Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the ...outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial.
We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search.
Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia.
With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Implantable cardioverter-defibrillator (ICD) systems are established for the prevention of sudden cardiac death. Long-term data on ICD function in children and adolescents is rare ...and has suggested higher rates of lead failure as well as oversensing, both leading to inappropriate therapy. The present study displays a long-term single-center follow-up of young patients having received an S-ICD.
Methods and results
The present study represents a single-center experience of patients younger than 25 years who received an S-ICD (n=49). Follow-up data included regular in-house follow-up as well as unscheduled hospitalisations in our center. Mean age at implantation was 19.2±4.1 years and 33 patients (67.4%) were male. In 21 patients (42.9%) electrical heart disease or idiopathic ventricular fibrillation represented the underlying condition of ICD implantation. 15 patients suffered from HCM (30.6%). Median follow-up duration was 2 years. No patient died during the observation period. Appropriate shocks occurred in 7 patients (14.3%). Inappropriate shock delivery was recorded in 6 patients (12.3%). T-wave oversensing was the main cause for inappropriate shock delivery (5/6 patients), in the other patient myopotentials were the reason for inappropriate therapy. In one patient, operative refixation of the subcutaneous lead was necessary due to hypermobility leading to oversensing. After modification of the sensing vector as well as activation of the SMART pass filter no further oversensing episodes occurred in any patient.
Conclusion
ICD therapy in children and adolescents is effective for prevention of sudden cardiac death. Every episode was terminated by the first therapy. The rate of appropriate shock as well as inappropriate therapies was quite high compared to typical ICD cohorts. In particular T-wave oversensing seems to be challenging for the S-ICD detection algorithms also in this cohort.
Funding Acknowledgement
Type of funding source: None
Abstract
Background
Commonly, innovative antiarrhythmic strategies are derived from single cell studies that frequently yield promising in vitro findings. However, these results may differ on the ...whole-heart level, since multicellular electrophysiology is characterized by several emergent features. In previous cellular studies, we have identified the Na+/Ca2+-exchanger (NCX) as a promising target for an innovative antiarrhythmic strategy, as NCX upregulation is present in major cardiac diseases (e.g. heart failure) and promotes independently cellular early and late afterdepolarizations (EADs and DADs). Vice versa, we found that genetic and pharmacological NCX inhibition protects against EADs and DADs. To date, it is unknown, whether the concept of NCX inhibition indeed beneficially applies to the whole-heart level. Thus, we here investigate the in vivo inducibility and perpetuation of whole-heart arrhythmia using a heterozygous NCX-knockout mouse (KO) model that is protected against EADs and DADs on the cellular level.
Methods/Results
Programmed electrical right ventricular stimulation (PVS) and burst stimulation were performed in KO (n=22) and wild-type (n=34) mice by an octapolar mouse electrophysiological catheter introduced via the right jugular vein. Inducibility for ventricular tachycardia (VT) during PVS was similar in WT (73.5%) compared to KO (90.0%) (p=0.1707). With burst stimulation, VT inducibility was higher in KO (KO: 68.2%; WT: 32.4%; p=0.0134). During PVS, KO exhibited increased VT perpetuation as reflected in a significantly prolonged mean (in s; KO: 0.89±0.93; WT: 0.39±0.41; p=0.0097) and cumulative VT duration (in s; KO: 19.54±27.98; WT: 4.46±6.35; p=0.0019). Analysis of animals that were inducible for VT consistently yielded similar results. The ventricular refractory period (VRP) (in ms; KO: 15.1±3.5; WT: 18.7±4.1; p=0.0050) and the QTc interval were shortened in KO (in ms; KO: 46.5±5.8; WT: 53.2±5.9; p=0.0001).
