Zielgerichtete Fünftlinientherapie bei Patienten und Patientinnen mit metastasiertem Nierenzellkarzinom

Einleitung: Jährlich erkranken weltweit etwa 300 000 Menschen an einem Nierenzellkarzinom, etwa ein Drittel zeigt eine primäre Metastasierung. Zytokine waren lange der palliative Goldstandard der Therapie, wurden jedoch durch den Einsatz von zielgerichteten Target-Therapeutika abgelöst. Es konnten bereits mehrere Wirkstoffe etabliert werden, die das Gesamtüberleben und das progressionsfreie Überleben verlängern. Darunter fallen vascular-endothelial-growth-factor-Inhibitoren (VEGFi), mammalian-target-of-Rapamycin-Inhibitoren (mTORi) und seit neuestem ein Immun-Checkpoint-Inhibitor. Basierend auf Phase-III-Studien gibt es derzeit Empfehlungen bis zur Drittlinientherapie, in höheren Therapielinien existieren nur wenige retrospektive Auswertungen. Eine Therapieentscheidung basiert daher weitestgehend auf individueller Erfahrung und Präferenz. Das Ziel dieser Arbeit ist es, die Wirksamkeit und Verträglichkeit einer Fünftlinientherapie bei Patienten mit metastasiertem Nierenzellkarzinom zu evaluieren. Material und Methoden: Insgesamt entsprachen 25 Patienten, die sich aufgrund eines metastasierten Nierenzellkarzinoms an der urologischen Klinik der Charité Universitätsmedizin Berlin behandeln ließen, den Einschlusskriterien. Das Therapieansprechen wurde anhand der Response Evaluation Criteria in Solid Tumors (RECIST) Kriterien und die Verträglichkeit anhand der Common Toxicity Criteria for Adverse Events (CTCAE-Kriterien) bewertet. Die Datenauswertung erfolgte mit dem statistischen Bearbeitungssystem Statistical Package for Social Sciences (SPSS) Version 23. Das Gesamtüberleben (OS) und progressionsfreie Überleben (PFS) wurden durch die Kaplan-Meier-Methode geschätzt und dadurch die Wirksamkeit analysiert. Außerdem wurde das proportionale Hazard Modell (Cox-Regression) in einer univariaten und multivariaten Analyse angewendet um Prädiktoren für PFS und OS zu ermitteln. P-Werte <0,05 wurden als signifikant bewertet. Ergebnisse: Das mediane OS seit Beginn der Erstlinientherapie lag bei 50,2 Monaten (IQR: 38,9-76,7). Das mediane OS ab Beginn der Fünftlinientherapie ergab einen Wert von 6,2 Monaten (IQR: 3,1-23,8). Das mediane PFS in der Fünftlinientherapie lag bei 4,1 Monaten (IQR: 1,81-9,07) und korrelierte nicht mit dem Therapieansprechen in der Erstlinientherapie. Die Krankheitskontrollrate (komplette Remission + partielle Remission + stabile Krankheitssituation) betrug 20%. Der häufigste Grund eines Therapieabbruchs war ein diagnostizierter Progress der Erkrankung. Keiner der Patienten musste die Therapie toxizitätsbedingt abbrechen. Das retrospektive und unizentrische Design und die geringe Anzahl an Patienten limitieren die Aussagekraft der erzielten Ergebnisse. Schlussfolgerungen: Die hier dargestellten Ergebnisse weisen auf eine Wirksamkeit einer Fünftlinientherapie hin. Eine optimale Sequenz der Wirkstoffe konnte nicht identifiziert und eine sichere Empfehlung zur Durchführung der Fünftlinientherapie auf Grund der Limitationen dieser Arbeit nicht getroffen werden. Um eine Grundlage für eine Entscheidungsfindung bei der Therapiewahl in der klinischen Praxis zu schaffen, werden groß angelegte, multizentrische, prospektive Studien zur Wirksamkeit und Sequenzabfolge benötigt.Introduction: Every year there are approximately 300 000 new cases of renal cell carcinoma worldwide. Around one third is already metastasized at diagnosis which includes a poor prognosis. The introduction of targeted therapies for metastatic renal carcinoma (mRCC) led to significant prolonged overall survival (OS) and progression free survival (PFS). Five vascular endothelial growth factor inhibitors (VEGFi), one monoclonal antibody, two mammalian target of rapamycin inhibitors (mTORi) and one immune checkpoint inhibitor are approved for the treatment of mRCC. Current guidelines are based on phase III trials and provide guidance in the choice of medication up to the third line of therapy. Beyond third- or fourth-line therapy treatment decisions are based on individual experience because evidence based data is sparse. In this study we tried to evaluate the efficacy and toxicity of fifth-line targeted therapy in patients with mRCC retrospectively. Methods: At Charité Universitaetsmedizin Berlin Department of Urology 25 out of 406 patients with mRCC and more than four lines of targeted therapy were identified. The response to th treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and toxicity was evaluated by the Common Toxicity Criteria for Adverse Events (CTCAE). Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) Version 23. To evaluate treatment efficacy OS and PFS were estimated by the Kaplan-Meier method. Cox proportional hazard models were applied to identify predictors of PFS and OS in univariate analysis. Significant predictors were further analyzed in multivariate analysis. P-values < 0,05 were considered significant. Results: Median OS since initiation of first-line therapy was 50,2 months (IQR:38,9-76,7). Median OS from beginning of fifth-line therapy was 6,2 months (IQR:3,1-23,8). Disease control rate (complete response + partial response + stable disease) was 20%. Median PFS for fifth-line therapy was 4,1 months (IQR:1,81-9,07) and did not correlate with response to treatment in first-line therapy. None of the patients discontinued treatment because of toxicity and the main reason for treatment termination was progressive disease. The retrospective and unicentric study design and the small number of patients limit the validity of the results. Conclusion: The data of this study indicate that patients with mRCC might benefit from fifth-line targeted therapy independently from treatment response in first-line therapy but no optimal sequence of target agents was found. Larger prospective multicentric randomized trials evaluating the treatment efficacy and toxicity in fifth-line targeted therapy are needed for evidence-based decision-making in higher lines of therapy

