The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Interlaboratory study on rheological properties of cement pastes and reference substances: comparability of measurements performed with different rheometers and measurement geometries

This paper presents the results of an interlaboratory study of the rheological properties of cement paste and ultrasound gel as reference substance. The goal was to quantify the comparability and reproducibility of measurements of the Bingham parameters yield stress and plastic viscosity when measured on one specific paste composition and one particular ultrasound gel in different laboratories using different rheometers and measurement geometries. The procedures for both in preparing the cement paste and carrying out the rheological measurements on cement paste and ultrasound gel were carefully defined for all of the study’s participants. Different conversion schemes for comparing the results obtained with the different measurement setups are presented here and critically discussed. The procedure proposed in this paper ensured a reasonable comparability of the results with a coefficient of variation for the yield stress of 27% and for the plastic viscosity of 24%, despite the individual measurement series’ having been performed in different labs with different rheometers and measurement geometries

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials

Brain morphology alterations in the basal ganglia and the hypothalamus following prenatal exposure to antiepileptic drugs

Eine pränatale Antiepileptika-Exposition kann zu der Beeinträchtigung kognitiver Leistungen führen. Antiepileptika beeinflussen Ionenkanäle, Neurotransmitter und second Messenger Systeme im Gehirn. Diese Mechanismen sind für Lernprozesse, Gedächtnis sowie emotionales Verhalten von essentieller Bedeutung. Es wurde zudem gezeigt, dass Antiepileptika eine apoptotische Neurodegeneration im unreifen Gehirn verursachen können. Somit sind Antiepileptika über verschiedene Mechanismen in der Lage die Hirnentwicklung ungünstig zubeeinflussen. Im Rahmen dieser Studie wurden strukturelle Veränderungen im Gehirn nach pränataler Antiepileptika-Exposition untersucht. Hierzu wurden Magnetresonanztomographie (MRT)- Untersuchungen der Gehirne von 18 erwachsenen Probanden nach pränataler Antiepileptika-Exposition und 18 gesunden Probanden gleichen Alters (Kontrollgruppe) angefertigt und verglichen. Die lokalen Unterschiede der cerebralen Hirnmorphologie in der grauen und weißen Substanz wurden mittels der voxel-basierten Morphometrie anhand der volumen-übertragener MRT-Daten analysiert. Kontraste im Hinblick auf regionale Veränderungen des Volumens der grauen Substanz, d.h. Antiepileptika-exponierte Patienten < Kontrollgruppe, ergaben signifikante Unterschiede (p<0,05, SVC). Verminderungen der Volumina der grauen Substanz nach pränataler Antiepileptika-Exposition wurden im Gebiet des Nucleus lentiformis, sowohl im Pallidum als auch Putamen beidseits, sowie im Hypothalamus festgestellt. Diese Ergebnisse erlauben die Schlussfolgerung, dass die pränatale Antiepileptika-Exposition zu einer Verminderung der grauen Hirnsubstanz in den Basalganglien und im Hypothalamus beim Menschen führen kann.If humans are exposed prenatally to antiepileptic drugs (AEDs), cognitive impairment may be the consequence. Driven by results of experimental work showing that AEDs may induce neuronal death in the developing rodent brain, we wanted to explore whether prenatal exposure to AEDs (PAE) may result in structural changes in the human brain. For this purpose we investigated a group of healthy young adults with PAE and a group of age-matched unexposed healthy controls by magnetic resonance imaging (MRI) of the brain. Local differences in cerebral morphology associated with PAE were analysed in volumetric MRI data by use of voxelwise comparisons of grey and white matter images. Significant regional decreases of grey matter volumes were found in PAE subjects in the area of the lentiform nucleus, including both pallidum and putamen bilaterally, and the hypothalamus. No significant regional differences in white matter volumes were found. We conclude that PAE causes subtle morphological changes in grey matter of the human brain which are conform with lower cell numbers in the basal ganglia and the hypothalamus

Patient interest in mHealth as part of cardiac rehabilitation in Switzerland

PURPOSE Smartphone-based health interventions (mHealth) offer the potential to overcome barriers to accessibility of cardiac rehabilitation. We aimed (1) to examine patients’ interest in mHealth as part of the outpatient cardiac rehabilitation (phase II) and long-term aftercare (phase III) and (2) to identify the influence of sociodemographic and clinical patient characteristics on interest in mHealth. METHODS A questionnaire was consecutively handed out to 2041 patients concluding outpatient cardiac rehabilitation between March 2013 and December 2018 at the University Hospital Bern. Multivariate logistic models were used to identify influencing factors (age, sex, smartphone ownership, year, compliance with cardiac rehabilitation, physical fitness, body mass index, diabetes mellitus, German speaking) for mHealth interest. RESULTS The questionnaire was returned by 1025 patients (50.2% response rate). Seventy-one percent of the responding patients preferred the cardiac rehabilitation as offered with three weekly centre-based sessions, whereas 12% preferred and 17% considered replacing two out of the three centre-based sessions per week with mHealth. Forty-eight percent were interested in continuing exercise training using mHealth after completion of cardiac rehabilitation. Smartphone ownership was the most important indicator for patient interest in mHealth (odds ratio [OR] 2.54, 95% confidence interval [CI] 1.53–4.23), whereas age (per year) was not independently associated with mHealth interest for phase II (OR 0.99, 95% CI 0.98–1.01) and only weakly associated with phase III (OR 0.98, 95% CI 0.96–0.99). CONCLUSION In a Swiss urban region with easy access to cardiac rehabilitation, patients who participated in a centre-based cardiac rehabilitation programme between 2013 and 2018 showed little interest in mHealth during phase II. However, almost half of them expressed interest in continuing training with mHealth during phase III

Cardiac Rehabilitation in Patients With Ventricular Assist Device

PURPOSE: The aim of this study was to investigate changes in exercise capacity (EC) and quality of life (QoL) of patients with ventricular assist devices (VADs) during cardiac rehabilitation (CR). METHODS: Data from patients with VAD implantation and subsequent CR between 2007 and 2017 were analyzed retrospectively. Measures of the 6-min walk test [6MWT] distance, Functional Independence Measure [FIM], ergometry, MacNew Heart Disease Questionnaire [MNH], and Hospital Anxiety and Depression Scale [HADS] at entry and discharge were examined. RESULTS: Data from 110 patients (age 53 ± 12 yr; male 82%) were analyzed. Patients improved during CR significantly in the 6MWT (114 ± 85 m, P < .001), ergometry (20 ± 17 W, P = .002), FIM (8 ± 7 points, P < .001), and MNH (0.8 ± 0.7 points, P < .001). Initial HADS levels were high with a mean value of 9 and did not improve during CR (-0.4 ± 5 points, P = .637). Significant differences of improvements in the 6MWT were observed between left and biventricular VAD (129 ± 90 m vs 85 ± 67 m, P = .043) as well as destination therapy and bridge-to-transplant (184 ± 88 m vs 102 ± 82 m, P = .005). CONCLUSIONS: Patients with VAD implantation had statistically and clinically significant improvements in EC and QoL as assessed with the MNH during CR. Patients on destination therapy showed a larger benefit from CR than bridge-to-transplant patients and patients with left VAD improved more than biventricular VAD patients