Rolle des lysosomalen Enzyms Cathepsin A bei der Entstehung arrhythmogener Substrate im Vorhof an einem Rattenmodell mit ventrikulärer Ischämie und Reperfusion

1.1 Zusammenfassung Einleitung: Die Herzinsuffizienz ist mit der Entstehung arrhythmogener Substrate im Vorhof assoziiert. Die lysosomale Carboxypeptidase Cathepsin A (CatA) ist an Remodelingprozessen der extrazellulären Matrix beteiligt. Im Rahmen dieser Arbeit sollte der Einfluss eines CatA-Inhibitors (SAR) mit dem eines Hemmers des Angiotensin-Converting Enzyms (ACE) auf die Entstehung arrhythmogener Substrate im Vorhof in einem Rattenmodell mit Herzinsuffizienz untersucht werden. Methoden: In männlichen Wistar Ratten wurde durch eine 30-minütige Ligatur der linksanterioren deszendierenden (LAD) Koronararterie gefolgt von einer 3-monatigen Reperfusion (I/R) arrhythmogene strukturelle und kontraktile Veränderungen im Vorhof induziert. Während der 3-monatigen Reperfusionsphase wurden Ratten mit dem CatA-Inhibitor SAR (30 mg/kg/Tag, n=12) oder mit dem ACE-Inhibitor Ramipril (1 mg/kg/Tag, n=12) therapiert. 9 Sham-operierte und 13 Plazebo-therapierte I/R-Ratten dienten als Kontrollen. Nach 3 Monaten Reperfusion wurde die linksatriale (LA) Entleerungsfunktion mittels Magnet Resonanz Tomographie (MRT) und die LA Elektrophysiologie mittels einer elektrophysiologischen Studie untersucht, bevor die Herzen für weitere histologische und biochemische Analysen fixiert wurden. Ergebnisse: Nach drei monatiger Reperfusion zeigte sich im linken Ventrikel der I/R-Ratten eine verminderte linksventrikuläre (LV) Ejektionsfraktion, ein erhöhter LV enddiastolischer Druck, längere induzierbare Vorhofflimmerepisoden und eine reduzierte atriale Entleerungsfunktion. Die LA CatA Genexpression (2.1±0.3 vs. 1.3±0.3, p=0.009) und die ACE Plasma Aktivität waren erhöht in I/R-Ratten verglichen mit den Sham-operierten Ratten. SAR und Ramipril konnten bessere LA Entleerungsfunktion erhalten (47±2% und 46±3% jeweils gegen 37±3% in Plazebo-therapierten I/R-Ratten, p=0.008), die Verlängerung der induzierbaren Vorhofflimmerepisoden (1.4±0.4s und 4.3±1.7s jeweils gegen 32.6±19.0s in Plazebo-therapierten I/R-Ratten, p=0.02) und die Verlängerung der totalen atrialen Aktivierungszeit (11.9±0.6ms; 12.9±0.3ms jeweils gegen 15.2±1.7ms in Plazebo-therapierten I/R-Ratten, p=0.007). Der linksatriale Fibrosegehalt wurde durch SAR signifikant und durch Ramipril nur tendenziell reduziert (41±2% in Plazebo-therapierten I/R-Ratten; SAR: 34±1% (p=0.009 vs. Plazebo, Ramipril: 37.5±1.4% p>0.05 vs. Plazebo), die Kollagen 1a Genexpression (SAR: 9.05±1.3; Ramipril: 9.7±2.5 vs. 14.6±2.0 in Plazebo-therapierten I/R-Ratten, p=0.03) und die Lateralisierung des Connexins 43 bei I/R-Ratten. Eine Kardiomyozyten-spezifische CatA-Überexpression in einem transgenen Mausmodell war mit einer erhöhten atrialen Fibrosebildung, Hypertrophie und einer Verlängerung der induzierbaren Vorhofflimmerepisoden im linken Vorhof vergesellschaftet. Fazit: CatA ist an der Entstehung arrhythmogener Substrate im Vorhof beteiligt. Die pharmakologische Inhibition von CatA durch SAR reduzierte die Auslösbarkeit von Vorhofflimmern und die Verschlechterung der LA-Entleerungsfunktion bei I/R-Ratten vergleichbar zu Ramipril. Die atriale Fibrosebildung wird hauptsächlich durch SAR und nicht durch Ramipril beeinflusst.1.2 Summary Introduction: Congestive heart failure (CHF) is associated with the development of an arrhythmogenic substrate in the atria. The lysosomal carboxypeptidase Cathepsin A (CatA) has been shown to be involved in remodeling processes of the extracellular matrix. We investigated the effect of the novel inhibitor of CatA (SAR) in comparison to the inhibitor of the angiotensin converting enzyme (ACE) ramipril on susceptibility to atrial fibrillation (AF) and left atrial (LA) emptying function. Method: In male Wistar rats, we investigated the effect of chronic treatment with SAR (30 mg/kg/d, n=12) and ramipril (1 mg/kg/d, n=12) for 3 months on atrial electrophysiology and the development of an atrial arrhythmogenic structural and contractile substrate during CHF induced by 30min of myocardial ischemia followed by reperfusion (I/R). 9 sham-operated and 13 placebo-treated I/R-rats served as a control. LA-emptying function (magnetic resonance imaging) and atrial electrophysiological parameters were measured before the hearts were harvested for histological and biochemical analysis. In transgenic mice, the effect of CatA overexpression on atrial remodeling was investigated. Results: Three months after surgery I/R-rats showed increased left ventricular (LV) enddiastolic pressure, dilated LA, longer inducible AT-durations and reduced atrial contractile function. LA CatA gene-expression (2.1±0.3 vs. 1.3±0.3; p= 0.009) as well as ACE-plasma activity were increased in I/R-rats compared to sham operated rats. CatA inhibition by SAR and ACE-inhibition by ramipril attenuated the effect of I/R on LA total percent emptying (47±2% and 46±3%, respectively, vs. 37±3% in I/R, p=0.008), susceptibility to AF (1.4±0.4s and 4.3±1.7s, respectively, vs. 32.6±8.2s in I/R, p=0.02) and total atrial activation time (11.9±0.6ms; 12.9±0.3 ms, respectively vs. 15.2 ± 1.7ms in placebo, p<0.007). SAR and Ramipril treatment reduced the amount of total atrial fibrosis which SAR reduced significantly (SAR: 34±1%, Ramipril: 37.5±1.4 % vs. 41±2% in placebo treated I/R-rats, p=0.009), collagen1a mRNA expression (SAR: 9.05±1.3; Ramipril: 9.7±2.5 vs. 14.6±2.0 in placebo treated I/R-rats, p=0.03) and connexin 43 lateralization in I/R-rats. Transgenic mice overexpressing CatA demonstrated enhanced atrial fibrosis formation and increased AF-susceptibility. Conclusion: SAR attenuates the development of an atrial arrhythmogenic substrate and preserves LA-emptying function parameters in I/R-rats comparable to ramipril. Atrial fibrosis formation can mostly be affected by SAR and not by ramipril