Conclusions
As opposed to findings on the single cell level, KO mice exhibited an increased in vivo arrhythmia burden on the whole-heart level during PVS. This mainly resulted from increased perpetuation of artificially induced VTs, since the inducibility of VTs was not significantly increased in KO with PVS. As a mechanistic explanation of these surprising results, we found significantly reduced VRP and QTc durations in KO in line with the previously demonstrated action potential shortening in single KO cardiomyocytes, which promotes the perpetuation of VTs. We conclude that genetic NCX inhibition can protect from proarrhythmic cellular triggers like EADs and DADs that can initiate VT. However, VTs may perpetuate longer in KO most likely due to reduced refractory periods. This finding carries important translational limitations for the antiarrhythmic concept of NCX inhibition and demonstrates that the value of novel innovative strategies needs evaluation on both the cellular and the whole-heart level.
Acknowledgement/Funding
None
Infections with Scedosporium spp. are emerging in the past two decades and are associated with a high mortality rate. Microbiological detection can be associated with either colonization or ...infection. Evolution from colonization into infection is difficult to predict and clinical management upon microbiological detection is complex. Microbiological samples from 2015 to 2021 were retrospectively analyzed in a single tertiary care center. Classification into colonization or infection was performed upon first microbiological detection. Clinical evolution was observed until July 2023. Further diagnostic procedures after initial detection were analyzed. Among 38 patients with microbiological detection of Scedosporium spp., 10 were diagnosed with an infection at the initial detection and two progressed from colonization to infection during the observation time. The main sites of infection were lung (5/12; 41.6%) followed by ocular sites (4/12; 33.3%). Imaging, bronchoscopy or biopsies upon detection were performed in a minority of patients. Overall mortality rate was similar in both groups initially classified as colonization or infection 30.7% and 33.3%, respectively (P = 1.0). In all patients where surgical debridement of site of infection was performed (5/12; 42%); no death was observed. Although death occurred more often in the group without eradication (3/4; 75%) compared with the group with successful eradication (1/8; 12.5%), statistical significance could not be reached (P = 0.053). As therapeutic management directly impacts patients' outcome, a multidisciplinary approach upon microbiological detection of Scedosporium spp. should be encouraged. Data from larger cohorts are warranted in order to analyze contributing factors favoring the evolution from colonization into infection.
Background : Current diagnostic criteria for mature B-cell tumors require a combination of histopathological, immunophenotypic, cytogenetic, and genetic evaluations on tissue biopsy specimens (Campo, ...Blood 2022; Alaggio, Leuk 2022). Despite this battery of techniques, substantial heterogeneity remains in specific subgroups that can be further resolved using additional molecular diagnostic methods, including gene expression profiling (GEP). For example, among aggressive B-cell tumors, a subset recognized as high-grade B-cell lymphomas can be identified as harboring MYC+BCL2 lesions by FISH (HGBCL-DH-BCL2). However, a significant remaining high-risk subset also have a characteristic tumor gene expression “double-hit signature” or “dark zone signature” (DZsig) (Ennishi, JCO 2018; Alduaij, Blood 2023). Yet, inadequate tissue specimens can limit the application of these techniques for some patients. Separately, the invasive nature of tissue biopsies and their attendant risks can preclude adequate diagnostic evaluations in some patients, and logistical barriers for obtaining surgical tissue specimens can result in diagnostic delays. To address these unmet needs, we tested the performance of a novel noninvasive strategy to detect and classify mature B-cell tumors using plasma cfDNA, with special attention to HGBCL-DH-BCL2 and DZsig. Methods : We used EPIC-Seq to infer expression levels for genes of interest, using cfDNA fragmentomic signals at their transcription start sites (Esfahani, Nat Biotech 2022). We first curated and catalogued genes from prior GEP studies (n=56) of >10k diverse lymphoid tumors profiled by various RNA techniques. We systematically prioritized genes recurrently identified in multiple studies of tumor-specific expression profiles as compared with other tumor types and normal tissues. We included canonical markers used for immunodiagnosis by IHC and FACS, as well as key lineage and differentiation markers of normal B and T cells, and other leukocyte subsets. Finally, we also included recurrently mutated genomic regions and fusion hotspots for quantifying ctDNA levels using variant allelic fractions (VAF). To validate performance of DZsig in FFPE for HGBCL-DH-BCL2, we analyzed 95 FFPE biopsies by FISH (20% HGBCL-DH-BCL2), IHC, and RNA-seq. We then analyzed 36 corresponding pretreatment cfDNA samples (28% HGBCL-DH-BCL2) and used EPIC-Seq to infer gene expression. Results: Starting from our curated catalogue, we designed a targeted lymphoid EPIC-Seq panel (1676 genes; 2.6 MB) to resolve 11 major mature lymphoid malignancies and their clinically relevant molecular subtypes (cHL, DLBCL, HGBCL, FL, MCL, BL, MZL, PMBCL, SLL/CLL, PTCL, and MM). We next applied this EPIC-Seq panel to profile cfDNA samples from 207 lymphoma patients, including cHL (n=113), DLBCL (n=66), FL (n=15), and MCL (n=13) as well as healthy adults to assess specificity. We tested histology specific signatures derived from several existing RNA GEP datasets for cHL from sorted HRS cells (~85k by scRNA-Seq) and for DLBCL (n=959), FL (n=635), and MCL (n=100) from bulk RNA-Seq. Using this approach, we found high correlations between EPIC-Seq signature scores from cfDNA and corresponding circulating tumor VAFs in each histology cHL (R p=0.83), DLBCL (R p=0.83), FL (R p=0.87), MCL (R p=0.81); Fig A. In addition, when measuring these tumor derived signatures in cfDNA, each histology was significantly distinguishable from healthy controls (AUCs: cHL 0.94, DLBCL 0.91, FL 0.77, MCL 0.96). We next evaluated the DZsig when measured in LBCL patients and comparing paired tumor and cfDNA samples. We first confirmed the performance of the DZsig for detection of HGBCL-DH-BCL2 in 95 FFPE tumors by RNA-Seq (p<0.0001, AUC 0.85). We then noninvasively measured the DZsig in plasma cfDNA by EPIC-Seq (cfDZsig) and found significant discrimination of HGBCL-DH-BCL2 and DLBCL (p=0.0088, AUC 0.78, Fig B). Conclusions: These results confirm that inferred gene expression by cfDNA profiling allows noninvasive diagnosis of multiple lymphoma subtypes, including classification of challenging diagnostic entities such as HGBCL and DZsig+ tumors. Our ability to design and validate a pan-lymphoid gene panel for detection and classification of several lymphoma subtypes suggests the promise of this approach for other diverse tumors as well as the refinement of cfDZsig using a larger cohort.
Full text
Available for:
IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Climate change is one of the most challenging problems facing today’s global society (e.g., IPCC
2013
). While climate change is a widely covered topic in the media, and abundant information is made ...available through the internet, the causes and consequences of climate change in its full complexity are difficult for individuals, especially non-scientists, to grasp. Science education is a field which can play a crucial role in fostering meaningful education of students to become climate literate citizens (e.g., NOAA
2009
; Schreiner et al.,
41
, 3–50,
2005
). If students are, at some point, to participate in societal discussions about the sustainable development of our planet, their learning with respect to such issues needs to be supported. This includes the ability to think critically, to cope with complex scientific evidence, which is often subject to ongoing inquiry, and to reach informed decisions on the basis of factual information as well as values-based considerations. The study presented in this paper focused on efforts to advance students in (1) their conceptual understanding about climate change and (2) their socioscientific reasoning and decision making regarding socioscientific issues in general. Although there is evidence that “knowledge” does not guarantee pro-environmental behavior (e.g. Schreiner et al.,
41
, 3–50,
2005
; Skamp et al.,
97
(2), 191–217,
2013
), conceptual, interdisciplinary understanding of climate change is an important prerequisite to change individuals’ attitudes towards climate change and thus to eventually foster climate literate citizens (e.g., Clark et al.
2013
). In order to foster conceptual understanding and socioscientific reasoning, a computer-based learning environment with an embedded concept mapping tool was utilized to support senior high school students’ learning about climate change and possible solution strategies. The evaluation of the effect of different concept mapping scaffolds focused on the quality of student-generated concept maps, as well as on students’ test performance with respect to conceptual knowledge as well as socioscientific reasoning and socioscientific decision making.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
