A 54-year-old male presented with shortness of breath and was diagnosed with pulmonary emboli. Laboratory studies revealed hemolytic anemia. Flow cytometry showed a prominent white blood cell clone without CD59 in 85% (NV 0-3.0) and red blood cells with 8.5% CD59 absence (NV 0-3.0) confirming a diagnosis of paroxysmal nocturnal hemoglobinuria. Eculizumab was started to decrease the possibility of a thrombotic recurrence, with incidentally, a marked subjective improvement of symptomatology, as fatigue, was seen. We reviewed current literature regarding the improvement in fatigue seen in patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab.

e14582 Background: Post-embolization syndrome (PES) is characterized by fever, abdominal pain and leukocytosis after embolization of hepatic tumors and is likely caused by an inflammatory response to necrotic tissue. Despite the benign nature of PES, it has been suggested that this entity portends worse prognosis. We examined the outcomes of a large group of patients that underwent embolization with particular emphasis on the type of procedure performed. METHODS Retrospective chart review of 247 cases that underwent embolization procedures of hepatic tumors at our institution from January 2002 to January 2010. Progression-free survival (PFS) and overall survival (OS) were measured in days starting from the day of the first embolization. RESULTS Out of 247 patients, 173 were men (70%) and 74 were women (30%). The etiology of the hepatic tumors (Algorithm 1) was comprised of 190 cases of hepatocellular carcinoma (HCC), 23 cases of metastatic carcinomas, 12 cases of neuroendocrine tumors, 18 benign tumors, and others (4 cases). PES (Table 1) developed in 16 patients (6.4%) with a median length of hospitalization of 4.4 days (range 1-7 days). Subsequently we examined 190 patients with HCC as a separate group in which chemoembolization with doxorubicin drug eluting beads (DEB) was the most frequent type of procedure in 97 out of 190 HCC patients (51%), followed by bland microspheres in 73 patients (38%), polyvinyl alcohol (PVA) particles in 27 patients and 3 cases of epirubicin DEB embolization. Cox regression indicates that PES was not a statistically significant predictor of either PFS or OS, although the results showed a trend towards worse PFS in PES patients (p = 0.061). Patients that did not undergo liver transplantation had significantly worse PFS and OS (p < 0.001). Both PVA embolization (p = 0.019) and bland microsphere embolization (p = 0.027) patients had significantly worse OS when compared to chemoembolization. CONCLUSIONS PES heralds slight worse outcome albeit likely not directly associated to infectious complications but rather as a surrogate of other poor prognostic features. Despite the fact that most PES cases occurred after chemoembolization, such procedure still fairs favorably when compared to other types of embolization.

2018 Background: Current standard treatment for GBM consists in radiotherapy (RT) plus concomitant and adjuvant (adj) TMZ. Myelosupression is the dose limiting toxicity of TMZ with grade 3 and 4 cytopenia occurring in ~16%. We describe the difference in outcome of newly diagnosed GBM patients treated with TMZ who developed grade 3 and 4 cytopenia. Methods: A 10-year retrospective analysis of newly diagnosed adult GBM patients (pts) treated with first-line TMZ. All pts received concurrent TMZ and RT with or without investigational drug. If the pt did not progress on magnetic resonance imaging (MRI) adj TMZ was given. Cytopenia events during TMZ therapy were graded using the National Cancer Institute Common Toxicity Criteria (v3). Survival distribution was estimated by the Kaplan-Meier method. Results: Of 191 pts, 23% developed grade 3 and 4 cytopenia. 74% pts were ≤ 65 years, 75% had 80-100% karnofsky performance status and 78% had surgical resection at diagnosis. 93% pts received 6 wks of concurrent RT 60 Gy and TMZ 75 mg/m2/d. The median dose of adj TMZ was 150-200 mg/m2/d1-d5 every 28d cycle. The median cycles was 4 (range, 0-24). The median progression free survival (PFS) was 6.7 months (mo). The 6 mo and 12 mo PFS for pts who had grade 3 and 4 cytopenia was 73% (95% confidence interval [CI], 57%-83%) and 33% (95% CI, 20%-47%); while in pts with no grade 3 and 4 cytopenia was 51% (95% CI, 43%-59%) and 24% (95% CI, 17.9%-31.8%). The unadjusted hazard ratio (HR) for death or disease progression of pts with grade 3 and 4 cytopenia, as compared to those without grade 3 and 4 cytopenia, was 0.58 [95% CI, 0.40 to 0.82; p< 0.003]. The HR for death or disease progression was 0.68 (95% CI, 0.47-0.98; p<0.045) among those with a methylated MGMT promoter. The total dose of TMZ was not different between both groups (p=0.284 by Wilcoxon rank sum test). Conclusions: Our study supports that newly diagnosed GBM pts who develop grade 3 and 4 cytopenia during TMZ therapy have improved PFS. Further clinical trials are required to validate grade 3 and 4 cytopenia as a potential biomarker for TMZ efficacy in an attempt to optimize and personalize GBM therapy.

e16601 Background: Bevacizumab, an inhibitor of the vascular endothelial growth factor (VEGF), has been shown to improve progression-free survival (PFS) although current data does not support overall survival (OS) benefit. Studies have been designed in an attempt to find a marker for activity albeit ways to predict response to anti-VEGF therapy are currently lacking. Methods: Retrospective chart review of 454 patients exposed to bevacizumab since 2004 to 2009. The study comprised 157 patients with colon cancer, 127 with glioblastoma, 104 with lung cancer and 66 with breast cancer. Group A represented patients that while treated with bevacizumab developed hypertension or, if already hypertensive, required an increase on their antihypertensive regimen. Group B represented patients that while treated with bevacizumab did not develop hypertension or, if already hypertensive, did not require an increase on their antihypertensive regimen. Results: Median survival (Table 1) is significantly higher in group A (607 days) than group B (355 days), with a log-rank p-value of <0.0001. Median PFS (Table 2) is significantly higher in group A (197 days) than group B (117 days) with a log-rank p-value of <0.0001. Next, multivariate analyses were done for OS and PFS using Cox proportional hazards models. Age group, gender, line of treatment, and single agent versus combined use of bevacizumab were not significant predictors on univariate analyses thus only cancer type was entered into the multivariable model with group. The results for OS (Table 3) indicate that being in group B raises the risk of death by 53.3% when holding type of cancer constant. The results for PFS (Table 4) indicate that females have a 27.3% decreased risk of progression than males when holding group and type of malignancy constant. If a patient is in group A their risk of progression decreases by 32.6% when holding gender and type of malignancy constant. Conclusions: Bevacizumab has proven activity across malignancies nevertheless we have yet to determine which specific patients benefit from its use. Our study shows that hypertension is a clinical surrogate of response to bevacizumab and encourages continuation of anti-VEGF therapy while optimizing anti-hypertensive regimen.

6576 Background: The presence of elevated nucleated red blood cells (NRBC) in the peripheral blood smear points towards the presence of myelodysplastic syndrome or myelophthisis. The intent of our study is to assess the prognostic implications of the presence of increased NRBC in patients with myelophthisis. Methods: Retrospective single institution chart review over a period of 7 years. Our study population comprised 40 newly diagnosed cases of myelophthisis from solid tumors whose diagnoses were made by bone marrow (BM) examination. Results: 20 patients were male and 20 patients were female. Median age at diagnosis of myelophthisis was 60.7 years. 17 patients received a new diagnosis of malignancy via bone marrow biopsy while 23 patients already had a diagnosis of cancer. The most common hematologic presentation was bicytopenia (19 cases), followed by anemia (11 cases), pancytopenia (6 cases) and normal complete blood count (4 cases). Alkaline phosphatase was high in 32 patients and normal in 8 patients. Primary sites were documented in 38 of 40 metastatic cases (Table 1). There was no significant difference in survival between patients that had undetectable NRBC prior to BM examination (Algorithm 1) and patients that had increased NRBC prior to BM examination (p = 0.1459). There was no significant difference in survival between patients that had NRBC remain undetectable after BM examination and patients that had increased NRBC after BM examination (p = 0.6912). In this study, there was a significant difference in survival (Figure 1) between patients with metastatic nonhematological tumors that presented with an increased number of peripheral NRBC that subsequently cleared from circulation and patients that showed persistence of increased NRBC after bone marrow examination (p < 0.0001). Conclusions: The presence of nucleated red blood cells in the peripheral blood smear serves as a remarkable clue about a possible underlying malignancy and its disappearance after appropriate treatment portends improved survival. To our knowledge this is the first study documenting the prognostic implications of NRBC in the peripheral circulation of patients with myelophthisis.

Model transformations need to be configured in order to satisfy particular user requirements in real scenarios. This paper introduces an strategy for configuring ATL transformations. This strategy, that is currently in practice in the MOSKitt tool, follows a model driven approach, where both the specification of configuration options and the user selections of those options are implemented as models. Additionally, the user interfaces that are provided by MOSKitt for selecting the configuration options are briefly introduced.

555 Background: Trastuzumab, a humanized monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER-2), has been shown to be effective as therapy for breast malignancies that over express HER-2. Cardiotoxicity and a decrease in left ventricular ejection fraction (LVEF) occur in as many as 27% of women treated with trastuzumab. We present our experience regarding the use of beta-blockers or ACE (angiotensin converting enzyme) inhibitors before exposure to trastuzumab correlating its use with the development of cardiotoxicity. Methods: Women (n = 162) with HER2-overexpressing breast cancer who received trastuzumab over a 9-year period were divided into two groups. 39 patients were taking beta-blockers, ACE inhibitors or both due to history of hypertension before starting trastuzumab. 123 patients were not taking beta-blockers or ACE inhibitors before starting trastuzumab. To assess cardiotoxicity, patients were evaluated for LVEF at baseline and every 3 months during therapy with a 10%-15% decrease in LVEF as criteria for cessation of trastuzumab. Results: The patients that were taking beta-blockers or ACE inhibitors before starting trastuzumab were found to be older (59.9 versus 50.8 years, p = 0.001) and had a smaller decrease in LVEF (4.7 versus 10.3, p < 0.001) when compared to the 123 patients that were not taking beta-blockers or ACE inhibitors. There was a 57% decrease in the odds of having delays in the treatment with trastuzumab for those that were taking beta-blockers or ACE inhibitors which, although not statistically significant due to the small sample size, was suggestive of a positive association (p = 0.136). Also there was a 62% decrease in the odds of having a decrease in LVEF for those that are on beta- blockers or ACE inhibitors which was statistically significant (p = 0.03). Conclusions: This hypothesis generating study would encourage the development of a clinical trial to prospectively evaluate the role of beta-blockers and ACE inhibitors in preventing trastuzumab-related cardiotoxicity. Furthermore, repercussions span not only to the continuation of a targeted agent with a compelling oncologic response but also avoiding cardiac, economical and psychological damage. No significant financial relationships to disclose.

The rise in the number and complexity of pervasive systems is a fact. Pervasive systems developers need advanced development methods in order to build better systems in an easy way. Software factories and model-driven architecture (MDA) are two important trends in the software engineering field. This chapter applies the guidelines and strategies described by these proposals in order to build a methodological approach for the development of pervasive systems. Software factories are based on the definition of software families supported by frameworks. Individual system requirements are specified by means of domain-specific languages. Following this strategy, our approach defines a domain-specific language for pervasive systems (PervML). In order to support our modeling language, we introduce a software architecture for pervasive systems, which is implemented by a software framework using OSGi technology. The methodological approach presented in this chapter raises the abstraction level in the development of pervasive systems and provides highly reusable assets to reduce the effort in development projects.

In this work, we introduce a software engineering method for AmI applications which is based on a model driven strategy. This method allows us to describe an AmI application a high level of abstraction by means of a set of models and then automatically obtain code from these models by following an automatic code generation strategy. To do this, a method proposed by authors in previous works is extended to support AmI applications properties. The introduced extensions are: (1) a set of models that allow us to represent the context information at conceptual level and (2) a strategy to allow the system infer knowledge in execution time to anticipate user actions and to adapt the system according to the context data. This method allows us to provide the development of AmI system with the benefits of using a software engineering method.

El trabajo presentado en esta tesis aborda el problema del desarrollo de software para sistemas pervasivos, Los sistemas pervasivos pretenden construir entornos donde los elementos de computacion desaparecen desde el punto de vista del usuario pero su funcionalidad se continua proporcionando. Esta vision fue inicialmente descrita por Weiser en los 90. La mayoria de los prototipos de sistemas pervasivos actuales se desarrollan ad-hoc, ya que el reto es conseguir sistemas funcionales, pero no aplican metodos de ingenieria de software. Este enfoque puede ser util para construir pruebas de concepto o los primeros sistemas comerciales, pero esta manera de desarrollar sistemas pervasivos no es escalable. Los enfoques artesanales aplicados al desarrollo de software son propensos a errores y el producto resultante suele ser defectuoso y dificil de evolucionar. Esta tesis presenta un enfoque metodologico para el desarrollo de sistemas pervasivos siguiendo los principios ingenieriles de la propuesta de las Factorias de Software y las guias del estandar MDA (Model Driven Architecture). Etas propuestas tienen puntos fuertes y debiles, pero un enfoque integrado puede aprovechar lo mejor de cada una. De las Factorias de Software se obtiene su objetivo de la reutilizacion mediante el desarrollo especifico de dominio (lenguajes especificos, frameworks de implementacion, etc.), mientras que de MDA se obtiene su objetivo de aumentar el nivel de abstraccion mediante lenguajes de modelado y las tecnicas estandar que propone. Por lo tanto, para aplicar estas propuestas al desarrollo de sistemas pervasivos, en esta tesis se realizan las siguientes contribuciones: un lenguaje de modelado para el dominio de los sistemas pervasivos. El lenguaje, que se ha llamado PervML, proporciona las primitivas conceptuales necesarias para describir los sistemas pervasivos desde su analisis (utilizando primitivas como servicio e interaccion) hasta su diseno (proporcionando primitivas como dispositivo).

This work presents the PervML Generative Tool (PervGT) that supports a model driven method for the development of pervasive services in ubiquitous environments. The tool, which is based on the Eclipse platform, provides facilities for the graphical description of pervasive systems using PervML, a UML-like modeling language. Once the pervasive system is specified, the PervML model is used as input to a transformation engine that generates source code and other implementation assets. This generated code extends an OSGi-based framework in order to build the final pervasive applications

Current pervasive systems are developed ad-hoc or using implementation frameworks. These approaches could be not enough when dealing with large and complex pervasive systems. In order to improve the productivity and reduce the number of errors, we propose to apply the newest trends in software engineering (the MDA and Software Factories approaches) to the development of pervasive systems. These strategies propose to use models for automatically generating the final system, and not only for generating documentation or for guiding the implementation process. The application of model driven approaches to the development of pervasive systems can provide many relevant benefits. We have developed such a kind of method providing several assets for supporting the development process.

The raise of the number and complexity of pervasive systems is a fact. This kind of systems involves the integration of physical devices and software components in order to provide services to the inhabitants of an environment. Current techniques for developing pervasive systems provide low-level abstraction primitives which makes difficult the construction of large systems. Software Factories and the Model Driven Architecture (MDA) are two important trends in the software engineering field that can provide sensible benefits in the development of pervasive systems. In this paper, we present an approach for building a Software Factory for pervasive systems, focusing in the definition of a product line for this kind of systems. We introduce a software architecture for pervasive systems, which is supported by a software framework implemented using the OSGi technology. Then, we integrate the framework into the MDA standard defining the framework metamodel and providing tool support for the automatic code generation.

The development of intelligent environments involves many different disciplines and skills, which makes unrealistic to think that a single research group or company can develop all the hardware and software required to build such an environment. If we want to effectively support Weiser’s vision, what is really needed is an integration platform which allows different components to seamlessly interact, in order to provide pervasive services and ambient intelligence. In this paper we give a first step towards such a platform by presenting a concrete example of integration, which involves two different projects developed at different universities. As a result, we identify a series of problems that we encountered during the integration process and provide knowledge (lessons learned) that can be used by other projects in order to integrate ubiquitous and ambient intelligence systems.