Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Remote pharmaceutical care for patients with rheumatoid arthritis and psoriasis.

BackgroundAccess to drugs with hospital-restricted dispensation, such as those for patients with rheumatoid arthritis or psoriasis, is regulated by healthcare policy. These drugs have the greatest cost-effective impact on the healthcare system. This is why a model for Pharmaceutical Care based on follow-up teleconsultations was defined in our hospital to improve patient well-being. Objective To evaluate clinical changes on patients when our remote Pharmaceutical Care model is applied and describe the work carried out by pharmacists when applying it. Setting Pharmacy Department of a Hospital in Barcelona, Spain. Method Cross-sectional observational study of the remote Pharmaceutical Care model developed by Clinical Pharmacists. All patients diagnosed with psoriasis or rheumatoid arthritis who were receiving active treatment with Hospital/Specialist only drugs, during the period from May to December 2018, were included. Main outcome measures The corresponding healthcare activity was recorded and to determine the utility of the model, the clinical response to treatment of patients included in the study was recorded. Results The implementation of teleconsultation is statistically related to the biological treatment response of patients with psoriasis (p = 0.006) and rheumatoid arthritis (p = 0.019). In those patients the healthcare activity of calculating and/or recording clinical variables of effectiveness/safety is statistically associated to biological treatment response (65.62% vs 35%, p = 0.015 and 73.14% vs 53.26%, p = 0.003). Conclusions The implementation of the model described lends added value to traditional pharmacotherapeutic management of biological treatments in patients with rheumatoid arthritis and psoriasis since response is improved but patient well-being is not diminished.

Receptors involved in dexketoprofen analgesia in murine visceral pain.

Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEXinduced antinociception.

Bacterial cellulose hydrogel loaded with lipid nanoparticles for localized cancer treatment.

The use of hybrid materials, where a matrix sustains nanoparticles controlling the release of the chemotherapeutic drug, could be beneficial for the treatment of primary tumors prior or after surgery. This localized chemotherapy would guarantee high drug concentrations at the tumor site while precluding systemic drug exposure minimizing undesirable side effects. We combined bacterial cellulose hydrogel (BC) and nanostructured lipid carriers (NLCs) including doxorubicin (Dox) as a drug model. NLCs loaded with cationic Dox (NLCs-H) or neutral Dox (NLCs-N) were fully characterized and their cell internalization and cytotoxic efficacy were evaluated in vitro against MDA-MB-231 cells. Thereafter, a fixed combination of NLCs-H and NLCs-N loaded into BC (BC-NLCs-NH) was assayed in vivo into an orthotopic breast cancer mouse model. NLCs-H showed low encapsulation efficiency (48%) and fast release of the drug while NLCs-N showed higher encapsulation (97%) and sustained drug release. Both NLCs internalized via endocytic pathway, while allowing a sustained release of the Dox, which in turn rendered IC50 values below of those of free Dox. Taking advantage of the differential drug release, a mixture of NLCs-N and NLCs-H was encapsulated into BC matrix (BC-NLCs-NH) and assayed in vivo, showing a significant reduction of tumor growth, metastasis incidence and local drug toxicities.

Consumption of seafood and its estimated heavy metals are associated with lipid profile and oxidative lipid damage on healthy adults from a Spanish Mediterranean area: A cross-sectional study.

The association between the consumption of seafood and its benefits on cardiovascular (CVD) risk can be challenged by its heavy metal (HM) content. This study aimed to explore the association of seafood consumption and its estimated HM contents with the lipid profile and lipid oxidation biomarkers in adults from a Spanish Mediterranean area who do not present risk factors for CVD. In this cross-sectional study, the clinical history, three-day dietary record, lipid profile (LDLc, HDLc, APOB/A, and triglyceride levels), plasma oxidised LDL (oxLDL) and 8-isoprostane levels of 81 adults without risk factors for CVD [43% men, with a mean age of 43.6 years (95%CI: 40.1-47.1)] were assessed. The HM [arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb)] contents of seafood were estimated according to data from analyses of marine species in the same Mediterranean area. Moderate adherence to the Mediterranean diet (score: 4.6 of 9) with a mean seafood consumption of 74.9g/day (95%CI: 59.9-89.9), including 22.7g of shellfish per day (95%CI: 13.5-31.9), was observed. The estimated HM contents were lower than the provisional tolerable weekly intakes (PTWIs): 21.12µg/kg/week As, 0.57µg/kg/week InAs, 0.15µg/kg/week Cd, 1.11µg/kg/week Hg and 0.28µg/kg/week Pb. After adjusting by confounder variables, an increase in shellfish consumption was associated with increases in the levels of LDLc (P=0.013), non-HDLc (P=0.015), APOB/A (P=0.02) and plasma oxLDL (P=0.002). Moreover, an increase in the estimated As and Hg levels in shellfish was associated with an increase in LDLc (P=0.015 and P=0.018, respectively), non-HDLc (P<0.008 and P<0.008, respectively), APOB/A ratio (P=0.008 and P=0.009, respectively), and oxLDL (P≤0.001 and P≤0.001, respectively) levels. In conclusion, in adults without risk factors for CVD, increasing shellfish consumption, even by a moderate amount, could favour a pro-atherogenic lipid profile and a higher level of oxidised LDL. These associations are likely influenced by the estimated exposure to As and Hg from shellfish despite these values are lower than the PTWIs.

Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).

BACKGROUND: Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis MATERIAL AND METHODS: Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p <0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathway CONCLUSIONS: This study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Home enteral nutrition in Spain; NADYA registry 2011-2012.

OBJECTIVE: To describe the results of the home enteral nutrition (HEN) registry of the NADYA-SENPE group in 2011 and 2012. MATERIAL AND METHODS: We retrieved the data of the patients recorded from January 1st 2011 to December 31st 2012. RESULTS: There were 3021 patients in the registry during the period from 29 hospitals, which gives 65.39 per million inhabitants. 97.95% were adults, 51.4% male. Mean age was 67.64 ± 19.1, median age was 72 years for adults and 7 months for children. Median duration with HEN was 351 days and for 97.5% was their first event with HEN. Most patients had HEN because of neurological disease (57.8%). Access route was nasogastric tube for 43.5% and gastrostomy for 33.5%. Most patients had limited activity level and, concerning autonomy, 54.8% needed total help. Nutritional formula was supplied from chemist's office to 73.8% of patients and disposables, when necessary, was supplied from hospitals to 53.8% of patients. HEN was finished for 1,031 patients (34.1%) during the period of study, 56.6% due to decease and 22.2% due to recovery of oral intake. CONCLUSIONS: Data from NADYA-SENPE registry must be explained cautiously because it is a non-compulsory registry. In spite of the change in the methodology of the registry in 2010, tendencies regarding HEN have been maintained, other than oral route.

Objetivos: Describir los resultados del registro de nutrición enteral domiciliaria (NED) del grupo NADYASENPE de los años 2011 y 12. Material y métodos: Se recopilaron los datos introducidos en el registro desde el 1 de enero de 2011 al 31 de diciembre de 2012. Resultados: Hubo 3021 pacientes en el registro durante el periodo, procedentes de 29 hospitales, lo que da una prevalencia de 65,39 casos por millón de habitantes. 97.95% fueron adultos, 51,4% varones. La edad media fue 67,64 ± 19,1 años y la mediana 72 años para los adultos y 7 meses para los niños. La duración media de la NED fue 351 días y para el 97,5% fue el primer episodio con NED. La mayoría de pacientes tenían NED por una enfermedad neurológica (57,8%). La vía de acceso fue sonda nasogástrica para el 43,5% y gastrostomía para el 33,5%. La mayoría de pacientes tuvieron un nivel de actividad física limitado y, respecto a la autonomía, 54,8% necesitaba ayuda total. La fórmula de nutrición se suministró desde las oficinas de farmacia para el 73,8% y los fungibles, cuando fueron necesarios, desde los hospitales para el 53,8%. La NED se suspendió en 1.031 pacientes (34,1%) durante el periodo de estudio, 56,6% debido a fallecimiento y 22,2% debido a recuperación de la vía oral. Conclusiones: Los datos del registro NADYA-SENPE deben ser interpretados con precaución ya que se trata de un registro voluntario. A pesar del cambio de metodología del registro en 2010, las tendencias en NED se han mantenido, salvo la importancia cuantitativa de la vía oral.

Comparación de la profundidad de fotopolimerización de resinas fluidas a través de 4 porcelanas de alta opacidad / Comparison of the light cure depth of flowable resins through 4 high-opacity porcelains

Se estudia la profundidad de polimerización que se obtiene en resinas compuestas fluidas al ser iluminadas a través de bloques de cerámica de distinta composición y distintos grosores. En formadores metálicos cilíndricos de 4mm de alto y 6mm de diámetro se depositó resina fluida hasta enrasar en superficie y posteriormente se iluminó por 60 seg interponiendo las distintas cerámicas entre la luz y la resina. Se utilizó una lámpara led para la iluminación del material. Algunos de los grupos en estudio presentaron diferencias significativas entre sí dependiendo del grosor de la cerámica y el tipo de ella. Es posible polimerizar resina fluida a través de cerámicas de distinta opacidad obteniendo grosores de resina mayores a los que se establecen para la línea de cementación de las restauraciones de cerámica libre de metal. Relevancia: A través de bloques de cerámica de diferente opacidad y composición se obtiene polimerización de resina compuesta fluida, lo que permitiría usar esta resina como medio de cementación de restauraciones a base de cerámicas cuyos grosores permitan el paso de la luz.

We studied the depth of cure obtained in flowable composite resins when illuminated through ceramic blocks of different composition and different thicknesses. The flowable composite resin was deposited in forming metal cylinders of 4mm of high and 6mm of diameter, brought to volume and then illuminated for 60 sec interposing the different ceramics between light and resin. A LED lamp was used to illuminate the material. Some of the groups exhibited significant differences among them depending on the thickness of the ceramic and its type. Flowable resin may polymerize through ceramics of different thicknesses and could be used for the cementation of ceramic restorations.

Predictors of haemoconcentration at delivery: association with low birth weight.

PURPOSE: [corrected] To assess the factors associated with risk of haemoconcentration at delivery, such as initial haemoglobin levels and alterations in the HFE gene, and its effect on low birth weight in pregnant women supplemented with moderate doses of iron. METHODS: Case-control study nested in a longitudinal study conducted on 217 healthy pregnant women taking moderate iron supplementation and their newborns. Women were classified according to the risk of haemoconcentration at delivery, defined as Hb > 130 g/L. Each subject's obstetric and clinical history, smoking habit, and iron biochemical parameters (haemoglobin (Hb), serum ferritin and transferrin saturation) were recorded at 1st, 2nd and 3rd trimester and at delivery. Polymorphisms of the HFE gene (C282Y, H63D and S65C) were also measured. RESULTS: The average of iron supplementation of all the women was 43.9 mg/dia (geometric mean, 95 % CI: 43.6-44.1). Higher levels of Hb at early gestation and the presence of HFE mutations were associated with greater risk of haemoconcentration at delivery, adjusted odds ratios of 1.14 (95 % CI: 1.05-1.25) and 5.35 (95 % CI: 1.6-17.8). Haemoconcentration at delivery was associated with a greater risk of low birth weight, adjusted odd ratio of 11.48 (95 % CI: 1.13-116.6). CONCLUSIONS: Moderate daily doses of supplementary iron may be harmful for foetal growth in women with alterations in HFE gene and who started pregnancy with good haemoglobin levels. Overall, this suggests the importance of determining a woman's iron status early in her pregnancy in order to establish a more appropriate pattern of supplementation.

[Early of late supplementation: similar evolution of the iron status during pregnancy]. / Suplementación temprana o tardía: similar evolución del estado de hierro durante el embarazo.

The highest iron demands during pregnancy occur in the third trimester, although preventive iron supplementation is recommended from early stages of the pregnancy. The aim of the study was to compare whether early supplementation with moderate iron doses better prevents the decrease of iron levels during gestation than the late supplementation. One hundred and eighty-four pregnant women participated. They received iron supplements before or after week 20 of pregnancy. At each quarter, serum ferritin (SF), transferrin saturation (TS) and hemoglobin (Hb) were determined. Gestational age-standardized hemoglobin (zHb) was calculated. The early supplementation group received a mean of 40.5 ± 15.7 mg/day and the late group 43.1 ± 11.9 mg/day. Iron deficiency (impaired SF and TS) iron deficiency anemia increased as pregnancy progressed without significant differences between the early and late supplementation groups. More than half of the women ended up their pregnancy with iron deficiency and more than 20% with iron deficiency anemia. In conclusion, although early intake of iron supplements is recommended in pregnancy, no better preventive effect is observed on the decrease of iron levels with early supplementation as compared to late supplementation when moderate iron doses are used.

Depleted iron stores without anaemia early in pregnancy carries increased risk of lower birthweight even when supplemented daily with moderate iron.

BACKGROUND: Gestational iron-deficiency anaemia has adverse pregnancy outcomes. Antenatal iron supplementation can be beneficial in anaemic women, but the effects in non-anaemic women are controversial. This observational study assessed the relationship of maternal iron stores (depleted or non-depleted) at gestational Weeks 8-12 with birthweight, in non-anaemic pregnant women following the guidelines of the Ministry of Health of Spain. METHODS: Healthy, non-anaemic pregnant women (n = 205) were studied. At the first antenatal visit, a general clinical assessment was conducted, and basal blood taken. Women were classified as having non-depleted or depleted iron stores [serum ferritin (SF) < 12 µg/l)]. Daily antenatal iron supplements (48 mg on average) were started at 17 (range: 16-18) weeks. Blood haemoglobin, SF and transferrin saturation (TS) were measured in each trimester. RESULTS: Of the study sample, 20, 54 and 66% had SF < 12 µg/l in the first, second and third trimesters, respectively. The prevalence of iron-depletion (SF < 12 µg/l) and iron-deficiency (SF < 12 µg/l and TS < 16%) was greater during the entire pregnancy in women with initial iron depletion versus no depletion (81.6 and 73.7% versus 61.7 and 55.4%, respectively, in the third trimester, P < 0.05). Women with initial iron-depletion delivered babies weighing on average 192 g less than that with initial iron stores, after adjusting for confounding variables (P = 0.028). CONCLUSIONS: Beginning pregnancy with non-depleted iron stores is beneficial for the maternal iron status during pregnancy and infant birthweight. These findings reaffirm the importance of health promotion to ensure that women have adequate iron stores prior to, or early in, pregnancy when supplemented with moderate daily iron doses.

Aplicación del consentimiento informado en la práctica odontológica en el área del gran Asunción en el año 2008 / Implementation of informed consent in dental practice in the area of large Asunción in 2008

El consentimiento informado es la manifestación libre y voluntaria del paciente previa información clara, real y completa sobre sus derechos, los procedimientos, riesgos y efectos para su salud y su vida. Este documento deberá suscribirse con antelación al procedimiento y anexarse a la historia clínica. El odontólogo, respetando principios éticos, además de garantizar la confidencialidad a sus pacientes, debe presentar las distintas alternativas de tratamiento, obtener el consentimiento y respetar sus decisiones. A pesar de que los conocimientos teóricos sobre la práctica del consentimiento informado son escasos, existe una tendencia significativa a destinar tiempo en la consulta dental para su empleo, especialmente en la nueva generación. Las características de los profesionales y las de consentimientos prestados tienen que ser estudiadas todavía sistemáticamente, por lo que el objetivo de este trabajo fue evaluar la aplicación del consentimiento informado en la práctica odontológica en el área del Gran Asunción en el año 2008. El estudio fue del tipo observacional descriptivo de corte transverso. Los datos fueron obtenidos a través de un cuestionario auto-administrado, participando 106 odontólogos que ejercen activamente la profesión en distintos lugares de la capital y área metropolitana (Gran Asunción). Los resultados demuestran que el 85% de los encuestados conoce lo que es el consentimiento informado, el 80% considera necesario obtenerlo antes de realizar un tratamiento odontológico y todavía una importante cantidad de profesionales utiliza el contrato verbal o no lo establece

[Drotrecogin alfa (activated): specific treatment for serious sepsis]. / Drotrecogina alfa (activada): tratamiento específico para la sepsis grave.

Severe sepsis is a high prevalent disease at Intensive Care Units with no specific treatment till recently. Several clinical trials show low serum levels of activated protein C in this kind of patients. Recently, drotrecogin alfa (activated), a recombinant human activated protein C, has been approved in Spain for severe sepsis treatment in addition to the best patient care. Protein C (activated) has antithrombotic, profibrinolitic an antiinflamatory properties. So far, Prowess (phase 3 trial) is the most important clinical trial conducted with drotrecogin alfa (activated) at the moment. It demonstrates not only its efficacy and safety, but also a 19.4% reduction in the relative risk of death. Nevertheless, it is difficult to decide which patients would be candidate for this new therapy due to its lack of experience, high cost and the risk-benefit relationship. This review attempts to provide an overview about this new hospital drug.