Trends in the evolution of the elasmobranch melanocortin-2 receptor: Insights from structure/function studies on the activation of whale shark Mc2r.

To understand the mechanism for activation of the melanocortin-2 receptor (Mc2r) of the elasmobranch, Rhincodon typus (whale shark; ws), wsmc2r was co-expressed with wsmrap1 in CHO cells, and the transfected cells were stimulated with alanine-substituted analogs of ACTH(1-24) at the "message" motif (H6F7R8W9) and the "address" motif (K15K16R17R18P19). Complete alanine substitution of the H6F7R8W9 motif blocked activation, whereas single alanine substitution at this motif indicated the following hierarchy of position importance for activation: W9 > R8, and substitution at F7 and H6 had no effect on activation. The same analysis was done on a representative bony vertebrate Mc2r ortholog (Amia calva; bowfin; bf) and the order of position importance for activation was W9 > R8 = F7, (alanine substitution at H6 was negligible). Complete alanine substitution at the K15K16R17R18P19 motif resulted in distinct outcomes for wsMc2r and bfMc2r. For bfMc2r, this analog blocked activation-an outcome typical for bony vertebrate Mc2r orthologs. For wsMc2r, this analog resulted in a shift in sensitivity to stimulation of the analog as compared to ACTH(1-24) by two orders of magnitude, but the dose response curve did reach saturation. To evaluate whether the EC2 domain of wsMc2r plays a role in activation, a chimeric wsMc2r was made in which the EC2 domain was replaced with the EC2 domain from a melanocortin receptor that does not interact with Mrap1 (i.e., Xenopus tropicalis Mc1r). This substitution did not negatively impact the activation of the chimeric receptor. In addition, alanine substitution at a putative activation motif in the N-terminal of wsMrap1 did not affect the sensitivity of wsMc2r to stimulation by ACTH(1-24). Collectively, these observations suggest that wsMc2r may only have a HFRW binding site for melanocortin-related ligand which would explain how wsMc2r could be activated by either ACTH or MSH-sized ligands.

Rendimiento y seguridad de las colonoscopías de screening en dos grupos etarios de pacientes de la tercera edad

Objetivo: Comparar el rendimiento y seguridad de las colonoscopías de screening en el diagnóstico del cáncer colorrectal en dos grupos de pacientes añosos. Materiales y Método: Un análisis retrospectivo de pacientes sometidos a colonoscopías de screening en Clínica INDISA, desde noviembre de 2017 hasta marzo de 2019. Se excluyeron pacientes con síntomas de alarma según criterios de Roma IV, colonoscopías de urgencia y terapéuticas. Se compararon 2 grupos de pacientes: Grupo I entre 70-79 años y Grupo II mayores de 80 años. El objetivo primario fue el rendimiento diagnóstico de la colonoscopía de screening, definida como su capacidad para identificar hallazgos significativos definidos como la presencia de adenomas, displasia de alto grado y cáncer colorrectal. Los resultados secundarios consideraron la morbilidad y mortalidad del procedimiento. Análisis estadístico descriptivo e inferencial. Resultados: Un total de 125 pacientes cumplieron con los criterios de inclusión; Grupo I: 70 pacientes y Grupo II: 55 pacientes. Los hallazgos significativos se presentaron en un 27,1% en el Grupo I y en 30,9% en el Grupo II (p = 0,675). No se observaron diferencias en la calidad de la preparación intestinal o las complicaciones relacionadas con el procedimiento. Discusión y Conclusión: Las colonoscopías de screening en el diagnóstico de cáncer colorrectal son bien toleradas en pacientes mayores de 80 años, con un rendimiento equivalente en comparación al grupo más joven. Dado el aumento de la esperanza de vida, se recomienda realizar colonoscopías en octogenarios, especialmente en aquellos con buen estado de salud.

Aim: To compare diagnostic yield of significant findings rate and safety of screening colonoscopies in two groups of elderly patients. Materials and Method: A retrospective analysis was performed on patients who underwent screening colonoscopies at INDISA Clinic, from November 2017 to March 2019. Exclusion criteria were those with "alarm" symptoms according to Rome IV criteria, emergencies and therapeutic colonoscopies were excluded. Comparison groups were patients between 70-79 years old (Grupo I), and those over 80 years old (Grupo II). The primary outcome was the diagnostic yield of screening colonoscopy, defined as its capacity to identify adenomas, high-grade dysplasia, and colorectal cancer. Secondary outcomes were morbidity and mortality of the procedure. Statistical analysis was descriptive and inferential. Results: A total of 125 patients met our inclusion criteria; Grupo I: 70 and Grupo II 55 patients. Significant findings were observed in 27.1% in Grupo I and 30.9% in Grupo II (p = 0.675). No differences in bowel prep quality or procedure-related complications were observed between both groups. Discussion and Conclusion: Screening colonoscopies for colorectal cancer are well tolerated in patients over 80 years of age, with equivalent diagnostic rates compared with the younger patient group. Given the increasing life expectancy worldwide, it is recommended to continue checking for colorectal cancer with screening colonoscopies in octogenarians, particularly healthy ones.

Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions (AU)

Incidence of venous thromboembolic events in cancer patients receiving immunotherapy: a single-institution experience

Background Cancer and cancer therapies have been associated with an increased incidence of venous thromboembolic events (VTE). However, the incidence of VTE in patients on immunotherapy has not been well characterized. The aim of this study was to assess the incidence of VTE in cancer patients receiving immunotherapy and ascertain its prognostic utility. Materials and methods We conducted a single-institution retrospective study, including all cancer patients treated with anti-Programmed cell Death 1 (PD-1), anti-Programmed cell Death Ligand-1 (PD-L1), anti-Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), a combination of anti-PD-1/anti-PD-L1 and anti-CTLA4 or a combination including any of these drugs with chemotherapy, antiangiogenic agents or both between June 2013 and April 2019 at La Paz University Hospital, Madrid (Spain). Results We selected 229 patients. VTE occurred in 16 of 229 patients (7%). VTE occurred more frequently in patients with lung cancer followed by melanoma. Female sex and melanoma were independently associated with an increased risk of VTE. 12 of 16 VTE (75%) were symptomatic. Progressive disease to immunotherapy [HR 31.60 (95% CI 11.44–87.22), p = 0.00], lung cancer [HR 2.55 (95% CI 1.34–4.86), p = 0.00] and melanoma [HR 2.42 (1.20–4.86), p = 0.01] were independently associated with shorter OS. VTE occurrence was not independently associated with shorter OS [HR 1.33 (95% CI 0.63–2.80), p = 0.44]. Conclusions The incidence of VTE in cancer patients receiving immunotherapy in our study appeared to be similar to the incidence previously reported in other series of cancer patients treated with systemic therapies. VTE occurrence did not correlate with the prognosis. Further and prospective studies are needed to derive definitive conclusions (AU)

SEOM Clinical Guideline of management of soft-tissue sarcoma (2020)

Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treatment, and management should be performed by an expert multidisciplinary team. MRI/CT of the primary tumor and biopsy is mandatory before any treatment. Wide surgical resection with tumor-free tissue margin is the mainstay for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not suitable for re-excision. Perioperative chemotherapy should be discussed for high-risk sarcomas of the extremities and trunk-wall. In the case of oligometastatic disease, patients should be considered for local therapies. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. Other drugs have shown activity in second-line therapy and in specific histological subtypes but options are limited and thus, a clinical trial should always be discussed (AU)

Serum caspase-3 levels during the first week of traumatic brain injury / Niveles séricos de caspasa-3 durante la primera semana de un traumatismo craneoencefálico

