65 research outputs found
Controlled expiration in patients with chronic obstructive pulmonary disease on ventilatory support
Chronic respiratory failure develops over the years in many patients with chronic obstructive
pulmonary disease (COPD). During exacerbations of COPD the gas-exchange is known to
deteriorate in these patients. This acute-on-chronic respiratory failure may ultimately lead to
hypercapnic coma. Mechanical ventilation has to be applied to maintain gas-exchange. As this
treatment does not affect the pathophysiological mechanisms leading to the respiratory failure,
mechanical ventilation can only be considered as rescue therapy.
Altered respiratory mechanics associated with COPD may hamper ventilatory support. For the
same reasons weaning from the ventilator is considered to be a cumbersome process, in many
patients requiring long-tenn ventilatory support. These altered respiratory mechanics can be
elucidated in tenns of elastic recoil of the lung and airways resistance. In this chapter these
features will be described with emphasis on spontaneous breathing as well as mechanical
ventilation. Adaptations of equipment used for ventilatory support and weaning purposes that
may improve ventilation and gas-exchange in COPD, will be reviewed. Finally an outline of the
investigations described in this thesis will be given.
The popUlation of patients that is the subject of this thesis consists of those who are suffering
from severe chronic airways obstruction in whom loss of elasticity of lung tissue may be
present. Though COPD may not be the exactly right nomenclature for the condition present in
all of those patients, it was applied to all patients because destruction of elastic tissue of a minor
degree is difficult to demonstrate or exclude in a living person
Enhancing Dendritic Cell Therapy in Solid Tumors with Immunomodulating Conventional Treatment
Improving lung cancer survival; time to move on
Background: During the past decades, numerous efforts have been made to decrease the death rate among lung cancer patients. Nonetheless, the improvement in long-term survival has been limited and lung cancer is still a devastating disease.Discussion: With this article we would like to point out that survival of lung cancer could be strongly improved by controlling two pivotal prognostic factors: stage and treatment. This is corresponding with recent reports that show a decrease in lung cancer mortality by screening programs. In addition, modulation of the patient's immune system by immunotherapy either as monotherapy or combined with conventional cancer treatments offers the prospect of tailoring treatments much more precisely and has also been shown to lead to a better response to treatment and overall survival of non-small cell lung cancer patients.Summary: Since only small improvements in survival can be expected in advanced disease with the use of conventional therapies, more research should be focused on lung cancer screening programs and patient tailored immunotherapy with or without conventional therapies. If these approaches are clinically combined in a standard multidisciplinary policy we might be able to advance the survival of patients with lung cancer
Controlled expiration in mechanically-ventilated patients with chronic obstructive pulmonary disease (COPD)
In patients with severe chronic obstructive pulmonary disease (COPD), lung
emptying may be affected by flow limitation. We tested the hypothesis that
the airway compression leading to flow limitation can be counteracted by
controlling the expiratory flow. The effects of an external resistor on
lung emptying were studied in six patients with COPD, who were
mechanically ventilated whilst sedated and paralysed. Respiratory
mechanics were obtained during ventilatory support with and without the
resistor. Airway compression was assessed using the interruptor method.
For the study, a turbulent resistor was applied with the highest
resistance level that did not increase the end-expiratory lung volume. At
this resistance level, external positive end-expiratory pressure (PEEP)
was generated in all patients. As total PEEP levels remained unchanged at
both settings during the controlled expiration, the levels of intrinsic
PEEP were significantly decreased from 0.96+/-0.30 to 0.53+/-0.19 kPa
(mean+/-SD). Comparison of the expiratory flow-volume curves at both
settings revealed that, during the controlled expiration, the flows were
significantly decreased during the first 40% of the expired volume and
significantly increased during the last 60%. As the end-expiratory lung
volumes remained unchanged during both settings, these increments in flow
indicated a decrease in effective resistance. Airway compression was
observed during unimpeded expirations in all patients using the
interruptor method. During the application of the resistor, airway
compression was no longer detectable. In patients with chronic obstructive
pulmonary disease receiving ventilatory support, the application of an
external resistor could decrease effective expiratory resistance by
counteracting airway compression, without increments in end-expiratory
lung volume
Renal toxicity from platinum/pemetrexed and pembrolizumab in the era of combination therapy
Background: Recently, the phase 3 keynote-189 trial showed that in previously untreated
patients with advanced non-squamous NSCLC without targetable mutations, the
progression-free and overall survival were significantly longer with addition of pembrolizumab to chemotherapy than with chemotherapy alone. Both chemotherapy and pembrolizumab can give renal toxicity, which can be a major challenge in the clinical setting.
Methods: In a prospective multicenter observational real-life cohort study [Visser Eur
Respir J 2018], we evaluated the incidence of acute/chronic kidney disease (AKD/
CKD), its related treatment discontinuation frequency and associated clinical variables
with AKD in patients with stage IIIB/IV NSCLC treated with platinum/pemetrexed. In
addition, the Keynote 189 toxicity data was used for the combination treatment. We
thereafter reviewed literature to generate an algorithm for diagnosis and treatment in
increased creatinine levels.
Results: 149 patients received pemetrexed platinum, of whom 44 patients (30%) continued
maintenance. During induction therapy 48 patients (50%) treated with cisplatinum/pemetrexed developed AKD and 15 patients (29%) treated with carboplatin/pemetrexed. During
maintenance 13 patients (30%) developed AKD, leading to CKD and treatment discontinuation in eight patients (62%). In the Keynote 189 trial combining pembrolizumab with chemotherapy, nephritis has been reported in 1,7% of patients in any grade (1,5% grade 3-4).
However, when looking at an increased blood creatinine in the group that was treated with
carboplatin, a total of 12,2% of patients showed any increase (0,7% grade 3-4).
Conclusions: Increased blood creatinine levels from pemetrexed and pembrolizumab
is a common entity, probably more common in a real-life setting. This elevation is clinically challenging in a population that receives three agents that can cause a creatinine
increase. Currently, there are no markers to distinguish between renal failure due to
chemotherapy of immunothera
Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy
Dendritic cells (DCs) are antigen-presenting cells (APCs) that are essential for the activation of immune responses. In various malignancies, these immunostimulatory properties are exploited by DC-therapy, aiming at the induction of effective anti-tumor immunity by vaccination with ex vivo antigen-loaded DCs. Depending on the type of DC-therapy used, long-term clinical efficacy upon DC-therapy remains restricted to a proportion of patients, likely due to lack of immunogenicity of tumor cells, presence of a stromal compartment, and the suppressive tumor microenvironment (TME), thereby leading to the development of resistance. In order to circumvent tumor-induced suppressive mechanisms and unleash the full potential of DC-therapy, considerable efforts have been made to combine DC-therapy with chemotherapy, radiotherapy or with checkpoint inhibitors. These combination strategies could enhance tumor immunogenicity, stimulate endogenous DCs following immunogenic cell death, improve infiltration of cytotoxic T lymphocytes (CTLs) or specifically deplete immunosuppressive cells in the TME, such as regulatory T-cells and myeloid-derived suppressor cells. In this review, different strategies of combining DC-therapy with immunomodulatory treatments will be discussed. These strategies and insights will improve and guide DC-based combination immunotherapies with the aim of further improving patient prognosis and care
Heterogeneity in immune cell content in malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) has become a major area of interest. In this review, we discuss the current knowledge of heterogeneity in immune cell content and checkpoint expression in MPM in relation to prognosis and prediction of treatment efficacy. Generally, immune-suppressive cells such as M2 macrophages, myeloid-derived suppressor cells and regulatory T cells are present within the TME, with extensive heterogeneity in cell numbers. Infiltration of effector cells such as cytotoxic T cells, natural killer cells and T helper cells is commonly found, also with substantial patient to patient heterogeneity. PD-L1 expression also varied greatly (16-65%). The infiltration of immune cells in tumor and associated stroma holds key prognostic and predictive implications. As such, there is a strong rationale for thoroughly mapping the TME to better target therapy in mesothelioma. Researchers should be aware of the extensive possibilities that exist for a tumor to evade the cytotoxic killing from the immune system. Therefore, no βone size fits allβ treatment is likely to be found and focus should lie on the heterogeneity of the tumors and TME
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