Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

A phase I/II dose-escalation multi-center study to evaluate the safety of infusion of natural killer cells or memory T cells as adoptive therapy in coronavirus pneumonia and/or lymphopenia: RELEASE study protocol.

BACKGROUND: Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19. METHODS: In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC. DISCUSSION: We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020.

Urinary tract infection caused by Enterococcus spp.: Risk factors and mortality. An observational study.

BACKGROUND AND OBJECTIVE: Urinary tract infections (UTIs) are frequently caused by Enterococcus spp. This work aims to define the risk factors associated with UTIs caused by Enterococci and to determine its overall mortality and predictive risk factors. MATERIALS AND METHODS: A retrospective study was conducted on bacteremic UTIs caused by Enterococcus spp. among inpatients. We compared 106 inpatients with bacteremic UTIs caused by Enterococcus spp. vs. a random sample of 100 inpatients with bacteremic UTIs caused by other enterobacteria. RESULTS: A total of 106 inpatients with UTIs caused by Enterococcus spp. were analyzed, 51 of whom had concomitant positive blood cultures. Distribution by species was 83% E. faecalis and 17% E. faecium. The mean Charlson Comorbidity Index score was 5.9±2.9. Upon comparing bacteremic UTIs caused by Enterococcus spp. vs. bacteremic UTIs caused by others enterobacteria, we found the following independent predictors of bacteremic UTI by Enterococcus: male sex, obstructive uropathy, nosocomial infection, cancers of the urinary system, and previous antimicrobial treatment. Overall, inpatient mortality was 16.5% and was associated with a higher Sequential Organ Failure Assessment (SOFA) score (>4); severe comorbidities such as immunosuppression, malignant hemopathy, and nephrostomy; and Enterococcus faecium species and its pattern of resistance to ampicillin or vancomycin (p<0.05). Appropriate empiric antibiotic therapy was not associated with a better prognosis (p>0.05). CONCLUSIONS: Enterococcus spp. is a frequent cause of complicated UTI in patients with risk factors. High mortality secondary to a severe clinical condition and high comorbidity may be sufficient for justifying the implementation of empiric treatment of at-risk patients.

Inflammatory agents partially explain associations between cortical thickness, surface area, and body mass in adolescents and young adulthood.

BACKGROUND/OBJECTIVES: Excessive body mass index (BMI) has been linked to a low-grade chronic inflammation state. Unhealthy BMI has also been related to neuroanatomical changes in adults. Research in adolescents is relatively limited and has produced conflicting results. This study aims to address the relationship between BMI and adolescents' brain structure as well as to test the role that inflammatory adipose-related agents might have over this putative link. METHODS: We studied structural MRI and serum levels of interleukin-6, tumor necrosis factor alpha (TNF-α), C-reactive protein and fibrinogen in 65 adolescents (aged 12-21 years). Relationships between BMI, cortical thickness and surface area were tested with a vertex-wise analysis. Subsequently, we used backward multiple linear regression models to explore the influence of inflammatory parameters in each brain-altered area. RESULTS: We found a negative association between cortical thickness and BMI in the left lateral occipital cortex (LOC) and the right precentral gyrus as well as a positive relationship between surface area and BMI in the left rostral middle frontal gyrus and the right superior frontal gyrus. In addition, we found that higher fibrinogen serum concentrations were related to thinning within the left LOC (ß = -0.45, p < 0.001), while higher serum levels of TNF-α were associated to a greater surface area in the right superior frontal gyrus (ß = 0.32, p = 0.045). Besides, we have also identified a trend that negatively correlates the cortical thickness of the left fusiform gyrus with the increases in BMI. It was also associated to fibrinogen (ß = -0.33, p = 0.035). CONCLUSIONS: These results suggest that adolescents' body mass increases are related with brain abnormalities in areas that could play a relevant role in some aspects of feeding behavior. Likewise, we have evidenced that these cortical changes were partially explained by inflammatory agents such as fibrinogen and TNF-α.

[Physical activity programmes to reduce overweight and obesity in children and adolescents; a systematic review]. / Programas de actividad física para reducir sobrepeso y obesidad en niños y adolescentes; revisión sistemática.

INTRODUCTION: Obesity treatment has been the subject of much controversy; various authors have recommended the application of a comprehensive treatment programme, and in the light of this previous research, we consider the question of what is the most effective programme of physical activity to reduce overweight and obesity in children and adolescents. AIMS: To analyse major studies on the effectiveness of physical activity in reducing overweight and obesity in children and adolescents. METHOD: Systematic review of the results of physical activity programmes, published in scientific articles, to reduce overweight and obesity. Using an automated database search in PubMed and Google Scholar, conducted from October 2013 to March 2014, we identified 85 valid items. In selecting the items, the criteria applied included the usefulness and relevance of the subject matter and the credibility or experience of the research study authors. The internal and external validity of each of the articles reviewed was taken into account. CONCLUSIONS: This review confirmed the effectiveness of physical activity in reducing overweight and obesity in children and adolescents. The most effective programmes were those combining aerobic and anaerobic exercises. It is generally accepted that at least 180 minutes per week should be dedicated to exercise, in the form of three 60-minute sessions of moderate intensity. Such programmes could be sufficient for persons with overweight or obesity. Researchers in this field agree that when a diet based on an appropriate distribution of meals is combined with regular physical activity, they reinforce each other, and thus optimum results are obtained. Weight reduction programmes that take account of family involvement are more effective than nutrition education itself or other routine interventions that fail to consider family involvement. The role of pa rents and of the persons around the child or adolescent is essential to reinforce positive behaviour toward lifestyle change.

Introducción: El tratamiento contra la obesidad ha sido muy discutido y varios autores abogan por un tratamiento integral de la obesidad. Todos los referentes conducen a plantear ¿cuál es el programa de actividad física más efectivo para reducir el sobrepeso y la obesidad de niños y adolescentes? Objetivo: Analizar los principales estudios sobre la eficacia de la actividad física para reducir el sobrepeso y la obesidad de niños y adolescentes. Método: Revisión sistemática de los resultados de programas de actividad física para reducir el sobrepeso y la obesidad publicados en artículos científicos. Se identificaron 85 artículos a través de la búsqueda automatizada en las bases de datos PUBMED y Google Scholar; se llevó a cabo entre los meses de octubre de 2013 y marzo de 2014. Para seleccionar los artículos fue preciso considerar la utilidad y la relevancia del tema estudiado y la credibilidad o experiencia de los autores en la temática. Se tuvo en cuenta la validez interna y externa de cada uno de los artículos revisados. Conclusiones: Se identificó la efectividad de la actividad física para reducir el sobrepeso y la obesidad de niños y adolescentes. El programa de actividad física más efectivo es el que combina ejercicios aeróbicos y anaeróbicos. Existe consenso en acumular más de 180 minutos a la semana dedicados a estos fines, con 3 sesiones de 60 minutos cada una de ejercicio físico a la semana. De una intensidad moderada, podrían ser suficientes para ejecutar un programa de ejercicio físico para esas personas con sobrepeso y obesidad. Coinciden los autores en que, cuando se combina una dieta controlada por una adecuada distribución de las comidas y con la práctica de actividad física, se potencian mutuamente, con lo que se obtie nen los mejores resultados. Los programas de reducción de peso que tengan en cuenta la participación familiar son más eficaces que la propia educación alimentaria y otras intervenciones de rutina que no consideren esa participación familiar. El rol de los padres y de las personas que rodean al niño y al adolescente es fundamental para reforzar las conductas positivas hacia el cambio de estilo de vida.

[Monogenic human obesity: role of the leptin-melanocortin system in the regulation of food intake and body weight in humans]. / Obesidad monogénica humana: papel del sistema leptina-melanocortina en la regulación de la ingesta de alimentos y el peso corporal en humanos.

Human obesity is a disorder of multifactorial origin in which genetic and environmental factors are involved. To understand the mechanisms regulating energy intake and fat accumulation in the body, it is important to study the genetic alterations causing monogenic obesity. Most of the genes involved in monogenic obesity are associated with the leptin-melanocortin system; hence the importance of studying this system by analysing natural mutations in mice. Previous studies have described mutations in leptin and its receptor, proopiomelanocortin and prohormone convertase 1 associated with human obesity of monogenic origin. The aim of this study is to provide an updated review of the main characteristics and functioning of the leptin-melanocortin system, and its implications and potentialities in regulating food intake and body weight.

Does preoperative fine needle aspiration-biopsy produce tumor recurrence in patients following liver transplantation for hepatocellular carcinoma?

INTRODUCTION: Liver transplantation (OLT) has been advocated for patients with carcinoma hepatocellular (HCC). A preoperative biopsy (fine needle aspiration biopsy) [FNA] facilitates preoperative diagnosis of adverse pathological factors: vascular invasion or histologicalic differentiation. But a biopsy may cause abdominal dissemination and be related to a higher incidence of recurrence. PATIENTS AND METHODS: From April 1986 to December 2003, we performed 95 OLT for HCC. We divided them in two groups: group A without FNA-biopsy (67.9%) and group B with FNA-biopsy (32.1%). RESULTS: We obtained the diagnosis of HCC in only 15 patients (57.6%). In two patients an OLT was avoided due to the presence of abdominal dissemination at the time of transplant. Recurrence incidence was higher among group B patients (5.9% vs 31.8%; P = .003) due to extrahepatic recurrence (2% vs 27.3%; P = .003). No differences were observed in morbidity or mortality. The two groups were homogeneous in epidemiological and pathological variables except: sex distribution, Child status, AFP level, tumor size, and pTNM stage. If we compare recurrence rates in the two groups attending to these nonhomogeneous variables, it was significantly higher among patients with tumors larger than 3 cm, pTNM I-III stage, Child B-C, AFP >200 ng/mL, and males or females. CONCLUSIONS: Preoperative liver biopsy is associated with a larger incidence of tumor recurrence, so we believe that it is not necessary prior to an OLT for HCC.

Short- and long-term outcomes after living donor liver transplantation.

INTRODUCTION: Living donor liver transplantation was first described as a way to alleviate the organ shortage. Extensive studies of both the prospective donor and the recipient are necessary to ensure successful outcome. In this paper we describe our results in 28 living donor liver transplantations from the perspective of the donor and the recipient. METHODS: A prospective, longitudinal, observational, comparative study was conducted from April 1995 to October 2004, including 28 living donor liver transplantations. RESULTS: After a mean follow-up time of 25.6 +/- 20.58 months, all donors are alive, showing normal liver function tests. All of them have been reincorporated into their normal lives. At the end of the study and after a mean follow-up time of 21.2 +/- 14.3 months, 86.3% of the adult recipients are alive. Actuarial recipient survivals at 6, 12, and 36 months were 86.36%. Actuarial mean survival time was 44 months (95% CI, 37 to 51). At the end of the study, 77.3% of the grafts are functioning. Actuarial graft survivals at 6, 12, and 36 months were 77.27%. Actuarial mean graft survival time was 32 months (95% CI, 25 to 39). The main complications were hepatic artery thrombosis (n = 2) and small for-size syndrome (n = 2). At a mean follow-up of 20.33 +/- 7.74 months, all pediatric recipients are alive. Actuarial recipient survivals at 12 and 36 months were 100% and actuarial graft survivals were 80%. CONCLUSIONS: Living donor liver transplantation may increase the liver graft pool, and therefore reduce waiting list mortality. Nevertheless caution must be deserved to avoid surgical morbidity and mortality in with the donor the recipient.

Hepatic vein reconstruction in living donor liver transplantation.

INTRODUCTION: Living donor liver transplantation has emerged as a response to the cadaveric graft shortage, especially for adult recipients. Both right and left liver grafts are widely used, although some technical problems remain unresolved. Herein we describe our technique for reconstruction of the venous outflow in living donor liver transplantation. METHODS: From April 1986 to September 2004, 1012 liver transplantations were performed including 30 living donor liver transplantations between April 1995 and September 2004. We have selected the first 28 cases to ensure a mean follow-up of 21.07 +/- 13.11 months. We transplanted 18 right lobe grafts, 7 left lobe grafts, and 3 left lateral segment grafts. A surgical technique is described herein. RESULTS: No venous outflow obstruction developed among living donor liver transplantation recipients. CONCLUSION: We recommend reconstruction of the hepatic veins in living donor liver transplantation including joining together the three hepatic veins in the recipient to avoid venous outflow obstruction.

Exceptional bilateral adrenalectomy after secondaries from colorectal cancer.

We report a very uncommon case of bilateral adrenal metastasis treated at our institution. The patient was 65 years old, with a history of low anterior resection for colorectal cancer in 2001. One year later, he was diagnosed with bilateral adrenal metastasis, based on the results of abdominal computed tomography-scan. A bilateral adrenalectomy extended to distal pancreatectomy and splenectomy was performed. Postoperative course was uneventful. He is alive and free of disease 12 months after adrenalectomy. We conclude adrenal metastasis from colorectal cancer should be managed surgically, even if they are bilateral.

Pulmonary hypoplasia in Jarcho-Levin syndrome

Jarcho-Levin syndrome, also known as spondylothoracic dysplasia and characterized by short trunk dwarfism, "crab-like" rib cage, with ribs and vertebral defects; it is not uncommon in Puerto Ricans. Many patients die in early infancy due to respiratory compromise associated to lung restriction and the reported cases emphasize mostly the skeletal malformations associated to the syndrome. We report the autopsy findings in a newborn with isolated Jarcho-Levin syndrome emphasizing pulmonary pathology. He was a pre-term male who died of respiratory failure at three hours old and, autopsy findings confirmed the clinical diagnosis. Internal examination showed hypoplastic lungs with normal lobation. The histological structure appeared normal and relatively mature; the diaphragm showed eventration and unilateral absence of musculature. This case shows the worst spectum of the Jarcho-Levin syndrome: pulmonary hypoplasia not compatible with extrauterine life. Since thoracic restriction is present during the fetal period, the degree of pulmonary hypoplasia probably defines survival beyond the neonatal period.

Live liver donation: a prospective analysis of exclusion criteria for healthy and potential donors.

INTRODUCTION: Living donor liver transplantation represents a controversial option to increase the donor pool. DESIGN: Prospective and descriptive clinical study. OBJECTIVE: (1) To identify risk factors (exclusion criteria) for live donation; (2) to determine the rate of recipients that benefit from a living donor. METHODS: Between May 1995 (first adult-to-adult living donor liver transplantation in Spain) and November 2002, we evaluated 74 healthy volunteers and performed 12 living donor liver transplants (no donor mortality). RESULTS: All actual donors and volunteers are alive and healthy. After a mean time of 3.2+/-0.5 weeks, 72% of potential donors were considered unsuitable for live donation. Exclusion criteria were grouped in three categories: (primary) donor safety reasons (68%); (secondary): ABO mismatch (17%) and (tertiary): cadaveric graft transplantation (15%). Consequently, just 43.7% of the recipients presenting to us with a potential living donor, did finally benefit from these organs. The mortality rate was 8.3% for 43 recipients presenting with a living donor in comparison to 15% for those who did not (321 recipients between May 1995 and November 2001). CONCLUSIONS: ALDLT can benefit a significant number of recipients on the waiting list (43.7% of those presenting with a donor). The most frequent exclusion criteria concern donor safety, namely, unsuspected chronic liver diseases and unsuspected thrombophilic disorders.

Liver transplantation for hepatocellular carcinoma: our experience from 1986.

UNLABELLED: Currently liver transplantation is the treatment of choice for early hepatocellular carcinoma and end-stage liver disease. We analyzed our experience to identify factors that could be used to select patients who will benefit from liver transplantation. PATIENTS AND METHODS: From April 1986 to December 2001, 71 (8.7%) of 816 LT performed in our institution, were for patients with hepatocellular carcinoma. In 25 patients the tumor was observed incidental by (35.2%). All patients had liver cirrhosis, most due to hepatitis C related (35) or alcoholic (14) diseases. Before liver transplantation, chemoembolization was performed in 18 patients (25.4%). RESULTS: Bilateral involvement was present in seven patients. Eight patients showed macroscopic vascular invasion, and eight others showed satellite nodules. Most patients were stage TNM II (29) and IVa (16). Overall 1-, 3-, and 5-year survival were 79.3%, 61%, and 50.3% with recurrence-free survivals of 74.6%, 57.5%, and 49%, respectively. With a mean follow-up of 42 months, 12 patients (19%) developed recurrence and 29 patients died (only 11 due to recurrence). Stage TNM IVa, macroscopic vascular invasion, and the presence of satellite nodules significantly affected overall survival and recurrence-free survival rates and histologic differentiation and bilateral involvement only recurrence-free survival. Patients with solitary tumors less than 5 cm or no more than three nodules smaller than 3 cm showed better recurrence-free survival and lower recurrence rates. DISCUSSION: In our experience, liver transplantation proffers good recurrence-free survival and low recurrence rates among patients with limited tumor extension. The most important prognostic factor was macroscopic vascular invasion.

Relation between serum lipoperoxide concentrations and iron or copper status over one year in Cuban adult men.

The aims of this study were to determine the relations between iron and copper status and lipid peroxidation at different periods over one year in low-income and low-energy intake healthy subjects. The study was conducted in 199 middle-aged healthy Cuban men from March 1995 to February 1996. Iron status was assessed by the determination of serum ferritin, transferrin saturation, whole blood hemoglobin and iron intakes. Copper status was evaluated by the determination of serum copper and copper intakes. Serum thiobarbituric acid substances (TBARS) determination was used as an index of lipid peroxidation. Rank correlations were observed between serum TBARS concentrations and iron or copper status indices at different periods. In period 3 (end of the rainy season), serum TBARS and ferritin concentrations were maximum whereas blood hemoglobin levels and iron intake were minimum. Serum TBARS concentrations were significantly higher than the reference values of the laboratory whereas, iron and copper status were within the reference ranges. These results suggested that iron and copper status may be associated with lipid peroxidation in subjects without metal overloads and that variations over the year needed to be taken in account.

[Role of anatomic variations and methods of hepatic artery reconstruction in the incidence of thrombosis following liver transplantation]. / Ruolo delle varianti anatomiche e delle metodiche di ricostruzione dell'arteria epatica nell'incidenza di trombosi dopo trapianto di fegato.

AIM: The aim of this study was to investigate the incidence of anatomic variations of hepatic artery (HA) in order to evaluate if anatomical anomalies may be associated with an increased incidence of hepatic artery thrombosis (HAT) after orthotopic liver transplantation (OLT). Moreover, we focused on arterial reconstructive technique associated with a low incidence of HAT. METHODS: We reported a consecutive series of 687 OLT in 601 patients (1986-1999). Hepatic arterial reconstruction was variable and dependent upon donor and recipient anatomy, even if arterial anastomosis was mainly of two types: the end-to-end anastomosis (EEA), used in 340/687 OLT (49.4%) and the branch patch anastomosis (BPA), performed in 347/687 OLT (50.5%). Interrupted sutures of 7/0 polypropylene always were used. RESULTS: The diagnosis of HAT was made in 17/687 patients (2.47%). Anomalous hepatic arteries were found in 5/17 cases (29.4%). In the EEA group HAT occurred in 12/340 patients (3.53%), whereas in the BPA group HAT was diagnosed in 5/347 cases (1.44%) (p = 0.078). DISCUSSION: Anatomic variations of HA, most frequently observed, were the left hepatic artery originating from the left gastric artery (9.7-18%) and the right hepatic artery originating from the superior mesenteric artery (7.5-18%). There was no increased incidence of HA complications in the presence of HA anomalies in the donor. Moreover, the existence of an anomaly in the recipient HA was not important if it had appropriate size anf flow. CONCLUSIONS: In our series, the branch patch technique, using the hepatic-gastroduodenal bifurcation, was our current preferred method of arterial anastomosis, with a HAT-rate of 1.44%.

Hepatic steatosis in liver transplant donors: common feature of donor population?

Fatty change in donor livers is a risk factor for poor function after orthotopic liver transplantation. Various prevalences of steatosis have been reported in time 0 biopsies. The aim of this research was to determine, in a longitudinal study, the degree (percent of hepatocytes involved) and type (size of vacuoles) of fatty change shown by various histologic techniques. Four staining methods were used on sections from three liver wedge biopsies--at liver procurement, at the back-table, and after reperfusion--from 83 consecutive donor livers. Results in Sudan III-stained (SS) sections showed the greatest sensitivity (87.1%), negative predictive value (91.8%), and agreement rate (k = 0.77) when compared with results in thin (1 micron) plastic-embedded toluidine blue-stained (TBS) sections. High-grade steatosis (> 30% steatotic hepatocytes) was identified in 49.4% of SS sections, 46.9% of TBS sections, 38.5% of frozen hematoxylin-eosin (H&E)-stained sections, and 20.7% of deparaffinated H&E-stained sections. Microscopic observations disclosed two types of steatotic pattern: (1) A predominantly small-droplet lipid vacuolzation (high-grade microsteatosis), similar to the steatosis associated with Reye syndrome, was seen in 29% of SS sections and 25% of TBS sections--approximately one-fourth of grafts; and (2) a combined pattern of large and small fat drops (high-grade macromicrosteatosis) was seen in 20% of SS sections and 22% of TBS sections. We concluded that moderate to severe steatosis is a frequent finding in donor livers. The difficulty in detecting lipidic microvacuoles in H&E-stained sections may be the reason for underestimating the grade of fatty change or even for diagnosing as normal some biopsies with high-grade microsteatosis.