Objective: Confluence between the intrinsic and extrinsic apoptosis pathways is reached at the point of caspase-3 activation, which induces death cell. Higher serum caspase-3 levels have been recorded on day 1 of traumatic brain injury (TBI) in 30-day non-survivors compared to survivors. The objectives of this study therefore were to determine whether serum caspase-3 levels are persistently higher in non-survivors than in survivors, and whether these levels may be used to predict 30-day mortality.DesignA prospective observational study was carried out.SettingSix Spanish Intensive Care Units.PatientsPatients with severe isolated TBI (defined as Glasgow Coma Scale <9 points and non-cranial Injury Severity Score <10 points).InterventionsSerum caspase-3 concentrations were measured on days 1, 4 and 8 of TBI.Main variables of interestThirty-day mortality was considered as the study endpoint.ResultsIn comparison with non-survivors (n=34), 30-day survivors (n=90) showed lower serum caspase-3 levels on days 1 (p=0.001), 4 (p<0.001) and 8 (p<0.001) of TBI. Analysis of the ROC curves showed serum caspase-3 concentrations on days 1, 4 and 8 of TBI to have an AUC (95% CI) in predicting 30-day mortality of 0.70 (0.61–0.78; p=0.001), 0.83 (0.74–0.89; p<0.001) and 0.87 (0.79–0.93; p<0.001), respectively.ConclusionsThe novel findings of our study were that serum caspase-3 levels during the first week of TBI were lower in survivors and could predict 30-day mortality. (AU)

Objetivo: La vía intrínseca y extrínseca de la apoptosis confluyen en la activación de caspasa-3. Se han encontrado mayores niveles séricos de caspasa-3 en el día 1 del traumatismo craneoencefálico (TCE) en los pacientes que fallecen en los primeros 30 días que en supervivientes. Por tanto, los objetivos de este estudio es determinar si los niveles séricos de caspasa-3 se mantienen superiores en los pacientes fallecidos que en los supervivientes, y si podrían utilizarse para predecir la mortalidad a 30 días.DiseñoEstudio observacional y prospectivo.ÁmbitoSeis unidades de cuidados intensivos españolas.PacientesEnfermos con un TCE grave y aislado (definido como escala de coma de Glasgow <9 y puntuación de gravedad de la lesión Score en lesiones no craneales <10).IntervencionesSe midieron los niveles séricos de caspasa-3 en los días 1, 4 y 8 del TCE.Variables de interés principalesMortalidad a los 30 días.ResultadosLos pacientes supervivientes a los 30 días (n=90) presentan menores niveles séricos de caspasa-3 en los días 1 (p=0,001), 4 (p<0,001) y 8 (p<0,001) del TCE que los fallecidos (n=34). Los niveles séricos de caspasa-3 en los días 1, 4 y 8 del TCE tenían un área bajo la curva (intervalo de confianza del 95%) para predecir la mortalidad de 0,70 (0,61-0,78; p=0,001), 0,83 (0,74-0,89; p<0,001) y 0,87 (0,79-0,93; p<0,001), respectivamente.ConclusionesLos nuevos hallazgos de nuestro estudio fueron que los niveles séricos de caspasa-3 durante la primera semana del TCE fueron menores en los pacientes supervivientes, y que pueden predecir la mortalidad a los 30 días. (AU)

Analysis of dynamic networks based on the Ising model for the case of study of co-authorship of scientific articles.

Two computational methods based on the Ising model were implemented for studying temporal dynamic in co-authorship networks: an interpretative for real networks and another for simulation via Monte Carlo. The objective of simulation networks is to evaluate if the Ising model describes in similar way the dynamic of the network and of the magnetic system, so that it can be found a generalized explanation to the behaviours observed in real networks. The scientific papers used for building the real networks were acquired from WoS core collection. The variables for each record took into account bibliographic references. The search equation for each network considered specific topics trying to obtain an advanced temporal evolution in terms of the addition of new nodes; that means 3 steps, a time to reach the interest of the scientific community, a gradual increase until reaching a peak and finally, a decreasing trend by losing of novelty. It is possible to conclude that both methods are consistent with each other, showing that the Ising model can predict behaviours such as the number and size of communities (or domains) according to the temporal distribution of new nodes.

