Nora Sundahl

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.

Pembrolizumab for the treatment of bladder cancer

ABSTRACT Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies. Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab. Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.

Alcohol-related emergency department admissions among adolescents in the Ghent and Sint-Niklaas areas

Alcohol abuse is a major health concern. The aim of this retrospective study was to analyse the alcohol-related emergency department (ED) admissions among adolescents in all hospitals of distinct areas during a 1-year period. In each hospital, all ED patients with a blood alcohol concentration (BAC) of at least 0.5 g/l were surveyed in a standardised way. Of the 3918 included patients, only 146 (3.7%) were < 18 years. The male-to-female ratio was 1.5:1. There was a strong preponderance of weekend and night time admissions. Most of the patients were transported by ambulance (77% of 138 patients with information on this item). The main reason for ED admittance was depressed level of consciousness (64%), trauma (12%), vomiting and/or abdominal pain (12%), agitation or aggression (4%), syncope (4%) and psychological problems (4%). The context of the alcohol intoxication was related to some kind of festivity in 85%, mental problems in 14% and chronic abuse in 1%. Median BAC values (and range) were 2.08 g/l (0.73–3.70 g/l) for boys and 1.51 g/l (0.73–2.90 g/l) for girls. Most patients (87%) could be discharged home within 24 hours. Our study confirms that problematic alcohol use leading to ED admissions starts in adolescence. Although the numbers of cases below 18 years are low when compared to adults, the phenomenon is alarming as it is associated with substantial health problems. Therefore, Belgium urgently needs a global national alcohol plan, with youngsters being one of the target groups.

A systematic review of exercise and psychosocial rehabilitation interventions to improve health-related outcomes in patients with bladder cancer undergoing radical cystectomy

Objective: Summarizing the evidence on the effects of pre- and postoperative exercise and psychosocial rehabilitation interventions on patient-reported outcomes (PROs) and physical fitness in bladder cancer patients undergoing radical cystectomy. Data sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science and the Physiotherapy Evidence Database were searched independently by two authors from inception until 10 November 2017. Cited references of the studies and citing references retrieved via Web of Science were also checked. Review methods: Randomized controlled trials (RCTs) and non-randomized studies assessing effects of exercise and psychosocial interventions in bladder cancer patients undergoing radical cystectomy were eligible. Primary outcome measures were PROs and physical fitness. Risk of bias was assessed using the Cochrane Collaboration tool and the Newcastle–Ottawa Scale. Results: Five RCTs (three exercise and two psychosocial studies) and one non-randomized psychosocial study comprising 317 bladder cancer patients were included. Timing of the intervention was preoperative (n = 2), postoperative (n = 2) or both pre- and postoperative (n = 2). Positive effects of exercise were found for physical fitness (n = 3), some health-related quality-of-life (HRQoL) domains (n = 2), personal activities in daily living (n = 1) and muscle strength (n = 1). Psychosocial interventions showed positive effects on anxiety (n = 1), fatigue (n = 1), depression (n = 1), HRQoL (n = 1) and posttraumatic growth (n = 1). Quality assessment showed most shortcomings with sample sizes and strong heterogeneity was observed between studies. Conclusion: The evidence relating to the effects of exercise in bladder cancer is very limited and is even less for psychosocial interventions.

Rehabilitation interventions to improve patient-reported outcomes and physical fitness in survivors of muscle invasive bladder cancer: a systematic review protocol

Introduction Survivors of muscle invasive bladder cancer (MIBC) experience physical and psychosocial side effects of cancer diagnosis and treatment. These negative side effects have a crucial impact on their health-related quality of life (HRQoL). To date, there is evidence that rehabilitation interventions such as physical activity and psychosocial support have a positive effect on the HRQoL of cancer survivors. Unfortunately, there are no specific guidelines for rehabilitation or survivorship programmes for MIBC survivors. Therefore, this systematic review aims to assess the effects of exercise-based and psychosocial rehabilitation interventions in MIBC survivors. Methods and analysis The approach of this review is consistent with the Cochrane methodology. Randomized controlled trials and non-randomised studies will be included. The population of interest is patients (≥18 years of age) with diagnosis of MIBC or high-risk non-MIBC for whom a radical cystectomy is indicated. There will be two eligible intervention types for inclusion: exercise-based and psychosocial rehabilitation interventions. The primary outcome measures are patient-reported outcomes (eg, HRQoL, fatigue and pain) and physical fitness. Studies will be identified independently by two review authors by searching the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science and the Physiotherapy Evidence Database. A third reviewer will be asked by disagreements. Risk of bias will be assessed using the Cochrane Collaboration tool and the Newcastle-Ottawa Scale. Data will be summarised descriptively. If homogeneity of the studies is sufficient, meta-analysis will be undertaken. The broad scope of this review (ie, different interventions and study designs) is needed to have a comprehensive view on effective rehabilitation interventions. Ethics and dissemination Ethics approval is not required, as no primary data will be collected. Results will be disseminated through a peer-reviewed publication.

A rare case of clinically and biochemically silent giant right pheochromocytoma: case report and review of literature

Abstract Non-secreting pheochromocytomas are rare adrenal tumours. We report the case of a clinically and biochemically silent giant pheochromocytoma that presented as bilateral pulmonary embolisms. Successful surgical resection was performed. Multiple endocrine neoplasia 2 syndrome and neurofibromatosis type 1 were clinically excluded. Subsequent DNA analysis of the succinate dehydrogenase complex subunits B and D (SDHB and SDHD), and Von Hippel–Lindau (VHL) genes revealed no mutations.

Effects of radiation on the metastatic process

Radiotherapy remains one of the corner stones in the treatment of various malignancies and often leads to an improvement in overall survival. Nonetheless, pre-clinical evidence indicates that radiation can entail pro-metastatic effects via multiple pathways. Via direct actions on cancer cells and indirect actions on the tumor microenvironment, radiation has the potential to enhance epithelial-to-mesenchymal transition, invasion, migration, angiogenesis and metastasis. However, the data remains ambiguous and clinical observations that unequivocally prove these findings are lacking. In this review we discuss the pre-clinical and clinical data on the local and systemic effect of irradiation on the metastatic process with an emphasis on the molecular pathways involved.

A patient with acquired factor X deficiency and metastatic transitional cell carcinoma of the bladder: is there a link between metastasis and factor deficiency in solid tumors?

Dear Editor, Acquired deficiency of factor X (FX) is commonly found during antivitamin K therapy in prevention of thrombosis or as a consequence of liver disease [1]. Less frequently, it has been observed as an isolated deficiency in a number of disease states. It has been associated with amyloidosis and hematologic malignancies [2], and few non amyloid-related cases have been reported. Association with solid tumors is rare [3–5]. We would like to present a patient with a transitional cell carcinoma who developed a FX deficiency. A 67-year-old man was diagnosed with a localized transitional cell carcinoma of the bladder. Hewas first admitted to our hospital in January 2014 for a second-opinion consultation. Transurethral resection of the bladder took place and neoadjuvant chemotherapy was administered at our hospital, followed by a cystectomy. During follow-up, suspicious lesions were noticed on medical imaging and a lung biopsy was carried out. Pathological examination revealed a metastasis of the transitional cell carcinoma. The patient subsequently received stereotactic body radiotherapy to all lung lesions yet had progressive disease 6 months later. He was then enrolled in a clinical trial (NCT02826564) in which he received pembrolizumab (Keytruda) and stereotactic body radiation therapy to one lung lesion according to the study protocol [6]. During follow-up, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen concentration were measured to assess his blood’s clotting status. First measurements were within reference ranges, but after the lung metastases were noticed and prior to administration of pembrolizumab, a prolongation of the PT (20s; reference ranges 11.5–14.5 s) and aPTT (51 s; reference ranges 28.9–38.1 s) was detected (Fig. 1). In the laboratory diagnostic workup, mixing patient’s plasma with normal pooled plasma showed correction of aPTT (37.6 s) and PT (14.2 s). Clotting factor activities for the extrinsic factors were determined by a one-stage clotting assay in a 1:10 sample predilution. Factor II, V, and VII levels were within normal ranges with 105, 71, and 98% activity but FX activity was 21% (factor reference ranges 70–120%). Testing was repeated in higher predilutions of 1:40 and 1:100, without increase of FX activity (20%). These findings were confirmed 3 weeks later. In FX deficiencies, FX activity correlates relatively well with bleeding and may be provoked by levels lower than 10% [1, 7]. If no active bleeding is diagnosed, as in our patient, careful monitoring and treatment of the underlying disease are sufficient. If bleeding occurs, it can be treated with prothrombin complex concentrate or plasma, keeping the target FX level above 20% of the normal reference population [7]. * T. Cammaert Timothy.cammaert@uzgent.be

Alcohol-related emergency department admissions in an elderly population

Abstract Objective: Alcohol abuse remains a major health concern. This study aimed to describe the characteristics of alcohol-related emergency department (ED) admissions in an elderly population. Methods: Between 1 September 2013 and 31 August 2014, we retrospectively analyzed patient charts of patients admitted with a blood alcohol concentration (BAC) of at least 0.5 g/L to the EDs of all five hospitals in two distinct areas. We focused on the population ≥65 years, divided in three subgroups (65–74, 75–84 and ≥85, respectively) and compared them to the 55–64 year group. Results: Of the 3918 included patients 645 (16.5%) were between 55 and 64, and 406 (10.4%) were ≥65 years (65–74: 267, 6.8%; 75–84: 128, 3.3%; ≥85: 11, 0.3%). The male-to-female ratio ranged between 2.1:1 and 2.7:1. BACs decreased with increasing age. In all age groups the majority of patients (71.0–77.8%) were transported by emergency medical services. The chief presenting complaint was trauma and its relative importance increased with age. Contextual factors consisted mostly of chronic abuse (43.1–57.8%). Most frequently patients could be discharged within 24 h, although hospital admission rates increased with age. Conclusion: Our study shows that alcohol-related ED admissions in the elderly are common, but less frequent than in younger age groups. More (preferentially prospective) studies are needed to give more insight in the living environment, prescription medication, socioeconomic cost, etc. Nonetheless, it is clear that a national action plan should be developed to tackle the alcohol abuse problem in all age groups.