Evaluation of T1 relaxation time in prostate cancer and benign prostate tissue using a Modified Look-Locker inversion recovery sequence

Purpose of this study was to evaluate the diagnostic performance of T1 relaxation time (T1) for differentiating prostate cancer (PCa) from benign tissue as well as high- from low-grade PCa. Twenty-three patients with suspicion for PCa were included in this prospective study. 3 T MRI including a Modified Look-Locker inversion recovery sequence was acquired. Subsequent targeted and systematic prostate biopsy served as a reference standard. T1 and apparent diffusion coefficient (ADC) value in PCa and reference regions without malignancy as well as high- and low-grade PCa were compared using the Mann-Whitney U test. The performance of T1, ADC value, and a combination of both to differentiate PCa and reference regions was assessed by receiver operating characteristic (ROC) analysis. T1 and ADC value were lower in PCa compared to reference regions in the peripheral and transition zone (p < 0.001). ROC analysis revealed high AUCs for T1 (0.92; 95%-CI, 0.87-0.98) and ADC value (0.97; 95%-CI, 0.94 to 1.0) when differentiating PCa and reference regions. A combination of T1 and ADC value yielded an even higher AUC. The difference was statistically significant comparing it to the AUC for ADC value alone (p = 0.02). No significant differences were found between high- and low-grade PCa for T1 (p = 0.31) and ADC value (p = 0.8). T1 relaxation time differs significantly between PCa and benign prostate tissue with lower T1 in PCa. It could represent an imaging biomarker for PCa

Sonication for Diagnosis of Catheter-Related Infection Is Not Better Than Traditional Roll-Plate Culture: A Prospective Cohort Study With 975 Central Venous Catheters

This prospective randomized controlled study with 975 nontunneled central venous catheters (CVCs) showed that the semiquantitative roll-plate culture technique (SQC) was as accurate as the sonication method for diagnosis of catheter-related infections. Sonication is difficult to standardize, whereas SQC is simpler, faster, and as reliable as the sonication method for culturing CVC

Dynamic metabolic rewiring enables efficient acetyl-CoA assimilation in Paracoccus denitrificans

During growth, microorganisms have to balance metabolic flux between energy and biosynthesis. One of the key intermediates in central carbon metabolism is acetyl-CoA, which can be either oxidized in the citric acid cycle or assimilated into biomass through dedicated pathways. Two acetyl-CoA assimilation strategies have been described in bacteria so far, the ethylmalonyl-CoA pathway (EMCP) and the glyoxylate cycle (GC). Here, we show that Paracoccus denitrificans uses both strategies for acetyl-CoA assimilation during different growth stages, revealing an unexpected metabolic complexity in the organism’s central carbon metabolism. The EMCP is constitutively expressed on various substrates and leads to high biomass yields on substrates requiring acetyl-CoA assimilation, such as acetate, while the GC is specifically induced on these substrates, enabling fast growth rates. Even though each acetyl-CoA assimilation strategy alone confers a distinct growth advantage, P. denitrificans recruits both to adapt to changing environmental conditions, such as a switch from succinate to acetate. Time-resolved single-cell experiments show that during this switch, expression of the EMCP and GC is highly coordinated, indicating fine-tuned genetic programming. The dynamic metabolic rewiring of acetyl-CoA assimilation is an evolutionary innovation by P. denitrificans that allows this organism to respond in a highly flexible manner to changes in the nature and availability of the carbon source to meet the physiological needs of the cell, representing a new phenomenon in central carbon metabolism

Structural Correlates of Taste and Smell Loss in Encephalitis Disseminata

BACKGROUND: Olfactory dysfunction in MS patients is reported in the literature. MRI of the olfactory bulb (OB) is discussed as a promising new testing method for measuring olfactory function (OF). Aim of this study was to explore reasons for and optimize the detection of olfactory dysfunction in MS patients with MRI. MATERIALS AND METHODS: OB and olfactory brain volume was assessed within 34 MS patients by manual segmentation. Olfactory function was tested using the Threshold-Discrimination-Identification-Test (TDI), gustatory function was tested using Taste Strips (TST). RESULTS: 41% of the MS patients displayed olfactory dysfunction (8% of the control group), 16% displayed gustatory dysfunction (5% of the control group). There was a correlation between the OB volume and the number and volume of MS lesions in the olfactory brain. Olfactory brain volume correlated with the volume of lesions in the olfactory brain and the EDSS score. The TST score correlated with the number and volume of lesions in the olfactory brain. CONCLUSION: The correlation between a higher number and volume of MS lesions with a decreased OB and olfactory brain volume could help to explain olfactory dysfunction

A case report of Burning Mouth Syndrome treated with individualized Homeopathy

Introduction Burning mouth syndrome (BMS) is a rare disease of unknown origin. No efficient treatment is known, and integrative approaches are warranted. So far, individualised homeopathy (iHOM) has not been evaluated or reported in any peerreviewed journal as a treatment option. Methods At the Centre of Complementary Medicine at a university institute in Switzerland, a 38-year-old patient with BMS and various co-morbidities was treated with iHOM between July 2014 and August 2018. The treatment involved prescription of individually selected homeopathic single remedies. During follow-up visits, outcome was assessed with two validated questionnaires concerning patient-reported outcomes. To assess whether the documented changes were likely to be associated with the homeopathic intervention, an assessment using the modified Naranjo criteria was performed. Results Over an observation period of 4 years, an increasingly beneficial result from iHOM was noted for oral dysaesthesia and pains as well as for the concomitant symptoms. Conclusion Considering the multi-factorial aetiology of BMS, a therapeutic approach such as iHOM that integrates the totality of symptoms and complaints of a patient might be of value in cases where an association of psychological factors and the neuralgic complaints is likely

optimizing acquisition and diagnostic use of multiparametric imaging

Ziel der vorliegenden Arbeit war es, die Bildqualität der MRT des Auges und der Orbita im Rahmen der technischen Möglichkeiten zu optimieren und den Einsatz innovativer Sequenzen hinsichtlich des klinischen Nutzens zu evaluieren. Die systematischen Untersuchungen mittels Empfangsspulen und Spulenkombinationen an Phantomen und 20 Patienten konnten zeigen, dass kleine Oberflächenringspulen das höchste SRV im Auge und der Orbita erzielen (Originalarbeit 1 und 2). Das Hinzuschalten der Kopfspule für eine Untersuchung des Auges sollte vermieden werden, da Kopplungseffekte das gemessene SRV und damit die Bildqualität negativ beeinflussen können. Das höchste mittlere SRV von 13,1 wurde mit der kleinsten Oberflächenspule (4 cm) bei 3 Tesla erzielt, gefolgt von 1,5 Tesla (9,6). Die in der Arbeit erzielten quantitativen und qualitativen Ergebnisse zeigen, dass die Oberflächenspule einen höheren Einfluss auf die Bildqualität hat, als die Feldstärke, d.h. optimale Bildqualität kann auch bei niedrigerer Feldstärke (1,5 Tesla) unter Einsatz einer kleinen Oberflächenspule erreicht werden (Originalarbeit 2). Mittels hochaufgelöster T1- und T2-gewichteter Datensätze von insgesamt 62 Patientenaugen konnte ein PLS (Partial least square) -Regressionsmodell entwickelt werden, welches einen statistischen Zusammenhang zwischen biometrischen Parametern des Augapfels und der Linsengröße herstellt. Die Linsengröße ist mit herkömmlichen Methoden präoperativ nicht genau bestimmbar, allerdings für Kataraktoperationen eine entscheidende Größe (Originalarbeit 3). Der Einsatz diffusionsgewichteter Sequenzen (DWI) beim Aderhautmelanom machte erstmals eine quantifizierbare Unterscheidung zur häufig vergesellschafteten Netzhautablösung möglich. Die quantitative Auswertung von DWI-Datensätzen von 40 Aderhautmelanomen ergab einen mittleren ADC-Wert von 891 (172) * 10-6 mm2/s (Originalarbeit 4). Zudem gelang es mit dem Einsatz von dynamischen, kontrastmittelgestützten Sequenzen (DCE) das Signalverhalten nach Kontrastmittelgabe von Aderhautmelanomen zu quantifizieren. Es wurde erstmals an einem großen Kollektiv (n = 40) demonstriert, dass Aderhautmelanome ähnlich zu anderen malignen Veränderungen einen raschen Signalanstieg nach Kontrastmittelgabe aufweisen und anschließend eine ‚Washout‘- oder ‚Plateau- Phase‘ zeigen. Zudem beobachteten wir bei jenen Patienten ein signifikant höheres Signal nach Kontrastmittelgabe, welche auch im Verlauf ein schlechteres klinisches Ergebnis (Lebermetastasen oder extraokuläres Wachstum) zeigten (Originalarbeit 5). Der vorteilhafte Einsatz der multiparametrischen Bildgebung (DWI und DCE) bei der Einordnung orbitaler Raumforderungen in benigne und maligne konnte in der vorliegenden Arbeit im Rahmen einer prospektiven Studie unter Einschluss von 65 Patienten demonstriert werden. Der ADC zeigte zwischen benignen und malignen Läsionen statistisch signifikante Unterschiede (1258 (577) * 10-6 mm2/s bei benignen Läsionen und 825 (437) * 10-6 mm2/s bei malignen Läsionen, p=0,001). Auch die Auswertung der DCE- Datensätze ergab signifikante Unterschiede und zeigte bei malignen Läsionen deutlich höhere Ktrans-, kep-, und iAUC-Werte (p < 0,01). Auch nahm die Übereinstimmung der Radiologen untereinander bei Hinzunahme der DWI und DCE deutlich zu (κ = 0,644). Es wird daher die Ergänzung von DWI- und DCE- Sequenzen im Routineprotokoll zur Diagnostik okulärer und orbitaler Pathologien empfohlen (Originalarbeit 6). Die in der vorliegenden Arbeit gewonnenen Ergebnisse der morphologischen Analyse des sogenannten ‚dritten' oder 'parietalen' Auges, der Glandula pinealis bei Patienten mit Retinoblastom können als Größenreferenz bei der diagnostischen Aufarbeitung hinsichtlich eines Pineoblastoms dienen (Originalarbeit 7). Insgesamt liefert diese Habilitationsschrift einen wissenschaftlichen Beitrag zu technischen Einflussgrößen zur Optimierung der Bildqualität und demonstriert den klinischen Nutzen der multiparametrischen Bildgebung bei der MRT-Diagnostik des Auges und der Orbita.The aim of this study was to optimize the image quality of magnetic resonance imaging (MRI) of the eye and orbit and to evaluate the clinical benefit of innovative pulse sequences. The application of various coils and coil combinations was evaluated on phantoms and 20 patients. Small surface coils were found to yield the highest signal-to-noise ratio (SNR) in the eye and orbit (Original papers 1 and 2). Adding the head coil for eye examinations should be avoided as coupling effects decrease the SNR and therefore may adversely affect image quality. The highest average SNR of 13.1 was achieved with the smallest surface coil (4 cm) at 3 Tesla, followed by 1.5 Tesla (9.6). Both quantitative and qualitative results indicate that the surface coil has a higher influence on image quality than magnetic field strength, showing that optimal image quality can also be achieved at lower field strength (1.5 Tesla) when a small surface coil is used (Original paper 2). High-resolution T1- and T2-weighted datasets of 62 patient eyes were used to develop a partial least square (PLS) regression model, which establishes a statistical relationship between biometric parameters of the eye and lens size. The lens size cannot be determined precisely with conventional methods preoperatively although it is crucial in cataract surgery (Original paper 3). The use of diffusion-weighted imaging (DWI) sequences in uveal melanoma for the first time enabled quantifiable differentiation from retinal detachment, which is frequently associated with this malignancy. Quantitative analysis of DWI datasets of 40 uveal melanomas revealed a mean apparent diffusion coefficient (ADC) of 891 (172) * 10-6 mm2 / s (Original paper 4). Furthermore, dynamic contrast- enhanced (DCE) MRI was used to quantify the signal behavior of uveal melanoma after contrast medium administration. This was the first study in a large population (n = 40) demonstrating that uveal melanomas show similar dynamic contrast behavior as other malignancies with a rapid initial increase in signal intensity followed by washout or a plateau phase. Moreover, we observed that patients with significantly higher signal intensity after contrast medium administration had a poorer clinical outcome (liver metastases or extraocular tumor spread) (Original paper 5). The benefit of multiparametric MRI (DWI and DCE) in differentiating benign and malignant orbital masses was demonstrated in a prospective study including 65 patients. Benign and malignant orbital lesions had statistically significant different ADC values (1258 (577) * 10-6 mm2 / s for benign lesions versus 825 (437) * 10-6 mm2 / s for malignant lesions; P = 0.001). Analysis of the DCE datasets also revealed significant differences, showing significantly higher Ktrans, kep, and iAUC values ​​for malignant lesions (p <0.01). Interobserver variability among the radiologists classifying the lesions improved markedly when DWI and DCE were added (κ = 0.644). Therefore, adding DWI and DCE sequences to the routine MRI protocol for imaging patients with ocular and orbital pathology is recommended (Original paper 6). The results of the morphological analysis of the so-called 'third' or 'parietal' eye, i.e., the pineal gland, in patients with retinoblastoma may serve as a size reference in the diagnostic work-up of pineoblastomas (Original paper 7). Overall, this habilitation thesis contributes scientific evidence for optimizing image quality and demonstrates the clinical benefit of multiparametric imaging in MRI of the eye and orbit

Magnetic resonance imaging in patients with Multiple sclerosis and olfactory dysfunction: Significance of diffusion-weighted imaging and volumetry of the olfactory bulb

Ziel der Arbeit war es Riechstörungen bei multipler Sklerose (MS) Patienten mit Veränderungen am Bulbus olfactorius sowie intrazerebralen Veränderungen zu korrelieren, wobei insbesondere der Stellenwert der diffusionsgewichteten Sequenzen herausgearbeitet werden sollte. Die Ethikkommission der Charité - Universitätsmedizin Berlin genehmigte diese Studie. Insgesamt konnten 36 MS Patienten in die Studie eingeschlossen werden, welche neurologisch sowie HNO- ärztlich untersucht wurden. Das Riechvermögen der MS Patienten wurde mittels TDI Test ermittelt, welcher die Riechschwelle (T), das Unterscheidungsvermögen von Gerüchen (D) und die Identifikation von Gerüchen (I) testet. Die Ergebnisse des Riechtests wurden mit jenen gesunder Probanden verglichen. Bei den Patienten wurde eine Magnetresonanztomographie (MRT) mit besonderer Berücksichtigung des Riechhirnes durchgeführt. Das Volumen des Bulbus olfactorius wurde mittels Segmentierung ermittelt. Ein Diffusionstensor Datensatz (DTI) wurde verwendet um die fraktionale Anisotropie (FA) in den MS Läsionen im gesamten Gehirn sowie im segmentierten Riechhirn zu bestimmen. Mittels Tract-based spatial statistics (TBSS) wurden die DTI-Datensätze mit jenen gesunder Probanden verglichen. Zusammenfassend zeigen die Ergebnisse der Studie, dass ein höherer Behinderungsgrad im Rahmen der MS mit einem schlechteren Riechvermögen einhergeht. Eine Korrelation zwischen Bulbus olfactorius-Volumina und dem Riechvermögen von MS Patienten besteht nur bei kleinen Bulbus-Volumina. Im Vergleich zu gesunden Probanden war die Geruchsidentifikation (I) des Riechvermögens bei MS Patienten signifikant schlechter. Das schlechtere Geruchsidentifikationsvermögen (I) korreliert mit schlechteren FA-Werten aus DTI-Datensätzen des Riechhirns der Patienten. Die TBSS-Analyse identifiziert dabei Regionen rechts frontobasal, welche bei Patienten mit einem schlechten Geruchsidentifikationsvermögen (I) auch schlechtere FA- Werte aufweisen.The aim of the study was to correlate olfactory dysfunction in multiple sclerosis (MS) patients with olfactory bulb and intracerebral abnormalities. In this context, the significance of diffusion-weighted sequences was investigated. The ethics committee of the Charité - Universitätsmedizin Berlin approved this study. A total of 36 MS patients were included in the study, which were examined by a neurologist and an ENT physician. The olfactory function of MS patients was measured by the TDI test, which investigates the olfactory threshold (T), the discrimination of odors (D) and the identification of odors (I). The results of the smelling test were compared with those of healthy volunteers. Magnetic resonance imaging (MRI) was performed with special emphasis on the olfactory system. The volume of the olfactory bulb was determined by segmentation. Diffusion tensor imaging (DTI) was used to evaluate fractional anisotropy (FA) determined in MS lesions within the brain and within the segmented olfactory brain. Tract-based spatial statistics (TBSS) was used to compare the DTI data with those of healthy subjects. In summary, the results of the study indicate that a higher level of disability in MS is associated with a poorer sense of smell. A correlation between olfactory bulb volume and olfactory function of MS patients is only true in small bulb volumes. Compared with healthy subjects, the odor identification (I) of the olfactory function was significantly worse in MS patients. The decreased odor identification ability (I) correlated with poorer FA values derived from DTI data of the olfactory brain of MS patients. The TBSS analysis identifies regions within the right frontobasal brain where decreased FA values are shown in patients with reduced smell identification ability (I)

Complementary individual homeopathy in paediatric cancer care: A case series from a University Hospital, Switzerland

The Department of Haematology/Oncology at the University Children’s Hospital Bern (HONK), has adopted an integrative approach in addition to state of the art oncological care and implemented a collaboration with the Institute of Complementary Medicine IKOM, University of Bern, over the past 10 years. Stakeholder satisfaction with this service was high. We present descriptive data and report on 4 exemplary patients treated with additional individualized homeopathy (iHOM). Data concerning frequency of consultations, pathologies, follow-ups and clinical results were reviewed and summarized using descriptive statistics. 94 paediatric oncologic patients consulted for iHOM. Indications for the complementary treatment was wideranging. No interactions with conventional treatment and no adverse side-effects of iHOM were detected. We present four characteristic patient histories, in which iHOM was used in addition to standard treatment for mucositis, permissive tissue infection, insomnia and affective dysfunctions. All four patients clinically improved in an immediate temporal relationship to the additional treatment. Conclusion: The collaboration between HONK and IKOM established iHOM in paediatric oncology in Bern. In this setting, iHOM was a safe and supportive additional treatment for various indications during the conventional cancer care. However, no generalizable results can be deducted from these data. We emphasize future research on this topic