in Verdan zones I and II and at least a 36-month follow-up. Patients were divided into two groups according to injury type (7 cases of primary tenorrhaphy rupture and 6 cases of chronic FDP injuries) and surgical technique (Z-plasty lengthening plus end-to-end suture or lateral suture to an adjacent undamaged FDP tendon at zone-V level, respectively). The results were evaluated according to Strickland's scoring system. Results: The average follow-up was 51 months. Time period between injury and surgery averaged 11.7 weeks (range, 2-24 weeks). Strickland scoring system results: excellent in 8 patients, good in 4 patients, and poor in 1 patient. Study average tendon advancement was 20.5mm. Conclusions: Non-conventional tendon advancement for primary tenorrhaphy ruptures or chronic FDP injuries in Verdan zones I and II proved to be a reproducible and effective treatment. Level of evidence: III

Association Between Norepinephrine Levels and Abnormal Iron Status in Patients With Chronic Heart Failure: Is Iron Deficiency More Than a Comorbidity?

Background Mechanisms underlying iron homeostasis dysregulation in patients with chronic heart failure remain unsettled. In cardiomyocyte models, norepinephrine may lead to intracellular iron depletion, but the potential association between catecholamines (sympathetic activation markers) and iron metabolism biomarkers in chronic heart failure is unknown. Methods and Results In this cross-sectional analysis, we studied the association between plasma norepinephrine levels and serum iron status biomarkers indicating iron storage (ferritin), iron transport (transferrin saturation), and iron demand (soluble transferrin receptor) in a prospective cohort of 742 chronic heart failure patients (mean age, 72±11 years; 56% male). Impaired iron status was defined as ferritin <100 µg/L or transferrin saturation <20%. Impaired iron status was observed in 69% of patients. In multivariate models, greater norepinephrine levels were associated with impaired iron transport (transferrin saturation <20%, odds ratio=2.28; 95% CI [1.19-4.35]; P=0.013), but not with impaired iron storage (ferritin <100 µg/L, odds ratio=1.25; 95% CI [0.73-2.16]; P=0.415). Norepinephrine was a significant predictor of increased iron demand (soluble transferrin receptor, standardized ß-coefficient=0.12; P=0.006) and low transferrin saturation (standardized ß-coefficient=-0.12; P=0.003). However, norepinephrine levels were not associated with iron or ferritin levels ( P>0.05). Adjusted norepinephrine marginal means were significantly higher in patients with impaired iron status compared with those with normal iron status (528 pg/mL [505-551] versus 482 pg/mL [448-518], respectively; P=0.038). Conclusions In chronic heart failure patients, increased sympathetic activation estimated with norepinephrine levels is associated with impaired iron status and, particularly, dysregulation of biomarkers suggesting impaired iron transport and increased iron demand. Whether the relationship between norepinephrine and iron metabolism is bidirectional and entails causality need to be elucidated in future research.

Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: The BleeMACS score.

BACKGROUND: Accurate 1-year bleeding risk estimation after hospital discharge for acute coronary syndrome (ACS) may help clinicians guide the type and duration of antithrombotic therapy. Currently there are no predictive models for this purpose. The aim of this study was to derive and validate a simple clinical tool for bedside risk estimation of 1-year post-discharge serious bleeding in ACS patients. METHODS: The risk score was derived and internally validated in the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registry, an observational international registry involving 15,401 patients surviving admission for ACS and undergoing percutaneous coronary intervention (PCI) from 2003 to 2014, engaging 15 hospitals from 10 countries located in America, Europe and Asia. External validation was conducted in the SWEDEHEART population, with 96,239 ACS patients underwent PCI and 93,150 without PCI. RESULTS: Seven independent predictors of bleeding were identified and included in the BleeMACS score: age, hypertension, vascular disease, history of bleeding, malignancy, creatinine and hemoglobin. The BleeMACS risk score exhibited a C-statistic value of 0.71 (95% CI 0.68-0.74) in the derivation cohort and 0.72 (95% CI 0.67-0.76) in the internal validation sample. In the SWEDEHEART external validation cohort, the C-statistic was 0.65 (95% CI 0.64-0.66) for PCI patients and 0.63 (95% CI 0.62-0.64) for non-PCI patients. The calibration was excellent in the derivation and validation cohorts. CONCLUSIONS: The BleeMACS bleeding risk score is a simple tool useful for identifying those ACS patients at higher risk of serious 1-year post-discharge bleeding. ClinicalTrials.govIdentifier: NCT02466854.

Prevalence and outcome of patients with cancer and acute coronary syndrome undergoing percutaneous coronary intervention: a BleeMACS substudy.

BACKGROUND: The prevalence and outcome of patients with cancer that experience acute coronary syndrome (ACS) have to be determined. METHODS AND RESULTS: The BleeMACS project is a multicentre observational registry enrolling patients with acute coronary syndrome undergoing percutaneous coronary intervention worldwide in 15 hospitals. The primary endpoint was a composite event of death and re-infarction after one year of follow-up. Bleedings were the secondary endpoint. 15,401 patients were enrolled, 926 (6.4%) in the cancer group and 14,475 (93.6%) in the group of patients without cancer. Patients with cancer were older (70.8±10.3 vs. 62.8±12.1 years, P<0.001) with more severe comorbidities and presented more frequently with non-ST-segment elevation myocardial infarction compared with patients without cancer. After one year, patients with cancer more often experienced the composite endpoint (15.2% vs. 5.3%, P<0.001) and bleedings (6.5% vs. 3%, P<0.001). At multiple regression analysis the presence of cancer was the strongest independent predictor for the primary endpoint (hazard ratio (HR) 2.1, 1.8-2.5, P<0.001) and bleedings (HR 1.5, 1.1-2.1, P=0.015). Despite patients with cancer generally being undertreated, beta-blockers (relative risk (RR) 0.6, 0.4-0.9, P=0.05), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR 0.5, 0.3-0.8, P=0.02), statins (RR 0.3, 0.2-0.5, P<0.001) and dual antiplatelet therapy (RR 0.5, 0.3-0.9, P=0.05) were shown to be protective factors, while proton pump inhibitors (RR 1, 0.6-1.5, P=0.9) were neutral. CONCLUSION: Cancer has a non-negligible prevalence in patients with acute coronary syndrome undergoing percutaneous coronary intervention, with a major risk of cardiovascular events and bleedings. Moreover, these patients are often undertreated from clinical despite medical therapy seems to be protective. Registration:The BleeMACS project (NCT02466854).

Optimal Medical Therapy in Patients with Malignancy Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome: a BleeMACS Sub-Study.

OBJECTIVE: Our objective was to define the most appropriate treatment for acute coronary syndrome (ACS) in patients with malignancy. METHODS AND RESULTS: The BleeMACS project is a worldwide multicenter observational prospective registry in 16 hospitals enrolling patients with ACS undergoing percutaneous coronary intervention. Primary endpoints were death, re-infarction, and major adverse cardiac events (MACE; composite of death and re-infarction) after 1 year of follow-up. The secondary endpoint was bleeding events during follow-up. We performed sub-study analyses according to whether ß-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, or proton pump inhibitors (PPIs) were prescribed at discharge. We also calculated the propensity score for optimal medical therapy (OMT; combination of BB, ACEI/ARB, and statins). The study included 926 patients. According to the multivariate analysis, ACEIs/ARBs (hazard ratio [HR] 0.58, 95 % confidence interval [CI] 0.36-1.94; p = 0.03) and statins (HR 0.37, 95 % CI 0.23-0.61; p < 0.01) reduced the risk of MACE, while the effects of BBs (HR 0.85, 95 % CI 0.55-1.32; p = 0.48) and PPIs (HR 1.33, 95 % CI 0.83-2.12; p = 0.23) were not significant. OMT was prescribed at discharge in 300 (32.4 %) patients; after propensity score analysis, OMT showed a significant reduction in death (3 % vs. 12.5 %, HR 0.21, 95 % CI 0.1-0.4; log-rank p < 0.001) and MACE (6.7 vs. 15.2 %, log-rank p = 0.01). CONCLUSION: In patients with ACS and malignancy, OMT reduces the risk of adverse events at 1 year; in particular, ACEIs/ARBs and statins were the most protective drugs. (Clinical trials identifier: NCT02466854).

Fracturas del humero proximal: analisis comparativo de resultados con placas de bloqueo angular fijo y poliaxial / Proximal humeral fractures: comparative results with fixed-angle and polyaxial locking plates

Introducción: No existe consenso en la elección de los implantes pero, sin duda, la aparición de las placas conbloqueo angular fijo y luego variable o poliaxial constituye un hito en el tratamiento de las fracturas del húmero proximal. El objetivo de este estudio es la evaluación comparativa de los resultados funcionales obtenidos con dos tipos de bloqueo cefálico. Materiales y métodos: Se evaluaron, en forma retrospectiva, 29 pacientes divididos en dos grupos: uno comprendió 17 pacientes (bloqueo fijo Philos, AxSos, LCP) y otro, 12 pacientes (bloqueo poliaxial Numelock), que fueron clasificados según los criterios de Neer. Se usó el puntaje de Constant y radiografías a los 3 y los 6 meses. En todos los casos se usó abordaje deltopectoral. Resultados: En el grupo 1 hubo consolidación radiológica en 16 casos y 1 seudoartrosis que fue reoperada. El promedio de Constant fue de 77,37 puntos a los 6 meses. En el grupo 2 la consolidación fue de 100 por ciento, hubo 1 caso de desplazamiento al varo y 1 caso de necrosis aséptica que representó el puntaje más bajo (50). El promedio de Constant fue de 75 puntos. Conclusiones: En ambos grupos el principal progreso en el puntaje a los 6 meses fue a expensas de la movilidad. El resultado en los dos grupos se encuentra en el rango bueno, comparable con las casuísticas internacionales. No se encontraron diferencias clínicas significativas.

Mallet finger: procedimiento de elección

Se presentan 27 casos de mallet finger operados entre 1991 y 1995. Veinte de ellos no habían recibido tratamiento quirúrgico previo. Fueron tratados por un procedimiento simple con el que no hemos tenido recidivas. Describimos, además, la técnica que empleamos en siete casos inveterados que habían sido operados en una o más oportunidades