Recensiones [Revista de Historia Económica Año XII Primavera-Verano 1994 n. 2 pp. 437-472]

Editada en la Universidad Carlos IIIRobert C. Allen. Enclosure and the Yeoman. The Agricultural Development of the SouthMidlands 1410-1850 (Por Gaspar Feliú).-- Ruggiero Romano. Conjonctures opposées. La «crise» du XVII siècle: en Europe et en Amérique ibérique (Por Gaspar Feliú).-- Simposio de Historia de las Mentalidades. Instituto Nacional de Antropología e Historia, México. Familia y poder en Nueva España (Por Juan Carlos Sola Corbacho).-- Leandro Prados de la Escosura y Samuel Amaral (Eds.). La independencia americana: consecuencias económicas (Por Javier Cuenca).-- M.ª Cruz Romeo Mateo. Entre el orden y la revolución. La formación de la burguesía liberal en la crisis de la monarquía absoluta (1814-1833) (Por Ricardo Robledo).-- José G. Cayuela Fernández. Bahía de ultramar. España y Cuba en el siglo XIX. El control de las relaciones coloniales (Por Candelaria Sáiz Pastor).-- José Manuel Pose Antelo. La economía y la sociedad compostelanas a finales del siglo XIX (Por Carlos Larrinaga Rodríguez).-- Frank Broeze. Mr Brooks and the Australian Trade. Imperial Business in the Nineteenth Century (Por Jesús M.ª Valdaliso).-- Robert H. Bremner. Desde lo más bajo. El descubrimiento de la pobreza en Estados Unidos / James T. Patterson. La lucha contra la pobreza en los Estados Unidos de América, 1900-1985 (Por Nuria Puig).-- Justo Navarro Clari. Curso de Historia Económica (Por Antonio Santamaría)Publicad

CX-072 (pacmilimab), a Probody® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

Background: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression

Determinants of activity and efficacy of anti-PD1/PD-L1 therapy in patients with advanced solid tumors recruited in a clinical trials unit: a longitudinal prospective biomarker-based study

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored

Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients

Las estanniocalcinas se expresan en el tejido del páncreas, y se sugirió una correlación directa entre la insulina circulante y las concentraciones de STC2 en el ser humano. Aquí, mostramos una correlación significativa entre STC1 y tanto la glucemia como la hemoglobina glicosilada entre los pacientes con DM2, mientras que los pacientes con DM2 que presentan los mayores valores de hemoglobina glicosilada exhibieron la menor expresión de STC2. Sin embargo, el tratamiento de los pacientes con fármacos antiglicémicos no modifica significativamente la expresión de ambas STC. Por otra parte, los ratones STC2-/- que mostraron sobrepeso neonatal y adulto presentaron además una glucemia desregulada cuando fueron alimentados con una dieta hipercalórica (pellet de cría, BP). Esta alteración es más evidente en las primeras etapas de la vida animal. La glucemia desregulada en estos ratones se confirmó mediante una prueba oral de glucosa. Además, los ratones STC2-/- presentan un aumento del tamaño del páncreas; así, el análisis histológico revela que los ratones WT responden a la dieta BP aumentando el tamaño de los islotes pancreáticos a través de la inducción de la división celular, y los ratones STC2-/- carecen de este mecanismo compensatorio. Contrariamente, los ratones alimentados con STC2-/- muestran un mayor número de islotes pero de tamaño similar a los alimentados con el pellet regular. El análisis histopatológico demuestra la alteración de la estructura de los tejidos y las infiltraciones de eritrocitos en los ratones STC2-/-, posiblemente debido al estrés evocado por la dieta BP. Por último, se observó una mayor inmunotinción de glucagón en el islote de los ratones STC2-/-, y el ensayo ELISA de glucagón confirmó el aumento del glucagón circulante. En resumen, presentamos pruebas del papel de los STC, principalmente el STC2, como posible marcador temprano durante el desarrollo de la diabetes mellitus.Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2-/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2-/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2-/- mice lack this compensatory mechanism. Contrary, BP fed STC2-/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2-/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2-/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus.• Ministerio de Economía y Competitividad. Becas 2013‐45564C2‐1‐P, BFU‐2016‐74932‐C2‐1‐P • Programa Juan de la Cierva. Becas IJCI‐2015‐25665, JC‐2012‐ 2934 • Junta de Extremadura. Beca PRIIB16046peerReviewe

Post-Hospital Syndrome and Hyponatremia

Introduction: Post-hospital syndrome (PHS) is defined as a period of vulnerability during the first 30 days after a patient is discharged from hospital, in which multiple factors come into play. Hyponatremia is the most frequent hydroelectrolytic disorder in hospitalized patients and may be related to the appearance of PHS. Objective: The objective is to estimate the prevalence of PHS that is assessed as the rate of readmissions in the first 30 days after discharge, in patients with hyponatremia. Material and Methods: It is a descriptive observational study of patients with hyponatremia who were discharged from 1 September 2010 to 2 February 2020 at the Internal Medicine Service of the Hospital University of San Juan (Alicante, Spain). Results: Of the 25 included patients, 5 (20%) were readmitted within a month of discharge, after a mean of 11.4 days (standard deviation [SD] 5.1). The overall mortality of the study was 20% (n = 5), with one case of death in the first 30 days post-hospitalization (4%). In 12 patients (48%) the origin of the hyponatremia was undetermined. The most frequently recorded etiology for the condition was pharmacological (n = 7, 28%), and there was pronounced variability in its clinical and laboratory study. The most widely used corrective measure was drug withdrawal, in 16 patients (64%). Water intake restriction was the most common treatment after discharge (5 patients, 20%), followed by urea (2 patients, 8%), while tolvaptan was not used. Conclusion: Hyponatremia may be the cause of PHS, which could increase the rate of early readmission. Hyponatremia is an underdiagnosed and undertreated entity, so it is necessary to apply an appropriate system to optimize its management and, in future studies, to assess its impact on PHS

Liquid biopsies come of age: towards implementation of circulating tumour DNA

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a ‘liquid biopsy’ for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.We would like to acknowledge the support of The University of Cambridge, Cancer Research UK (grant numbers A11906, A20240, A15601) (to N.R., J.D.B.), the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 337905 (to N.R.), the Cambridge Experimental Cancer Medicine Centre, and Hutchison Whampoa Limited (to N.R.), AstraZeneca (to R.B., S.P.), the Cambridge Experimental Cancer Medicine Centre (ECMC) (to R.B., S.P.), and NIHR Biomedical Research Centre (BRC) (to R.B., S.P.). J.G.C. acknowledges clinical fellowship support from SEOM

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Relationship between indoor ambient dose equivalent rates and the architectural style of standalone houses in locations with high naturally occurring radionuclide soil concentrations

There have been numerous studies relating house construction materials with the indoor gamma dose rate mainly coming from natural radionuclide activities. The relationship between the outdoor gamma dose rate and the soil's naturally occurring radionuclide content is well documented. Few studies, however, have investigated the historical evolution of indoor gamma dose levels due to the principal materials used in house construction in geographical areas where outdoor natural radiation levels are significant. The present work was carried out in an area of Spain with high outdoor gamma dose levels (on average, 0.267 µSv h-1) due to the natural radioactive characteristics of its soils, considering a great variety of standalone houses built from the beginning of the 18th century until today with different styles, architectural techniques, and materials in their construction. The measured ambient dose equivalent rates in thgese houses decreased the more recent the date of their construction was. In conclusion, today's architectural style for housing, which uses materials of practically universal origin, not only attenuates part of the irradiation due to the composition of a location's soils but also contributes less to the indoor gamma dose rate due to the relatively low naturally occurring radionuclide concentration of modern building materials. © 2020 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved