Effectiveness,safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real-world data from the noninterventional TACTIC study in Germany

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.     

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

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Do patient and ward-related characteristics influence the use of coercive measures? Results from the EUNOMIA international study

Purpose

This study aims to identify whether selected patient and ward-related factors are associated with the use of coercive measures. Data were collected as part of the EUNOMIA international collaborative study on the use of coercive measures in ten European countries.

Methods

Involuntarily admitted patients (N = 2,027) were divided into two groups. The first group (N = 770) included patients that had been subject to at least one of these coercive measures during hospitalization: restraint, and/or seclusion, and/or forced medication; the other group (N = 1,257) included patients who had not received any coercive measure during hospitalization. To identify predictors of use of coercive measures, both patients’ sociodemographic and clinical characteristics and centre-related characteristics were tested in a multivariate logistic regression model, controlled for countries’ effect.

Results

The frequency of the use of coercive measures varied significantly across countries, being higher in Poland, Italy and Greece. Patients who received coercive measures were more frequently male and with a diagnosis of psychotic disorder (F20–F29). According to the regression model, patients with higher levels of psychotic and hostility symptoms, and of perceived coercion had a higher risk to be coerced at admission. Controlling for countries’ effect, the risk of being coerced was higher in Poland. Patients’ sociodemographic characteristics and ward-related factors were not identifying as possible predictors because they did not enter the model.

Conclusions

The use of coercive measures varied significantly in the participating countries. Clinical factors, such as high levels of psychotic symptoms and high levels of perceived coercion at admission were associated with the use of coercive measures, when controlling for countries’ effect. These factors should be taken into consideration by programs aimed at reducing the use of coercive measures in psychiatric wards.     

Pseudomonas aeruginosa triggers CFTR-mediated airway surface liquid secretion in swine trachea

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the gene encoding for the anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Several organs are affected in CF, but most of the morbidity and mortality comes from lung disease. Recent data show that the initial consequence of CFTR mutation is the failure to eradicate bacteria before the development of inflammation and airway remodeling. Bacterial clearance depends on a layer of airway surface liquid (ASL) consisting of both a mucus layer that traps, kills, and inactivates bacteria and a periciliary liquid layer that keeps the mucus at an optimum distance from the underlying epithelia, to maximize ciliary motility and clearance of bacteria. The airways in CF patients and animal models of CF demonstrate abnormal ASL secretion and reduced antimicrobial properties. Thus, it has been proposed that abnormal ASL secretion in response to bacteria may facilitate the development of the infection and inflammation that characterize CF airway disease. Whether the inhalation of bacteria triggers ASL secretion, and the role of CFTR, have never been tested, however. We developed a synchrotron-based imaging technique to visualize the ASL layer and measure the effect of bacteria on ASL secretion. We show that the introduction of Pseudomonas aeruginosa and other bacteria into the lumen of intact isolated swine tracheas triggers CFTR-dependent ASL secretion by the submucosal glands. This response requires expression of the bacterial protein flagellin. In patients with CF, the inhalation of bacteria would fail to trigger ASL secretion, leading to infection and inflammation.The human airway is normally protected from injury caused by microbial colonization and viral infection by a complex immune defense system. The cornerstone of airway defense is mucociliary clearance. Particles, including bacteria, are captured in mucus and removed by an efficient mucociliary clearance mechanism. Airway host defense is compromised in individuals with cystic fibrosis (CF), whose lungs are thus prone to chronic bacterial infections, frequently with Pseudomonas aeruginosa, and inflammation that may eventually cause lung tissue damage and respiratory failure (1, 2). The events leading from cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation to airway disease are incompletely understood, but accumulating evidence suggests that CF airway disease results from abnormal microbial clearance (3, 4).Although chronic inflammation is a major aspect of CF lung disease, recent data show that the initial consequence of CFTR mutation is impaired ability to eradicate bacteria. In previous studies, lungs from animal models of CF (F508del and CFTR^−/− pigs) (5, 6) did not eradicate bacteria as effectively as lungs from WT littermates before the development of inflammation (3, 4). These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs (4).The failure to clear bacteria likely results from abnormal airway surface liquid (ASL) secretion and properties (6–10). The ASL consists of a layer of mucus that traps inhaled particles and a periciliary liquid layer that keeps the mucus an optimum distance from the underlying epithelia to maximize ciliary mobility (10, 11). The mucus layer is a complex mixture of water, salts, gel-forming mucins, and antimicrobial compounds that helps inactivate, kill, and trap pathogens and facilitates mucociliary clearance (10, 11). In CF airways, both the bacteria-killing properties and ASL secretion are abnormal (3, 9). The airway liquid produced by CFTR^−/− swine has weaker bactericidal properties compared with that produced by WT littermates, owing to abnormal pH (3, 4). In addition, human CF airways, 1-d-old CF piglets, newborn CFTR^−/− ferrets, and CFTR^−/− mice fail to respond to stimulatory signals that normally elicit strong ASL secretion (6–9). Consequently, it has been proposed that abnormal secretion of fluid and mucin in response to bacterial infection may contribute to the pathogenesis of CF lung disease (7–10, 12–15); however, the central questions of whether bacteria trigger ASL secretion in the airways, and the role of CFTR in such a process, have not been explored previously, owing to the lack of a suitable experimental technique.We have developed a novel synchrotron-based method to measure the height of the ASL layer covering the epithelium of intact, isolated swine trachea. We show that the introduction of P. aeruginosa into the lumen of intact isolated swine tracheas triggers CFTR-dependent ASL secretion by the submucosal glands. This is a local response that affects only the glands in close proximity to the bacteria and requires expression of the bacterial protein flagellin. We also show that Staphylococcus aureus and Haemophilus influenzae trigger CFTR-dependent ASL secretion, indicating that this response is not unique to P. aeruginosa. In patients with CF, the inhalation of bacteria would fail to trigger ASL secretion by submucosal glands, facilitating infection and inflammation.     

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma

Background

Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum.

Methods

After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated.

Results

After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth.

Conclusion

Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.