DNA and RNA oxidative damage are associated to mortality in patients with cerebral infarction / El daño oxidativo del ADN y ARN se asocian con la mortalidad en los pacientes con inf0arto cerebral

OBJECTIVE: Secondary injury due to oxidation may occur during ischemic stroke, possibly leading to oxidative damage to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Higher blood concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG) (through the oxidation of guanosine from DNA) have been found in ischemic stroke patients than in healthy subjects, and in patients with versus without post-ischemic stroke depression. The present study was carried out to explore the possible association between serum DNA and RNA oxidative damage and mortality in patients with cerebral infarction. METHODS: A prospective, multicenter observational study was carried out in the Intensive Care Units of 6 Spanish hospitals. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as ischemic changes evidenced by computed tomography in more than 50% of the middle cerebral artery territory and a Glasgow Coma Score (GCS)<9. Serum concentrations of the three oxidized guanine species (OGS) (8-hydroxyguanine from DNA or RNA, 8-hydroxyguanosine from RNA, and 8-OHdG from DNA) on the day of MMCAI diagnosis were determined. The study endpoint was 30-day mortality. RESULTS: We found higher serum OGS levels (p < 0.001) in non-surviving (n=34) than in surviving patients (n=34). Logistic regression analyses showed serum OGS levels to be associated to 30-day mortality controlling for lactic acid, GCS and platelet count (OR=1.568; 95%CI=1.131-2.174; p = 0.01). CONCLUSIONS: The novel observation in this study is the association between global serum OGS concentration and mortality in ischemic stroke patients

OBJETIVO: En el infarto cerebral puede aparecer una lesión cerebral secundaria debido a la oxidación del ácido desoxirribonucleico (ADN) y del ácido ribonucleico (ARN). Se han encontrado concentraciones sanguíneas de 8-hidroxi-2'-desoxiguanosina (8-OHdG) (por la oxidación de la guanosina del ADN) más altas en pacientes con infarto cerebral que en individuos sanos, y en pacientes con depresión tras un infarto cerebral. El objetivo de nuestro estudio fue determinar si existe una asociación entre el daño oxidativo del ADN y del ARN, y la mortalidad de los pacientes con infarto cerebral. MÉTODOS: Estudio prospectivo, observacional y multicéntrico realizado en unidades de cuidados intensivos de 6 hospitales españoles. Se incluyeron pacientes con un infarto maligno grave de la arteria cerebral media (MMCAI), definido como la presencia de cambios isquémicos en la tomografía en más del 50% del territorio de la arteria cerebral media y menos de 9 puntos en la escala Glasgow Coma Scale (GCS). Se determinaron los niveles séricos de las 3 especies oxidadas de la nucleobase guanina (OGS) (8-hidroxiguanina del ADN o ARN, 8-hidroxiguanosina del ARN y 8-OHdG del ADN) en el día del diagnóstico del MMCAI. La variable principal fue la mortalidad a 30 días. RESULTADOS: Encontramos concentraciones séricas de OGS (p < 0,001) más altas en los pacientes fallecidos (n=34) que en los supervivientes (n=34). La regresión logística mostró que los niveles séricos de OGS se asociaban con la mortalidad a los 30 días controlando por ácido láctico, GCS y recuento plaquetario (odds ratio=1,568; IC 95%=1,131-2,174; p = 0,01). CONCLUSIONES: El nuevo hallazgo de nuestro estudio fue la asociación entre los niveles séricos de OGS globales y la mortalidad de los pacientes con infarto cerebral

SEOM Clinical Guideline of management of soft-tissue sarcoma (2020).

Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treatment, and management should be performed by an expert multidisciplinary team. MRI/CT of the primary tumor and biopsy is mandatory before any treatment. Wide surgical resection with tumor-free tissue margin is the mainstay for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not suitable for re-excision. Perioperative chemotherapy should be discussed for high-risk sarcomas of the extremities and trunk-wall. In the case of oligometastatic disease, patients should be considered for local therapies. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. Other drugs have shown activity in second-line therapy and in specific histological subtypes but options are limited and thus, a clinical trial should always be discussed.

DNA and RNA oxidative damage are associated to mortality in patients with cerebral infarction.

OBJECTIVE: Secondary injury due to oxidation may occur during ischemic stroke, possibly leading to oxidative damage to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Higher blood concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) (through the oxidation of guanosine from DNA) have been found in ischemic stroke patients than in healthy subjects, and in patients with versus without post-ischemic stroke depression. The present study was carried out to explore the possible association between serum DNA and RNA oxidative damage and mortality in patients with cerebral infarction. METHODS: A prospective, multicenter observational study was carried out in the Intensive Care Units of 6 Spanish hospitals. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as ischemic changes evidenced by computed tomography in more than 50% of the middle cerebral artery territory and a Glasgow Coma Score (GCS)<9. Serum concentrations of the three oxidized guanine species (OGS) (8-hydroxyguanine from DNA or RNA, 8-hydroxyguanosine from RNA, and 8-OHdG from DNA) on the day of MMCAI diagnosis were determined. The study endpoint was 30-day mortality. RESULTS: We found higher serum OGS levels (p<0.001) in non-surviving (n=34) than in surviving patients (n=34). Logistic regression analyses showed serum OGS levels to be associated to 30-day mortality controlling for lactic acid, GCS and platelet count (OR=1.568; 95%CI=1.131-2.174; p=0.01). CONCLUSIONS: The novel observation in this study is the association between global serum OGS concentration and mortality in ischemic stroke patients.

Serum caspase-3 levels during the first week of traumatic brain injury.

OBJECTIVE: Confluence between the intrinsic and extrinsic apoptosis pathways is reached at the point of caspase-3 activation, which induces death cell. Higher serum caspase-3 levels have been recorded on day 1 of traumatic brain injury (TBI) in 30-day non-survivors compared to survivors. The objectives of this study therefore were to determine whether serum caspase-3 levels are persistently higher in non-survivors than in survivors, and whether these levels may be used to predict 30-day mortality. DESIGN: A prospective observational study was carried out. SETTING: Six Spanish Intensive Care Units. PATIENTS: Patients with severe isolated TBI (defined as Glasgow Coma Scale <9 points and non-cranial Injury Severity Score <10 points). INTERVENTIONS: Serum caspase-3 concentrations were measured on days 1, 4 and 8 of TBI. MAIN VARIABLES OF INTEREST: Thirty-day mortality was considered as the study endpoint. RESULTS: In comparison with non-survivors (n=34), 30-day survivors (n=90) showed lower serum caspase-3 levels on days 1 (p=0.001), 4 (p<0.001) and 8 (p<0.001) of TBI. Analysis of the ROC curves showed serum caspase-3 concentrations on days 1, 4 and 8 of TBI to have an AUC (95% CI) in predicting 30-day mortality of 0.70 (0.61-0.78; p=0.001), 0.83 (0.74-0.89; p<0.001) and 0.87 (0.79-0.93; p<0.001), respectively. CONCLUSIONS: The novel findings of our study were that serum caspase-3 levels during the first week of TBI were lower in survivors and could predict 30-day mortality.

Incidence of venous thromboembolic events in cancer patients receiving immunotherapy: a single-institution experience.

BACKGROUND: Cancer and cancer therapies have been associated with an increased incidence of venous thromboembolic events (VTE). However, the incidence of VTE in patients on immunotherapy has not been well characterized. The aim of this study was to assess the incidence of VTE in cancer patients receiving immunotherapy and ascertain its prognostic utility. MATERIALS AND METHODS: We conducted a single-institution retrospective study, including all cancer patients treated with anti-Programmed cell Death 1 (PD-1), anti-Programmed cell Death Ligand-1 (PD-L1), anti-Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), a combination of anti-PD-1/anti-PD-L1 and anti-CTLA4 or a combination including any of these drugs with chemotherapy, antiangiogenic agents or both between June 2013 and April 2019 at La Paz University Hospital, Madrid (Spain). RESULTS: We selected 229 patients. VTE occurred in 16 of 229 patients (7%). VTE occurred more frequently in patients with lung cancer followed by melanoma. Female sex and melanoma were independently associated with an increased risk of VTE. 12 of 16 VTE (75%) were symptomatic. Progressive disease to immunotherapy [HR 31.60 (95% CI 11.44-87.22), p = 0.00], lung cancer [HR 2.55 (95% CI 1.34-4.86), p = 0.00] and melanoma [HR 2.42 (1.20-4.86), p = 0.01] were independently associated with shorter OS. VTE occurrence was not independently associated with shorter OS [HR 1.33 (95% CI 0.63-2.80), p = 0.44]. CONCLUSIONS: The incidence of VTE in cancer patients receiving immunotherapy in our study appeared to be similar to the incidence previously reported in other series of cancer patients treated with systemic therapies. VTE occurrence did not correlate with the prognosis. Further and prospective studies are needed to derive definitive conclusions.

Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence.

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions.

Prognostic value of neutrophil-to-lymphocyte ratio and other inflammatory markers in patients with high-risk soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) have a high risk of relapse in spite of the use of (neo)adjuvant chemotherapy. In this context, looking for new prognostic biomarkers is an interesting field of research. Our aim is to analyze the prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and other serum markers in patients with STS who received chemotherapy with curative intent. MATERIALS AND METHODS: This is a retrospective observational study. We included all patients with STS (primary tumor, local recurrence or resected metastatic disease) treated with high-dose ifosfamide and epirubicin with curative intent from January 2007 to December 2018. The pretreatment NLR and other serum markers were calculated, selecting the median as the cut-off value for the survival and multivariate analysis. RESULTS: Seventy-nine patients were included. Median NLR, platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) were 2.83, 174.05 and 3.25, respectively. Median progression-free survival (PFS) was significantly longer in patients with low NLR [not reached (NR) vs 21, 92 months, P < 0.01]. No significant differences were found for PFS regarding PLR or LMR. For overall survival (OS), a significant survival advantage was also found for patients with low NLR (NR vs 65.45 months, P = 0.01), without differences for PLR or LMR. In multivariate analysis, NLR remains an independent prognostic factor for PFS. CONCLUSION: In our cohort, low NLR was significantly associated with a longer PFS and OS, and is consolidated as an independent prognostic factor.

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019).

In 2011, the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of venous thromboembolism (VTE) and cancer. This guideline was updated in 2014, and since then, multiple studies and clinical trials have changed the landscape of the treatment and prophylaxis of VTE in cancer patients. To incorporate the most recent evidence, including data from direct oral anticoagulants (DOACs) randomized clinical trials, SEOM presents a new update of the guideline.

Effect of cardiac resynchronization therapy on septal perfusion and septal thickening: Association with left ventricular function, reverse remodelling and dyssynchrony.

BACKGROUND: We evaluated the effect of cardiac resynchronization therapy (CRT) on septal perfusion and thickening at 6 months post implantation assessed on Tc99m-MIBI Gated myocardial perfusion SPECT (GMPS).We also studied the association of change in septal perfusion and thickening with primary outcome defined as at least one [improvement in ≥1NYHA class, left ventricular ejection fraction (LVEF) by ≥ 5%, reduction of end-systolic volume (ESV) by ≥ 15%, and improvement ≥ 5 points in Minnesota living with heart failure questionnaire (MLHFQ)]. METHOD: One hundred and five patients underwent clinical and GMPS evaluation before and at 6 months post CRT. RESULT: Post CRT there was significant improvement in mean normalized septal perfusion uptake and in septal thickening (P value = 0.001, both). There was no significant relation between improvement in septal perfusion and primary outcome. However, improvement in septal thickening was statistically significant with favorable primary outcome (P = 0.001).There was no significant correlation between improvement of septal perfusion and improvement in LVEF, reduction in End diastolic volume (EDV), ESV, and Left ventricular Dyssynchrony (LVD). But, there was significant correlation between improvement of septal thickening and these parameters. CONCLUSION: Improvement in septal thickening was associated with reverse remodeling, improvement in LVEF, and reduction of LVD.

PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models.

Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is ∼50-150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.

Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (< 10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed (AU)

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Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.