Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumour syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterised by MMR-deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade by pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year old female with known Lynch syndrome who presented with severe Cushing’s syndrome was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolaemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after twelve weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. Seven weeks later, the patient became jaundiced and died rapidly with fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supra-physiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage

Bone histomorphometric measures of physical activity in children from Medieval England

Objectives: Histomorphometric studies show consistent links between physical activity patterns and the microstructure underlying the size and shape of bone. Here we adopt a combined bone approach to explore variation in microstructure of ribs and humeri related to physical activity and historical records of manual labor in skeletal samples of children (n=175) from medieval England. The humerus reflects greater biomechanically induced microstructural variation than the rib which is used here as a control. Variation in microstructure is sought between regions in England (Canterbury, York, Newcastle), and between high- and low-status children from Canterbury. Materials and Methods: Thin-sections were prepared from the humerus or rib and features of bone remodeling were recorded using high-resolution microscopy and image analysis software. Results: The density and size of secondary osteons in the humerus differed significantly in children from Canterbury when compared to those from York and Newcastle. Amongst the older children, secondary osteon circularity and diameter differed significantly between higher and lower status children. Discussion: By applying bone remodeling principles to the histomorphometric data we infer that medieval children in Canterbury engaged in less physically demanding activities than children from York or Newcastle. Within Canterbury, high-status and low-status children experienced similar biomechanical loading until around seven years of age. After this age low-status children performed activities that resulted in more habitual loading on their arm bones than the high-status children. This inferred change in physical activity is consistent with historical textual evidence that describes children entering the work force at this age

The Impact of the EU–US Open Skies Agreement and the Resulting British Airway's Open Skies Initiative: Passenger Numbers in London, Amsterdam and Paris

Abstract The advent of the EU–US Open Skies Agreement has been widely anticipated. A number of consequences have been predicted, for example, impacts on fares, passenger volumes, choice and consumer welfare. Airline costs are also predicted to fall as a result of increased competitiveness and increased cooperation among airlines. For the short period since the implementation of the Agreement, it is relatively easy to assess the supply-side changes that have been made, but more difficult to make wider judgements. This paper indicates the data that will be required to make these judgements and notes some methodological difficulties. Early estimates of the impact on passenger numbers are given using time series analysis focusing on London airports, in particular London Heathrow and airports served by British Airway's Open Skies Airline from Paris Orly and Amsterdam Schipol. Impact de l'accord Ciel Ouvert entre l'UE et les États-Unis et de l'initiative Open Skies résultante de British Airways: nombre de passagers à Londres, Amsterdam et Paris Résumé L'avènement de l'accord Ciel ouvert entre l'UE et les États-Unis avait été très largement prévu, et on a prédit un certain nombre de conséquences, notamment l'impact sur le prix des billets, sur les volumes de passagers, sur le choix pour les consommateurs et sur leur bien-être, entre autres. On prévoit également que les coûts des compagnies d'aviation devraient baisser, en conséquence de l'augmentation non seulement de la compétitivité, mais aussi de la concurrence entre les compagnies. A l'issue de la courte période qui s'est écoulée depuis l'implémentation de l'Accord, il est relativement aisé d’évaluer les variations qui se sont produites du côté de l'offre, mais beaucoup plus difficile de formuler des opinions plus générales. La présente communication indique les données qui seront requises pour formuler ces jugements, et souligne certaines difficultés sur le plan de la méthodologie. Des premières évaluations de l'impact sur le nombre de voyageurs ont été avancées, sur la base d'analyses à série temporelle concentrées sur les aéroports de Londres, notamment l'aéroport Heathrow de Londres et les aéroports desservis par la compagnie Open Skies de British Airway entre Paris Orly et l'aéroport Schipol d'Amsterdam. El efecto del Acuerdo de Cielos abiertos entre la UE y EE.UU. y el resultado de la Iniciativa de Cielos abiertos de British Airways: número de pasajeros en Londres, Ámsterdam y París Resumen El advenimiento del Acuerdo de Cielos abiertos entre la EU y EE.UU. era algo ampliamente esperado. Se han pronosticado muchas consecuencias, por ejemplo, los efectos sobre las tarifas, los volúmenes de pasajeros, las opciones y el bienestar de los consumidores. También se ha pronosticado la caída de los costes de las aerolíneas debido a una mayor competitividad y el incremento de la cooperación entre las aerolíneas. En el corto periodo de implantación del Acuerdo, es relativamente fácil evaluar los cambios que se han dado en el lado de la oferta, sin embargo, es más difícil realizar estimaciones mayores. Este trabajo indica que se necesitan datos para realizar estas estimaciones y hace referencia a algunas dificultades metodológicas. Los primeros estimativos del efecto sobre los números de pasajeros se han obtenido mediante análisis de series de tiempo centrados en los aeropuertos de Londres, en particular, el de Heathrow, y en los aeropuertos atendidos por la Aerolínea de Cielos abiertos de British Airways de Orly, en París, y Schipol, en Ámsterdam.EU–US Open Skies, airline passenger numbers, data requirements, counterfactual, ARIMA models, C32, L51, L93,

