Advanced Modalizing Problems

I present an internal problem for David Lewis’s genuine modal realism. My aim is to show that his analysis of modality is inconsistent with his metaphysics. I consider several ways of modifying the Lewisian analysis of modality, but argue that none are successful. I argue that the problem also affects theories related to genuine modal realism, including the stage theory of persistence and modal fictionalism

Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study

<p>Abstract</p> <p>Purpose</p> <p>To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).</p> <p>Patients and Methods</p> <p>Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d₁), oxaliplatin (85 mg/m²on d₁), leucovorin (200 mg/m²) on days 1 and 2 and 5-Fluorouracil (400 mg/m²as i.v. bolus and 600 mg/m²as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.</p> <p>Results</p> <p>Fifty three patients (46 with a PS 0–1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.</p> <p>Conclusion</p> <p>The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.</p

Pooled Analysis of Elderly Patients with Non-small Cell Lung Cancer Treated with Front Line Docetaxel/Gemcitabine Regimen: The Hellenic Oncology Research Group Experience

IntroductionThirty to 40% of patients with non-small cell lung cancer (NSCLC) are older than 70 years and rarely are enrolled in clinical trials. Moreover, in clinical practice, >75% of patients older than 65 years with metastatic NSCLC never receive any kind of chemotherapy.PurposeTo retrospectively evaluate the impact of age on efficacy and toxicity of chemotherapy regimens in patients with advanced NSCLC treated with the docetaxel-gemcitabine combination.Patients and MethodsPooled data from six clinical trials of the Hellenic Oncology Research Group were analyzed. According to their age, patients were divided into two groups: those with age <70 years and those with ≥70 years.ResultsA total of 858 patients were included in this analysis. Six hundred sixty-six (77.6%) patients were younger than 70 years, whereas 192 (22.4%) patients where ≥70-year-old. Overall response rate was 30.3% and 30.2% for patients <70 years and ≥70 years, respectively (p = 0.974). The median time to tumor progression was 4.1 and 4.5 months for patients <70 years and ≥70 years, respectively (p = 0.948). Median overall survival was 9.9 and 9.2 months for patients <70 and ≥70, respectively (p = 0.117). The multivariate analysis revealed performance status (PS) (p = 0.0001) and stage (p = 0.0001) as independent factors with significant impact on the hazard of death. Chemotherapy was well tolerated, but the incidence of grade III/IV mucositis was significantly higher in elderly patients (0.2% versus 1.5% for patients <70 versus ≥70 years, respectively; p = 0.011).ConclusionThe docetaxel/gemcitabine regimen has a comparable efficacy and tolerance in young (<70 years) and elderly (≥70 years) patients

Contemporary management of heart failure patients with reduced ejection fraction: the role of implantable devices and catheter ablation

Heart failure (HF) is a complex clinical syndrome characterised by significant morbidity and mortality worldwide. Evidence-based therapies for the management of HF include several well-established neurohormonal antagonists and antiarrhythmic drug therapy to mitigate the onset of cardiac arrhythmia. However, the degree of rate and rhythm control achieved is often suboptimal and mortality rates continue to remain high. Implantable cardioverter-defibrillators (ICDs), cardiac resynchronization (CRT), and combined (CRT-D) therapies have emerged as integral and rapidly expanding technologies in the management of select patients with heart failure with reduced ejection fraction (HFrEF). ICDs treat ventricular arrhythmia and are used as primary prophylaxis for sudden cardiac death, while CRT resynchronizes ventricular contraction to improve left ventricular systolic function. Left ventricular assist device therapy has also been shown to provide clinically meaningful survival benefits in patients with advanced HF, and His-bundle pacing has more recently emerged as a safe, viable, and promising pacing modality for patients with CRT indication. Catheter ablation is another important and well-established strategy for managing cardiac arrhythmia in HF, demonstrating superior efficacy when compared with antiarrhythmic drug therapy alone. In this article, we provide a comprehensive and in-depth evaluation of the role of implantable devices and catheter ablation in patients with HFrEF, outlining current applications, recent advances, and future directions in practice

Nitrosative and Oxidative Stresses Contribute to Post-Ischemic Liver Injury Following Severe Hemorrhagic Shock: The Role of Hypoxemic Resuscitation

Purpose: Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. Methods: Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO2 = 95–105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO 2 = 35–40 mmHg) followed, modifying the FiO 2. Animals not subjected to shock constituted the sham group (n = 11, PaO 2 = 95–105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. Results: Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor- alpha, interleukin (IL)-1b and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. Conclusions: Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory respons

Evaluation of CK-19 mRNA in the peripheral blood and bone marrow of patients with metastatic breast cancer: correlation with disease prognosis and sensitivity to chemotherapy

Σκοπός της παρούσης μελέτης ήταν η διερεύνηση της προγνωστικής αξίας της ανίχνευσης κυκλοφορούντων καρκινικών κυττάρων (CTCs) στο αίμα γυναικών ασθενών με νεοδιαγνωσθέντα μεταστατικό καρκίνο μαστού (υποτροπιάζοντα ή εξαρχής μεταστατικό), πριν την έναρξη συστηματικής χημειοθεραπείας. […