High costs, low quality of life, reduced survival, and room for improving treatment: an analysis of burden and unmet needs in glioma

Gliomas are a group of heterogeneous tumors that account for substantial morbidity, mortality, and costs to patients and healthcare systems globally. Survival varies considerably by grade, histology, biomarkers, and genetic alterations such as IDH mutations and MGMT promoter methylation, and treatment, but is poor for some grades and histologies, with many patients with glioblastoma surviving less than a year from diagnosis. The present review provides an introduction to glioma, including its classification, epidemiology, economic and humanistic burden, as well as treatment options. Another focus is on treatment recommendations for IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, and glioblastoma, which were synthesized from recent guidelines. While recommendations are nuanced and reflect the complexity of the disease, maximum safe resection is typically the first step in treatment, followed by radiotherapy and/or chemotherapy using temozolomide or procarbazine, lomustine, and vincristine. Immunotherapies and targeted therapies currently have only a limited role due to disappointing clinical trial results, including in recurrent glioblastoma, for which the nitrosourea lomustine remains the de facto standard of care. The lack of treatment options is compounded by frequently suboptimal clinical practice, in which patients do not receive adequate therapy after resection, including delayed, shortened, or discontinued radiotherapy and chemotherapy courses due to treatment side effects. These unmet needs will require significant efforts to address, including a continued search for novel treatment options, increased awareness of clinical guidelines, improved toxicity management for chemotherapy, and the generation of additional and more robust clinical and health economic evidence

Intermediate and high-risk non-muscle-invasive bladder cancer: an overview of epidemiology, burden, and unmet needs

Bladder cancer ranks among the most common cancers globally. At diagnosis, 75% of patients have non-muscle-invasive bladder cancer (NMIBC). Patients with low-risk NMIBC have a good prognosis, but recurrence and progression rates remain high in intermediate- and high-risk NMIBC, despite the decades-long availability of effective treatments for NMIBC such as intravesical Bacillus Calmette-Guérin (BCG). The present review provides an overview of NMIBC, including its burden and treatment options, and then reviews aspects that counteract the successful treatment of NMIBC, referred to as unmet treatment needs. The scale and reasons for each unmet need are described based on a comprehensive review of the literature, including insufficient adherence to treatment guidelines by physicians because of insufficient knowledge, training, or access to certain therapy options. Low rates of lifestyle changes and treatment completion by patients, due to BCG shortages or toxicities and adverse events as well as their impact on social activities, represent additional areas of potential improvement. Highly heterogeneous evidence for the effectiveness and safety of some treatments limits the comparability of results across studies. As a result, efforts are underway to standardize treatment schedules for BCG, but intravesical chemotherapy schedules remain unstandardized. In addition, risk-scoring models often perform unsatisfactorily due to significant differences between derivation and real-world cohorts. Reporting in clinical trials suffers from a lack of consistent outcomes reporting in bladder cancer clinical trials, paired with an under-representation of racial and ethnic minorities in many trials

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1(+) neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh(+) neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response

The burden of cystic fibrosis beyond medical costs in Switzerland

Objectives: In Switzerland, about 1,000 people live with cystic fibrosis (CF). Despite advances in treatment and care, CF continues to burden affected individuals and healthcare systems in several ways. Patients and their caregivers incur costs beyond medical expenses that are not covered by the health or disability insurance. The aim of this study is to assess these costs in terms of non-medical expenses, quality of life and subjective burden associated with CF as well as production losses, that are affecting the entire society. Methods: We conducted a prevalence-based, cost-of-illness study. Electronic questionnaires were sent to adult CF patients, their caregivers, and parents of children with CF. Parents completed the questionnaire for their child, and the questions related to the production losses and burden assessment for themselves. Results: The survey covered 267 out of 973 (27.4%) patients in Switzerland. Extrapolated to all CF patients in Switzerland, direct non-medical costs of CF amount to CHF 2.7 million and total production losses to CHF 15.7 million annually. Production losses due to premature death account for the largest share of these costs, followed by production losses due to presenteeism. For adult CF patients the mean EQ-5D index score was 0.84 and the Visual Analogue Scale (VAS) score 68.93. Among children with CF the VAS score was 83.99. The subjective burden of CF measured by the BSFC-s (0: lowest; 30: highest) averaged at 11.1 for caregivers and at 11.9 for parents. Conclusions: CF imposes substantial costs on patients, their caregivers and the society in Switzerland, while the average quality of life of individuals with CF can be considered as good. The level and composition of these costs should raise awareness among policymakers

Wie wirkt sich Cystische Fibrose auf Betroffene und Gesellschaft aus?

Cystische Fibrose ist für Betroffene und ihre Angehörigen eine belastende Krankheit. Das Schweizer Gesundheitssystem unterstützt zwar die CF-Betroffenen bei der alltäglichen und finanziellen Bewältigung der Krankheit massgebend, aber allfällige direkte nicht-medizinische Kosten und Produktivitätsverluste haben Auswirkungen auf die gesamte Gesellschaft. In einer Studie im Auftrag von Cystische Fibrose Schweiz (CFS) wurden nun diese krankheitsbedingten Kosten und die Lebensqualität von CF-Betroffenen untersucht

A Systematic Literature Review and Meta-Analysis of the Incidence of Serious or Severe Hypersensitivity Reactions after Administration of Ferric Derisomaltose and Ferric Carboxymaltose

Background and Aims Intravenous (IV) iron is the preferred treatment for patients with iron deficiency (ID) and iron deficiency anemia (IDA) in a variety of clinical situations. Although uncommon, administration of modern IV iron formulations can result in hypersensitivity reactions and, very rarely, anaphylactic reactions. The objective of the present study was to systematically review the literature to identify and analyze data on the incidence of serious or severe hypersensitivity reactions (HSRs) after administration of different IV iron formulations. Methods A prospectively-registered systematic literature review (SLR) was conducted to identify prospective, active comparator randomized controlled trials (RCTs) comparing ferric derisomaltose (FDI) (also known as iron isomaltoside 1000) or ferric carboxymaltose (FCM) with other IV iron formulations or oral iron. The primary endpoint was the incidence of serious or severe hypersensitivity reactions occurring on the day or day after dosing of IV iron, based on pre-specified terms (MedDRA classification). Results Data were obtained from ten prospective, active comparator RCTs of FDI (N=3,474) and seven prospective, active comparator RCTs of FCM (N=2,683), two of which were head-to-head comparisons of FDI and FCM. The trials enrolled a total of 10,467 patients, of whom 6,157 were treated with either FDI or FCM. The number of patients experiencing any serious or severe hypersensitivity reactions was 5/3474 with FDI (0.14%) versus 29/2683 (1.08%) with FCM; Bayesian inference of proportions showed the reaction rates to be significantly lower with FDI relative to FCM (Figure). Conclusions To our knowledge, the present analysis represents the first SLR and meta-analysis of the incidence of serious or severe HSRs after administration of FDI vs FCM based on pre-specified MedDRA terms. The SLR conducted for the present meta-analysis, identified 15 prospective, head-to-head RCTs including 10,467 patients, of whom 3,474 and 2,683 were treated with FDI and FCM, respectively. The analysis demonstrated that serious or severe hypersensitivity reactions were uncommon with the newer high-dose IV iron formulations; and showed a significantly lower incidence of serious or severe hypersensitivity reactions with FDI compared to FCM. Figure 1 Disclosures Biggar: Vifor-Fresenius: Consultancy; Pharmacosmos: Consultancy; Medice: Consultancy. Pöhlmann: Pharmacosmos A/S: Consultancy. Pollock-Wilkins: Pharmacosmos A/S: Consultancy.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version (6 month embargo