The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome

Background Mast cell activation is thought to be involved in visceral hypersensitivity, one of the main characteristics of the irritable bowel syndrome (IBS). A study was therefore undertaken to investigate the effect of the mast cell stabiliser ketotifen on rectal sensitivity and symptoms in patients with IBS. Methods 60 patients with IBS underwent a barostat study to assess rectal sensitivity before and after 8 weeks of treatment. After the initial barostat, patients were randomised to receive ketotifen or placebo. IBS symptoms and health-related quality of life were scored. In addition, mast cells were quantified and spontaneous release of tryptase and histamine was determined in rectal biopsies and compared with biopsies from 22 age- and gender-matched healthy volunteers. Results Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. This effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life. The number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in patients with IBS than in healthy volunteers. Spontaneous release of histamine was mostly undetectable but was slightly increased in patients with IBS compared with healthy volunteers. Histamine and tryptase release were not altered by ketotifen. Conclusions This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H-1 receptor antagonism remains to be further investigate

Irritable bowel syndrome - An inflammatory disease involving mast cells

Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder - that is the presence of symptoms in the absence of demonstrable pathological abnormalities. In recent times, low grade inflammatory infiltrates in both the small and large bowel of some patients with IBS - often rich in mast cells, along with serological markers of low grade inflammation have focussed attention on IBS as an inflammatory disease. The observation that mast cells often lie in close association to enteric neurons, and in-vitro and in-vivo animal studies demonstrating that mast cell mediators may influence enteric motility provides a biologically plausible causal mechanism in IBS. Pilot studies on patients with IBS using the mast cell stabiliser sodium cromoglycate ('proof of concept') have been encouraging. The essential question remains why mast cells infiltrate the bowel of IBS patients. A disturbance of the 'brain-gut axis' is the current favoured hypothesis, whereby childhood stress or psychiatric comorbidity act via neuro-immune mechanisms to modulate low grade inflammation. An alternative hypothesis is that food allergy may be responsible. Serum specific IgE, and skin prick tests are not elevated in IBS patients, suggesting type 1 IgE mediated food allergy is not the cause. However questionnaire based studies indicate IBS patients have higher rates of atopic disease, and increased bronchial reactivity to methacholine has been demonstrated. In this review, we highlight the potential role of mast cells in IBS, and current and future research directions into this intriguing condition

Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit

OBJECTIVES: Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time. DESIGN: Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein. RESULTS: Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=−0.32, p=0.005) and HV (r=−0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140–426) to 1031 (435–2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency. CONCLUSIONS: The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D. CLINICALTRIALS.GOV: NCT00745004

[F-18]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules:a blinded, randomised controlled multicentre trial

Purpose To assess the impact of an [F-18]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT and were randomised to an [F-18] FDG-PET/CT-driven or diagnostic surgery group. In the [F-18]FDG-PET/CT-driven group, management was based on the [F-18]FDG-PET/CT result: when the index nodule was visually [F-18]FDG-positive, diagnostic surgery was advised; when [F-18]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hurthle cell and Hurthle cell nodules. Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [F-18] FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [F-18]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hurthle cell and 13% (2/15 [95% CI, 2-40%]) in I-Liable cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [F-18]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively. Conclusion An [F-18]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hurthle cell nodules

Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management

Functional gastrointestinal disorder (FGID) is one of the commonest digestive diseases worldwide and leads to significant morbidity and burden on healthcare resource. The putative bio-psycho-social pathophysiological model for FGID underscores the importance of psychological distress in the pathogenesis of FGID. Concomitant psychological disorders, notably anxiety and depressive disorders, are strongly associated with FGID and these psychological co-morbidities correlate with severity of FGID symptoms. Early life adversity such as sexual and physical abuse is more commonly reported in patients with FGID. There is mounting evidence showing that psychological disorders are commonly associated with abnormal central processing of visceral noxious stimuli. The possible causal link between psychological disorders and FGID involves functional abnormalities in various components of the brain-gut axis, which include hypothalamic-pituitary-adrenal system, sympathetic and parasympathetic nervous system, serotonergic and endocannabinoid systems. Moreover, recent studies have also shown that psychological distress may alter the systemic and gut immunity, which is increasingly recognized as a pathophysiologic feature of FGID. Psychotropic agent, in particular antidepressant, and psychological intervention such as cognitive behavioral therapy and meditation have been reported to be effective for alleviation of gastrointestinal symptoms and quality of life in FGID patients. Further studies are needed to evaluate the impact of early detection and management of co-morbid psychological disorders on the long-term clinical outcome and disease course of FGID

Efficacy and mode of action of mesalazine in the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D): a multicentre, parallel-group, randomised placebo-controlled trial

BackgroundDiarrhoea-predominant irritable bowel syndrome (IBS-D) is a common outcome after inflammation due to bacterial gastroenteritis. Several studies have shown ongoing immune activation in the mucosa of patients with IBS-D and a number of studies have suggested that mesalazine slow-release granule formulation (2?g; PENTASA®, Ferring Pharmaceuticals Ltd) may provide benefit including a reduction in stool frequency.ObjectivesOur primary aim was to compare the effect of mesalazine with placebo on stool frequency. Our secondary aims were to assess the effect of mesalazine on abdominal pain, stool consistency, urgency and satisfactory relief of irritable bowel syndrome (IBS) symptoms.Design/participants/interventionWe performed a double-blind, randomised placebo-controlled trial of 2?g mesalazine twice daily compared with placebo for 3 months in Rome III criteria patients with IBS-D.SettingsParticipants were recruited from the primary care research network and secondary care hospitals. Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of ‘satisfactory relief of IBS symptoms’. Those recruited in Nottingham had sigmoid biopsies and/or magnetic resonance imaging of the abdomen at the start and end of the trial.ResultsA total of 136 patients with IBS-D (82 female, 54 male) were randomised; 10 patients withdrew from each group. Analysis by intention to treat showed that the mean daily average stool frequency during weeks 11 and 12 was 2.8 [standard deviation (SD) 1.2] in the mesalazine group and 2.7 (SD 1.9) in the placebo group, with a group difference of 0.1 (95% confidence interval –0.33 to 0.53); p?=?0.66.ConclusionsMesalazine did not improve abdominal pain, stool consistency or percentage with satisfactory relief compared with placebo during the last 2 weeks’ follow-up. A post hoc analysis in 13 postinfectious patients with IBS appeared to show benefit but this needs confirmation in a larger group. More precise subtyping based on underlying disease mechanisms may allow more effective targeting of treatment in IBS.Trial registrationCurrent Controlled Trials ISRCTN76612274.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.<br/

A mechanistic multi-centre, parallel group, randomised placebo controlled trial of Mesalazine for treatment of irritable bowel syndrome with diarrhoea (IBS-D)

Introduction: Immune activation has been reported in the mucosa of irritable bowel syndrome patients with diarrhoea (IBS-D) and some small studies have suggested that Mesalazine may reduce symptoms. We performed a double blind, randomised placebo controlled trial of 2g Mesalazine twice daily versus placebo for 3 months in Rome III criteria IBS-D patients. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of “satisfactory relief of IBS symptoms”. Results: 136 patients with IBS-D (82 F, 54 M) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in Mesalazine and 2.7 (1.9) in placebo group with no significant group difference (95% confidence interval) 0.1 (-0.33,0.53); p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared to placebo during the last 2 weeks follow up. Conclusion: This study does not support any clinically meaningful benefit or harm of Mesalazine compared with placebo in unselected IBS with diarrhoea. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. (ClinicalTrials.gov number NCT01316718

The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [I-123]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. The HV subjects comprised 12 women and 8 men (mean age 31 +/- 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 +/- 5 years). The FD patients had a lower left plus right average striatal binding potential (BPNP) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BPNP in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathway