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Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth-arrest and act immune-stimulatory, while others are tumor-promoting. We evaluated whether metronomic, i.e. long-term, repetitive low-dose, drug treatment induces senescence in vitro and in vivo. And importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified.We demonstrate that metronomic application of chemotherapeutic drugs induces therapy-induced senescence, characterized by cell cycle arrest, p21WAF/CIP1 up-regulation and DNA double-strand breaks selectively in MYCN-amplified NB. Low-dose topotecan (TPT) was identified as an inducer of a favorable SASP while lacking NFKB1/p50 activation. In contrast, Bromo-deoxy-uridine induced senescent NB-cells secret a tumor-promoting SASP in a NFKB1/p50-dependent manner. Importantly, TPT-treated senescent tumor cells act growth-inhibitory in a dose-dependent manner on non-senescent tumor cells and MYCN expression is significantly reduced in vitro and in vivo. Furthermore, in a mouse xenotransplant-model for MYCN-amplified NB metronomic TPT leads to senescence selectively in tumor cells, complete or partial remission, prolonged survival and a favorable SASP.This new mode-of-action of metronomic TPT treatment, i.e. promoting a tumor-inhibiting type of senescence in MYCN-amplified tumors, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles.

The aim of the study was to update previously published public health impact and cost-effectiveness analyses of the recombinant zoster vaccine (RZV), in the German population aged ≥50 years of age (YOA), with the latest vaccine efficacy (VE) estimates against herpes zoster (HZ). The updated estimates are derived from a long-term follow-up study. A previously published multi-cohort Markov model following age cohorts over their lifetime was used. Demographic, epidemiological, cost, and utility data were based on German specific sources. Vaccine coverage was assumed to be 40%, with a second dose compliance of 70%. The estimated VE at time 0 was 98.9% (95% C.I.: 94.0–100%) with an annual waning of 1.5% (95% CI: 0.0–3.4%) for the age group 50–69 YOA. Corresponding values were 95.4% (95% C.I.: 89.7–100%) and 2.3% (95% CI: 0.3–4.4%) for the age group ≥70 YOA. It was estimated that, over the remaining lifetime since vaccination, RZV would prevent approximately 884 thousand (K), 603 K, and 538 K HZ cases in three age cohorts 50–59, 60–69, and ≥70 YOA, respectively. The number needed to vaccinate to prevent one HZ and one postherpetic neuralgia case was 6 and 36 (50–59 YOA cohort), 6 and 34 (60–69 YOA cohort), 10 and 48 (≥70 YOA cohort). The incremental cost-effectiveness ratio of vaccination ranged from €26 K/quality-adjusted life year (QALY) in 60 YOA to €35 K/QALY in 70 YOA. Due to the higher, sustained, RZV VE, improved public health and cost-effectiveness results were observed compared to previous analyses.

Introduction Several chronic underlying conditions (UCs) are known to be risk factors for developing herpes zoster (HZ) and to increase the severity of HZ and its risk of recurrence. The aim of this study was to investigate the incidence and recurrence of HZ in adult patients with one or multiple UCs. Methods A retrospective cohort study based on claims data representing 13% of the statutory health insurance population from 2007 to 2018 in Germany was performed. Patients aged ≥ 18 years were included when at least one of the following UCs was diagnosed: asthma, chronic heart failure, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), depression, diabetes mellitus type 1 or 2, and rheumatoid arthritis (RA). Exact matching was used to account for differences in the distribution of age and sex between the case and matched control cohorts. Multi-morbidity was considered in sensitivity analyses by analyzing patients with only one UC. Results Patients with asthma, CHD, COPD, depression, and RA had, on average, a 30% increased risk of developing acute HZ compared to patients without any UC. RA was found to have the highest odds ratio among these conditions, varying from 1.37 to 1.57 for all age groups. Patients with depression also showed a high risk of developing HZ. Analysis of recurrence indicated that patients with at least one UC in the age groups 18–49 years and 50–59 years had the highest risk for a recurrent HZ. After experiencing a first recurrence, patients, regardless of age group, had a two- to threefold higher risk for a second recurrence. Conclusion This study of representative claims data shows a higher HZ incidence and recurrence frequency in patients with UCs. These results provide relevant information for national health care guidelines and disease management programs. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00535-7.

We propose a user-driven method for the segmentation of neuroblastoma nuclei in microscopic fluorescence images involving the gradient energy tensor. Multispectral fluorescence images contain intensity and spatial information about antigene expression, fluorescence in situ hybridization (FISH) signals and nucleus morphology. The latter serves as basis for the detection of single cells and the calculation of shape features, which are used to validate the segmentation and to reject false detections. Accurate segmentation is difficult due to varying staining intensities and aggregated cells. It requires several (meta-) parameters, which have a strong influence on the segmentation results and have to be selected carefully for each sample (or group of similar samples) by user interactions. Because our method is designed for clinicians and biologists, who may have only limited image processing background, an interactive parameter selection step allows the implicit tuning of parameter values. With this simple but intuitive method, segmentation results with high precision for a large number of cells can be achieved by minimal user interaction. The strategy was validated on handsegmented datasets of three neuroblastoma cell lines.

Introduction: Invasive meningococcal disease (IMD) is an uncommon, severe, life-threatening disease primarily affecting infants, with potential lifelong sequelae. Neisseria meningitidis (Nm) serogroup B (MenB) causes most IMD cases in Germany, many of which can be prevented with four-component MenB (4CMenB) vaccination. The potential public health and economic impact of introducing routine 4CMenB infant vaccination in Germany was assessed. Methods: A dynamic transmission-based costeffectiveness model adapted for Germany assessed the impact of infant 4CMenB universal mass vaccination (UMV) versus no vaccination. The model included the latest real-world evidence on vaccine effectiveness, the comprehensive burden of disease on patients (sequelae)

Background: Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis, and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth arrest and act in an immune-stimulatory fashion, while others are tumor promoting. Studies on low-dose long-term, i.e., metronomic, treatment schedules have demonstrated effects on the tumor microenvironment, but have not comprehensively analyzed cellular responses in tumor cells. Methods and Results: We evaluated efficacy and mode of action of low-dose metronomic treatment schedules in in vitro and in vivo NB models. Importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified. Our preclinical work has demonstrated that low-dose long-term topotecan (TPT) treatment (0.1 mg/kg/d, i.p., daily over 15 weeks) improves survival in mouse NB xenografts and leads to long-term cure in 40% of mice. TPT induces a tumor-inhibiting type of senescence, accompanied by changes in the tumor transcriptome and secretome, specifically in MYCN-amplified NB cells. As senescent NB cells showed a reduced MYCN copy number and strongly downregulated MYCN expression, we investigated the mechanism of MYCN inactivation. This showed that upon senescence MYCN is epigenetically silenced and gene copies are recruited to the nuclear periphery where changes in the nuclear lamina composition take place. Conclusion: This new mode of action of metronomic TPT treatment, i.e., promoting a tumor-inhibiting type of senescence selectively in MYCN-amplified neuroblastoma, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles. Citation Format: Sabine Taschner-Mandl, Teresa Gerber, Magdalena Schwarz, Johanna Blaha, Maximilian Kauer, Florian Kromp, Nelli Frank, Fikret Rifatbegovic, Tamara Weiss, Ruth Ladenstein, Martin Hohenegger, Inge M. Ambros, Peter F. Ambros. Metronomic topotecan causes MYCN inactivation and impedes tumor growth selectively in MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy-induced senescence [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A17.

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