Asthma and COPD "overlap": a treatable trait or common several treatable-traits?

Summary: In the last years, disease classification of chronic respiratory diseases (CRD) has been vivaciously discussed and new concepts have been introduced, namely asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO). Controversially the GOLD consensus document of 2020 considered that we should no longer refer to ACO, as they constitute two different diseases that may share some common traits and clinical features. The treatable traits approach has numerous strengths that are applicable to several levels of health care. In this paper we review the application of the treatable traits to CRD and describe in detail the ones already identified in patients with asthma and COPD. Treatable traits in CRD can be divided in pulmonary, extra-pulmonary and behavior/lifestyle risk factors. Patients with both asthma and COPD patients have clearly recognized treatable traits in all these subtopics but it is notorious the severe and frequent exacerbations, the associated cardiovascular disease and the low health related quality of life and productivity of these patients.

Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility.

This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties. CB13-loaded lipid nanoparticles (LNP) formulations were developed through solvent-emulsion evaporation and optimized in terms of physicochemical properties, long-term stability, integrity under gastric simulated conditions and in vitro interaction with NIH 3T3, HEK 293T and Caco-2 cells. An optimized formulation of LNP containing CB13 was obtained from a wide range of conditions assayed and analyzed. The selection of the lipid core, production conditions and the inclusion of lecithin proved to be key factors for the final properties of encapsulation, integrity and performance of the carriers. The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.

Ophthalmic wild olive (ACEBUCHE) oil nanoemulsions exert oculoprotective effects against oxidative stress induced by arterial hypertension.

Oxidative stress plays a key role in several systemic and ocular diseases, including hypertensive eye diseases. In this context, we previously showed that oral administration of wild olive (acebuche, ACE) oil from Olea europaea var. sylvestris can counteract ocular damage secondary to arterial hypertension by modulating excess reactive oxygen species (ROS) produced by the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Therefore, this work describes the development of an ACE oil-based formulation for ocular administration as a local therapy to counteract hypertension-related oxidative damage. Specifically, ACE oil nanoemulsions (NEs) were successfully produced and characterized, exhibiting appropriate features for ophthalmic administration, including a nanometer size (<200 nm), moderate negative ZP, adequate osmolality and pH, and colloidal stability in biorelevant fluids. Likewise, the NEs presented a shear thinning behavior, especially convenient for ocular instillation. In vivo evaluation was performed through either intravitreal injection or topical ophthalmic administration in mice with hypertension induced via administration of Nω-nitro-L-arginine-methyl-ester (L-NAME). Both routes of administration reduced hypertensive morphological alterations and demonstrated a noticeable antioxidant effect thanks to the reduction of the activity/expression of NADPH oxidase in cornea and retina. Thus, an ACE oil ophthalmic formulation represent a promising therapy for ocular pathologies associated with arterial hypertension.

Thromboelastometry-guided surgery in neuroblastoma complicated with disseminated intravascular coagulation. / Cirugía guiada por tromboelastometría en neuroblastoma complicado con coagulación intravascular diseminada.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required thromboelastometry-guided surgery. OBSERVATION: A 6-year-old female diagnosed with intermediate risk adrenal neuroblastoma developed tumor-related DIC after chemotherapy first cycle. She remained stable without clinical bleeding and emergent tumor resection guided by intraoperative-thromboelastometry was decided. DIC resolved early after surgery and complete remission was achieved. CONCLUSION: Treatment of the underlying condition is critical to manage DIC. Thromboelastometry can guide goal-directed therapy, including surgery in pediatric patients. However, larger studies are needed to examine its applicability in different clinical settings, such as cancer related DIC.

INTRODUCCION: La coagulación intravascular diseminada (CID) es una urgencia oncológica poco común. Describimos el caso de un neuroblastoma pediátrico complicado con CID que precisó de cirugía guiada por tromboelastometría. CASO CLINICO: Paciente de seis años diagnosticada de neuroblastoma suprarrenal de riesgo intermedio que desarrolló CID asociada al tumor tras el primer ciclo de quimioterapia. Permaneció estable sin hemorragia clínica, decidiéndose una resección tumoral de urgencia guiada por tromboelastometría intraoperatoria. La CID se resolvió poco después de la cirugía, consiguiéndose una remisión total. CONCLUSION: El tratamiento de la patología subyacente es clave a la hora de manejar la CID. La tromboelastometría puede guiar la terapia orientada a objetivos, también en cirugías realizadas en pacientes pediátricos. No obstante, hacen falta mayores estudios que analicen su aplicabilidad en distintos contextos clínicos, como la CID relacionada con cáncer.

Morphological traits and RAPD markers for characterization and identification of minor Spanish olive cultivars from the Extremadura region.

A total of 91 wild olive accessions and 31 olive cultivars growing in the Extremadura region of central-western Spain were analyzed using morphological traits and RAPD markers. We focused on three main and 16 minor Spanish olive cultivars that are recognized as native or local to the Extremadura region. The five arbitrary 10-mer primers tested on the olive cultivars gave 67 polymorphic bands, representing 91% of the total amplification products. The number of bands per primer ranged from 9 to 18, whereas the number of polymorphic bands ranged from 8 to 17. All the cultivars could be identified by a combination of three primers (OPF-6, OPA-8, and OPK-16); four cultivar-specific markers were detected. The minor local "Jariego" and "Tempranillo" cultivars showed the most distal similarities. The resulting dendrogram, using the unweighted pair-group method with arithmetic mean clustering algorithm, depicted the pattern of relationships between the local Extremadura cultivars and the cultivars from geographically connected regions. This analysis showed a correlation between most of the minor local cultivars and the geographical origin; there was no apparent clustering according to morphological traits or fruit use of olive cultivars when these parameters were used as analysis criteria.

Paediatric Horner syndrome. A case series of 14 patients in a tertiary hospital.

BACKGROUND: Horner syndrome (HS) is characterised by the triad of upper eyelid ptosis, miosis, and facial anhidrosis. Due to its wide variety of causes, it can occur at any age, and is uncommon in paediatrics. The aetiology and diagnostic approach of paediatric HS (PHS) is controversial. OBJECTIVE: The purpose of this study is to describe the clinical characteristics of a 14 case series, focusing on the aetiology of HS and the clinical evolution the patients presented. METHODS: A retrospective observational study was conducted on patients under 14 years-old (enrolled between 1st January 2009 and 30th April 2020). Depending on the age at diagnosis (before or after the first 5 months of life), the study cases were divided into two groups: congenital or acquired. RESULTS: Fourteen patients, with a mean age of 8.5 months, were enrolled. The most frequent cause of PHS were tumours (6/14), with the most representative neoplasm being neuroblastoma (4/14). Of the acquired cases (8/14), the most frequent cause was iatrogenic (5/8), mainly secondary to cervical or thoracic surgery. The main origin of congenital HS (6/14) was neuroblastoma (4/6), being the first manifestation of the disease in 50% of patients (2/4). CONCLUSION: HS may be the first sign of a major underlying disease, such as neuroblastoma. For this reason, children presenting with HS of unknown origin require imaging studies to exclude a life threatening disease. A thorough examination is essential for early diagnosis of these patients.

Influence of the technique and comorbidities in hypofractionated radiotherapy for prostate cancer.

PURPOSE: To analyze the differences in toxicity and biochemical relapse-free survival with hypofractionated radiotherapy with three-dimensional radiotherapy (3D-CRT) or volumetric arc therapy (VMAT) for prostate cancer taking into account comorbidity measured using the Charlson Comorbidity Index (CCI). METHODS: From January 2011 to June 2016, 451 patients with prostate cancer were treated with 60 Gy (20 daily fractions). VMAT or 3D-CRT was used. Distribution by stage: 17% low-risk, 27.2% intermediate-risk; 39.2% high-risk, 16.6% very high-risk. Mean CCI was 3.4. RESULTS: With a median follow up of 51 months, most patients did not experience any degree of acute GI toxicity (80.9%) compared to 19.1%, who experienced some degree, mainly G-I /II. In the multivariate analysis, only technique was associated with acute GI toxicity ≥ G2. Patients treated with VMAT had greater acute GI toxicity compared with those who received 3D-CRT (23.9% vs. 13.5%, p = 0.005). With respect to acute GU toxicity, 72.7% of patients experienced some degree, fundamentally G-I/II. Neither age, CCI, nor androgen deprivation therapy (ADT) were associated with greater toxicity. Overall survival at 2, 5 and 7 years was 97%, 88% and 83% respectively. The only factor with statistical significance was CCI, with a greater number of events in individuals with a CCI ≥ 4 (p < 0.03). CONCLUSIONS: Hypofractionated radiotherapy for prostate cancer is an effective, well-tolerated treatment even for elderly patients with no associated comorbidity. Longer follow up is needed in order to report data on late toxicity.

Perforation of Meckel's diverticulum by a chicken bone mimicking acute appendicitis. Case report.

Meckel's diverticulum (MD) is a congenital disorder that results from an incomplete obliteration of the vitelline duct. MD may give rise to bleeding, intestinal obstruction and inflammation; however its perforation by a foreign body is an extremely rare life-threatening complication. We report on a 52 years-old Brazilian Amazon man presenting symptoms and signs of acute abdomen with an initial suspicion of acute appendicitis. However, the right diagnosis was made only during exploratory laparotomy when the appendix was found to be normal, whereas MD was found to be inflamed and perforated by a chicken bone. The patient was treated successfully with resection of a segment of the ileum, including the perforated diverticulum, and had an uncomplicated postoperative course.

Modeling chromosomal translocations using conditional alleles to recapitulate initiating events in human leukemias.

Recurrent reciprocal chromosomal translocations are present in more than 50% of leukemias. A deeper understanding of how they affect cancer initiation is essential for evaluating the origins of cancer and the potential for therapy based on the translocation products. Mouse models of chromosomal translocations are required for this. Here we summarize three methodologies developed in our laboratory to model chromosomal translocations (knock-in, translocator, and invertor methods). We have used these models to study leukemias caused by fusions of the mixed lineage leukemia (MLL) gene and the Ews-ERG fusion gene to evaluate oncogenicity and elucidate some general principles about translocation products. We show that MLL fusions have the capacity to cause hematopoietic tumors only if expressed in permissive cells and that the Mll-Enl fusion can cause lineage reassignment if the chromosomal translocation occurs in lineage noncommitted progenitors. The leukemia-initiating cells generated by Mll fusions or by Ews-ERG fusion can be committed cells within the hematopoietic pathway. Our translocation mimic models are applicable to any human reciprocal chromosomal translocation.

MLL gene fusions in human leukaemias: in vivo modelling to recapitulate these primary tumourigenic events.

Recurrent reciprocal chromosomal translocations are frequently found in leukaemias and sarcomas as initiating events in these cancers. Mouse models of chromosomal translocations are not only important for the elucidation of the mechanism of these factors underlying the disease but are also important pre-clinical models for assessing new drug combinations, developing new rational therapeutic strategies based on new drugs and testing novel macromolecular drugs. We describe three technologies for creating chromosomal translocation mimics in mice, applied specifically to understand how the MLL-fusions contribute to leukaemia. An important finding of this work is that the lineage of the tumours can be controlled by the MLL-protein fusion. The translocation mimic methods can be applied to any human reciprocal chromosomal translocation.

Tuberculosis in a low-incidence US area: local consequences of global disruptions.

SETTING: Tuberculosis (TB) in the United States is increasingly concentrated among foreign-born persons. The northeastern states, including Connecticut, are among those with the highest proportion of foreign-born patients. METHODS: This retrospective analysis of surveillance data from Connecticut for 1996 through 2005 compared TB case rates and risk factors among US-born and foreign-born persons. RESULTS: Between 1996 and 2005, TB cases declined by 8.7% in foreign-born persons and by 53.6% in US-born persons. The median annual incidence rate for foreign-born persons was 19.7 cases per 100000 population compared with 1.5 for US-born persons. Refugees had the highest TB rate (116 cases/100000) in the first year of their arrival. Resistance to any drug was more common among foreign-born persons (15.0%) than among US-born persons (9.3%). Although the proportion of multidrug-resistant TB was highest among foreign-born persons with prior TB (5.6%), most cases occurred in those without prior TB. Risk factors for TB, such as human immunodeficiency virus infection, drug use, incarceration and homelessness, were more common among US-born TB patients than among foreign-born patients. CONCLUSIONS: Although TB case rates for US-born persons in Connecticut have declined dramatically, foreign-born persons, including refugees fleeing conflict, contribute disproportionately to the TB burden. Future efforts to eliminate TB must be directed toward immigrants and refugees.

Outbreak of tuberculosis in a correctional facility: consequences of missed opportunities.

In May 2006, the Department of Public Health investigated a tuberculosis (TB) outbreak at a correctional facility after two recently discharged inmates were diagnosed with TB. Based on epidemiological and genotyping data, one infectious patient was determined to be the source of infection for the other. Despite prolonged symptoms and abnormal chest radiographs, the index patient was not diagnosed while incarcerated. Among the estimated 910 exposed inmates tested, 53 (5.8%) had newly positive tuberculin skin tests (TSTs). Ten (2.1%) of 485 corrections staff tested converted their TSTs. This investigation highlights the consequences of missed TB diagnoses in prisons.

Spatial clusters of latent tuberculous infection, Connecticut, 2010-2014.

SETTING: In the United States, tuberculosis (TB) control is increasingly focusing on the identification of persons with latent tuberculous infection (LTBI). OBJECTIVE: To characterize the local epidemiology of LTBI in Connecticut, USA. METHODS: We used spatial analyses 1) to identify census tract-level clusters of reported LTBI and TB disease in Connecticut, 2) to compare persons and populations in clusters with those not in clusters, and 3) to compare persons with LTBI to those with TB disease. RESULTS: Significant census tract-level spatial clusters of LTBI and TB disease were identified. Compared with persons with LTBI in non-clustered census tracts, those in clustered census tracts were more likely to be foreign-born and less likely to be of white non-Hispanic ethnicity. Populations in census tract clusters of high LTBI prevalence had greater crowding, persons living in poverty, and persons lacking health care insurance than populations not in clustered census tracts. Persons with LTBI were less likely than those with TB disease to be of Asian ethnicity, and persons with LTBI were more likely than those with TB disease to reside in a clustered census tract. CONCLUSIONS: Characterizing fine-scale populations at risk for LTBI supports effective and culturally accessible screening and treatment programs.

Radiotherapy in soft-tissue sarcoma of the extremities.

Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease.

Cirugía guiada por tromboelastometría en neuroblastoma complicado con coagulación intravascular diseminada / Thromboelastometry-guided surgery in neuroblastoma complicated with disseminated intravascular coagulation

Introducción: La coagulación intravascular diseminada (CID) es una urgencia oncológica poco común. Describimos el caso de un neuroblastoma pediátrico complicado con CID que precisó de cirugía guiada por tromboelastometría. Caso clínico. Paciente de seis años diagnosticada de neuroblastoma suprarrenal de riesgo intermedio que desarrolló CID asociada al tumor tras el primer ciclo de quimioterapia. Permaneció estable sin hemorragia clínica, decidiéndose una resección tumoral de urgencia guiada por tromboelastometría intraoperatoria. La CID se resolvió poco después de la cirugía, consiguiéndose una remisión total. Conclusión. El tratamiento de la patología subyacente es clave a la hora de manejar la CID. La tromboelastometría puede guiar la terapia orientada a objetivos, también en cirugías realizadas en pacientes pediátricos. No obstante, hacen falta mayores estudios que analicen su aplicabilidad en distintos contextos clínicos, como la CID relacionada con cáncer.(AU)

Background: Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required thromboelastometry-guided surgery. Observation. A 6-year-old female diagnosed with intermediate risk adrenal neuroblastoma developed tumor-related DIC after chemotherapy first cycle. She remained stable without clinical bleeding and emergent tumor resection guided by intraoperative-thromboelastometry was decided. DIC resolved early after surgery and complete remission was achieved. Conclusion. Treatment of the underlying condition is critical to manage DIC. Thromboelastometry can guide goal-directed therapy, including surgery in pediatric patients. However, larger studies are needed to examine its applicability in different clinical settings, such as cancer related DIC.(AU)

A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology.

MLL-AF4 fusion is the most common consequence of chromosomal translocations in infant leukaemia and is associated with a poor prognosis. MLL-AF4 is thought to be required in haematopoietic stem cells to elicit leukaemia and may be involved in tumour phenotype specification as it is only found in B-cell tumours in humans. We have employed the invertor conditional technology to create a model of MLL-AF4, in which a floxed AF4 cDNA was knocked into Mll in the opposite orientation for transcription. Cell-specific Cre expression was used to generate Mll-AF4 expression. The mice develop exclusively B-cell lineage neoplasias, whether the Cre gene was controlled by B- or T-cell promoters, but of a more mature phenotype than normally observed in childhood leukaemia. These findings show that the MLL-AF4 fusion protein does not have a mandatory role in multi-potent haematopoietic stem cells to cause cancer and indicates that MLL-AF4 has an instructive function in the phenotype of the tumour.

Analysis of fiducial markers used for on-line verification in the external-beam radiotherapy of patients with cranial tumours.

PURPOSE: Evaluate the fiducial marker-based position verification in the external-beam radiotherapy of patients with cranial tumour. METHODS: Thirteen patients with intracranial tumours were treated with external- beam radiotherapy using 3 gold markers implanted in the skull. Before each fraction the patient was positioned on the treatment table and 2 orthogonal portal images were performed to localise the 3 gold seeds and the target position was calculated using a commercialised computer program (ISOLOC software, MEDTEC). This program provides the couch movements required to move the target to the isocentre. RESULTS: When the set-up error was corrected using the coordinates of the 3 markers, the final movements were less than 2 mm in all cases: lateral, mean v., 1.21 mm; longitudinal, 1.23 mm; and anteroposterior, 1.18 mm. No serious complications related to the gold marker insertion were noted. CONCLUSION: The use of 3 implanted fiducial seeds is an optimal technique for precise set-up in patients with brain tumours treated with external radiotherapy. This commercial system is highly suitable for fractionated stereotactic irradiation.

Performance of urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and N-acetyl-ß-D-glucosaminidase to predict chronic kidney disease progression and adverse outcomes.

Urinary biomarkers can predict the progression of chronic kidney disease (CKD). In this study, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-ß-D-glucosaminidase (NAG) were correlated with the stages of CKD, and the association of these biomarkers with CKD progression and adverse outcomes was determined. A total of 250 patients, including 111 on hemodialysis, were studied. Urinary KIM-1, NGAL, and NAG were measured at baseline. Patients not on dialysis at baseline who progressed to a worse CKD stage were compared with those who did not progress. The association of each biomarker and selected covariates with progression to more advanced stages of CKD, end-stage kidney disease, or death was evaluated by Poisson regression. NGAL was moderately correlated (rs=0.467, P<0.001) with the five stages of CKD; KIM-1 and NAG were also correlated, but weakly. Sixty-four patients (46%) progressed to a more advanced stage of CKD. Compared to non-progressors, those patients exhibited a trend to higher levels of KIM-1 (P=0.064) and NGAL (P=0.065). In patients not on dialysis at baseline, NGAL was independently associated with progression of CKD, ESKD, or death (RR=1.022 for 300 ng/mL intervals; CI=1.007-1.037, P=0.004). In patients on dialysis, for each 300-ng/mL increase in urinary NGAL, there was a 1.3% increase in the risk of death (P=0.039). In conclusion, urinary NGAL was associated with adverse renal outcomes and increased risk of death in this cohort. If baseline urinary KIM-1 and NGAL predict progression to worse stages of CKD is something yet to be explored.

Improving efficacy and efficiency through the implementation of a new organisational model in a Radiation Oncology Department.

BACKGROUND: To evaluate a new organisational model, "process management" (PM), implemented in the Hospital Universitario Virgen de la Victoria (HUVV) compared with traditional models used in other Radiation Oncology Departments (RODs), in terms of efficacy and efficiency. METHODS: The study period ranged from September 2011 to August 2012. Efficacy was assessed, comparing the number of patients attended in first consultation and treated per month, average waiting time from referral to first visit and average waiting time from first visit to treatment. Data were collected from two public hospitals in Andalusia: the HUVV and another Public Hospital in Andalusia (PHA1). Efficiency was assessed comparing the costs per patient attended in first visit and treated at HUVV in 2012 compared with those of a second Public Hospital in Andalusia (PHA2) for 2008. The number of sessions saved using hypofractionation versus classical schemes during the year 2012 in HUVV was estimated, and the money saved was calculated. RESULTS: In the efficacy analysis, we found significant differences in the average waiting time for first visit, start of treatment, and the number of patients seen and treated annually. After calculating the total cost generated in the ROD, the efficiency analysis showed a lower cost per patient attended in first visit (EUR 599.17) and per patient treated (EUR 783.50), with a saving of 6035 sessions using hypofractionated schemes. CONCLUSIONS: Process management in an ROD reduces time, both to first medical visit and to treatment initiation, allowing an optimisation of linear accelerator (LINAC) capacity.