Predicting air-transport demand

In this paper, the efficiency of autoregressive integrated moving average (ARIMA) and regression models in simulating air-transport passengers by route are compared and constrasted. It is concluded that ARIMA models are far superior not only in their simulation capabilities but also in their applicability to such data. In the context of the UK Civil Aviation Authority's approach to forecasting, it is suggested that ARIMA models, including those with intervention terms, bear closer examination.

Ryanair's Impact on Airline Market Share from the London Area Airports: A Time Series Analysis

Ryanair tends to operate to destinations from its UK bases that are not the main airports in the country being served and in this it differs from many other European low-cost carriers. Although direct competition is not provided in the way that rival services operate between identical pairs of airports, indirect competition is provided. This raises the question, when Ryanair commence services, what is the impact on the market share of the incumbent airlines at these other airports? It seems that total traffic is stimulated on these sectors and that the incumbent's traffic generally falls while their share, and probably their yield, also falls as Ryanair competes. Ryanair appears to gain more market share than its initial stimulus to the market. © 2007 LSE and the University of Bath

Freight distribution model predictions compared: a test of hypotheses

The transportation problem and a doubly constrained gravity model with a power deterrence function are used to find predictions of a number of 134 x 134 freight matrices detailing tonnages moved in Great Britain in 1972. The matrices detail movements by thirty commodity groups, and predictions are obtained for movements by road for all but one of the commodities and for the principal items carried by rail. These predicted matrices are used to examine a number of questions. The relationships between some alternative goodness-of-fit statistics are examined to establish which commodities are best modelled by each technique and to point out empirically which statistics give unreliable rankings. Various summary measures of the actual matrices are examined to see if it is possible to predict which matrices will be best modelled by each technique. The modelling techniques are compared to indicate which provides the best predictions for each matrix, and some conclusions are offered on the absolute efficiency of the best models.

Freight distribution model predictions compared: some further evidence

This paper reviews the comments made by Gordon (1979) on the paperby Pitfield (1978) and, where appropriate, provides further evidence. In particular, intrazonal error in the gravity model is examined for twenty-eight commodities and it is concluded that the error is not as serious as implied. There is no evidence for bias in the diagonal elements of the distance matrix, and a deterrence function, used as an alternative to the negative-power function, does not provide better predictions. It is also shown that the P EP statistic is not corrected for scale in the same way as the other standardised statistics and so its correlation with these other statistics is strongly influenced by the scale of entries in the matrices. Minor points are made on the questions of speed of gravity-model convergence as β tends to infinity and on the suitability of the χ 2 test.

Some Speculations and Empirical Evidence on the Oligopolistic Behaviour of Competing Low-Cost Airlines

This paper reviews the theory of cost recovery and oligopoly with a view to advancing some judgements as to the way in which European low-cost airlines manage yield, depending upon the market morphology that applies. Routes with more than one operator in direct (at the same airport) competition or indirect (at an adjacent airport) competition will manage their yield in a manner that is traditional for their sector of the industry, but where this will be affected by the yield management process of the competitors. This paper draws on evidence of airline price setting when there is direct competition. It would seem that there is evidence of price leadership and more generally of a strong correlation between the fares of the differentiated product that the airlines offer in competition. © 2005 LSE and the University of Bath