A brief report on combination chemotherapy and anti–programmed death (ligand) 1 treatment in small-cell lung cancer: Did we choose the optimal chemotherapy backbone?

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive cancer that remains very hard to treat. The life expectancy of a patient diagnosed with this disease has not changed over the past three decades. Recently, three large clinical studies showed a survival benefit by adding an anti–programmed death (ligand) 1 (PD-(L)1 antibody to the current chemotherap

The role of inhibitory neurons in the ventromedial medulla in the control of locomotion.

Locomotion is a complex function that requires the control of initiation, posture, speed, rhythm, tone and direction. These features allow normal gait performances. In the elderly, gait is often impaired. This is frequently the result of a neurological disease. To develop effective treatments we need to understand the neural circuitries involved in both normal and pathological gait. To perform a motor task the integrated activity of a diverse set of neural circuits is demanded. A variety of regions in the nervous system aid in the execution of locomotion, from spinal motoneurons to spinal interneurons, to brainstem reticulospinal systems and forebrain and midbrain control regions. Motoneurons innervating different muscles are organized into distinct longitudinal columns in the ventral horn of the spinal cord. In mice, the species used in this project, the cervical cord contains motoneurons steering fore limb muscles and the lumbar cord contains motoneurons steering hind limb muscles active during locomotion. It is widely accepted that the spinal cord contains sets of interneurons that have assembled themselves into ordered networks capable of controlling activity and output of spinal motoneurons. These networks, central pattern generators (CPG’s), are the link between the brain and the motoneurons. In this project, we will focus on the projections to motoneurons from the ventromedial medulla, a part of the brainstem. These projections descend trough the reticulospinal system. Besides excitatory and serotonergic neurons, the medulla contains inhibitory reticulospinal (vgat+) neuronen, projecting to motoneurons. Interestingly, some motoneuron groups do receive a larger projection from this system than others and this system seems to project directly to motoneurons, bypassing the CPG’s. We would like to know which motoneuron pools the most projections receive and what the function of this inhibitory system is. New techniques allow us to genetically dissect the role of inhibitory, excitatory and serotonergic neurons in the medulla. The use of conditional adeno associated viral vectors (AAVs) makes it possible to visualize only those neurons that express cre-recombinase with a tracer. An antergrade tracer is injected in vgat+ neurons in the ventromedial medulla and is transported to the ventral horn of the spinal cord, A retrograde tracer is injected in the muscles and is transported to the motoneurons in the ventral horn of the spinal cord. Immunohistochemistry allowed the visualization of both tracers in the confocal microscope. We expected the inhibitory projections from the VMM to target specific areas of the spinal ventral horn and not being evenly distributed to every motoneuron pool. The results do show a difference between the amount of projections received by motoneuron pools of different muscles. In the cervical enlargement, the triceps does get a hard hit of this inhibitory medullary system and in the lumbar enlargement, the gastrocnemius is striking. Looking at the total numbers, the lumbar enlargement seems to get a slightly stronger projection than the cervical enlargement. However, the relatively small amount of data per muscle and per mouse did not allow the performance of meaningful statistical tests. In the future, implanting the triceps and the gastrocnemius muscles with EMG wires is likely to produce interesting data.

Cost-Effectiveness and Budget Impact of Future Developments With Whole-Genome Sequencing for Patients With Lung Cancer

Objectives: This study aimed to investigate the cost-effectiveness, budget impact (BI), and impact of uncertainty of future developments concerning whole-genome sequencing (WGS) as a clinical diagnostic test compared with standard of care (SoC) in patients with locally advanced and metastatic non–small cell lung cancer. Methods: A total of 3 likely scenarios to take place within 5 years (according to experts) were simulated using a previously developed, peer reviewed, and published decision model. The scenarios concerned “WGS results used for treatment selection” (scenario 1), “WGS-based biomarker for immunotherapy” (scenario 2), and “off-label drug approval for WGS results” (scenario 3). Two diagnostic strategies of the original model, “SoC” and “WGS as a diagnostic test” (base model), were used to compare our scenarios with. Outcomes were reported for the base model, all scenarios separately, combined (combined unweighted), and weighted by likelihood (combined weighted). Cost-effectiveness, BI, and value of information analyses were performed for WGS compared with SoC. Results: Total costs and quality-adjusted life-years for SoC in metastatic non–small cell lung cancer were €149 698 and 1.235. Incremental outcomes of WGS were €1529/0.002(base model), −€222/0.020(scenario 1), −€2576/0.023(scenario 2), €388/0.024(scenario 3), −€5041/0.060(combined unweighted), and −€1715/0.029(combined weighted). The annual BI for adopting WGS for this population in The Netherlands ranged between €682 million (combined unweighted) and €714 million (base model). The consequences of uncertainty amounted to €3.4 million for all scenarios (combined weighted) and to €699 000 for the diagnostic yield of WGS alone (combined weighted). Conclusions: Our findings suggest that it is likely for WGS to become cost-effective within the near future if it identifies more patients with actionable targets and show the impact of uncertainty regarding its diagnostic yield. Modeling future scenarios can be useful to consider early adoption of WGS while timely anticipating on unforeseen developments before final conclusions are reached

Tobacco Smoking-Related Mutational Signatures in Classifying Smoking-Associated and Nonsmoking-Associated NSCLC

Introduction: Patient-reported smoking history is frequently used as a stratification factor in NSCLC-directed clinical research. Nevertheless, this classification does not fully reflect the mutational processes in a tumor. Next-generation sequencing can identify mutational signatures associated with tobacco smoking, such as single-base signature 4 and indel-based signature 3. This provides an opportunity to redefine the classification of smoking- and nonsmoking-associated NSCLC on the basis of individual genomic tumor characteristics and could contribute to reducing the lung cancer stigma. Methods: Whole genome sequencing data and clinical records were obtained from three prospective cohorts of metastatic NSCLC (N = 316). Relative contributions and absolute counts of single-base signature 4 and indel-based signature 3 were combined with relative contributions of age-related signatures to divide the cohort into smoking-associated (“smoking high”) and nonsmoking-associated (“smoking low”) clusters. Results: The smoking high (n = 169) and smoking low (n = 147) clusters differed considerably in tumor mutational burden, signature contribution, and mutational landscape. This signature-based classification overlapped considerably with smoking history. Yet, 26% of patients with an active smoking history were included in the smoking low cluster, of which 52% harbored an EGFR/ALK/RET/ROS1 alteration, and 4% of patients without smoking history were included in the smoking high cluster. These discordant samples had similar genomic contexts to the rest of their respective cluster. Conclusions: A substantial subset of metastatic NSCLC is differently classified into smoking- and nonsmoking-associated tumors on the basis of smoking-related mutational signatures than on the basis of smoking history. This signature-based classification more accurately classifies patients on the basis of genome-wide context and should therefore be considered as a stratification factor in clinical research

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma

Purpose: Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet. Patients and methods: Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples. Results: A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4–3.0), and median overall survival was 7.0 months (95% CI: 4.7–not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4–4.2), and median overall survival was 7.2 months (95% CI: 5.9–not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes. Conclusion: Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations