Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition — A Descriptive Observational Retrospective Multicenter Analysis

Introduction Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia. Methods This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+). Results In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4–49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia. Conclusion Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded

Particle image velocimetry - an advanced experimental tool for the investigation of turbulent flow fields

For the characterization of turbulent flows it is often required to measure both, the temporal behavior of the velocity fluctuations along with their spectral contents and the spatial flow structure. Conventional point-wise measurement techniques such as hot-wire or laser Doppler velocimetry have been applied for a long time in order to obtain the temporal information at a single point. Since a few years the Particle Image Velocimetry (PIV) technique, which for the first time allows to measure instantaneous velocity vector maps, enables quantitative insight into the development of the spatial structures as well. It will be shown that by employing more complex multi-laser, multi-camera set-ups for PIV, it becomes possible to measure other relevant quantities required for the understanding of turbulent flows such as the complete velocity gradient tensor or the components of the spatio-temporal correlation tensor for example

Fundamentals of multiple plane stereo PIV

For complex flow analysis in air a stereoscopic particle image velocimetry based system has been developed, tested and applied which allows the determination of all three velocity components in spatially separated planes simultaneously (in order to determine the vorticity vector field for example) or separated in time (for space-time investigations). For this purpose the flow field has been illuminated with orthogonally linearly polarized light delivered by four frequency doubled Nd:YAG lasers. The light scattered by the tracer particles is separated by means of a polarizing beam splitter pair onto the sensors of four progressive scan CCD cameras in an angular imaging configuration with Scheimpflug correction

Near Wall Turbulent Boundary Layer

The following PIV application performed in 1996 in a turbulent boundary layer at the wall of a flat plate illustrates two problems: obtaining PIV data close to a wall and recovering PIV data even in a flow with gradients (due to the velocity profile of the boundary layer). In the present series of experiments the measurement position was 2.3 m downstream of a tripping region in the low-turbulence wind tunnel at the DLR-Göttingen research center [17]. At this position the turbulent boundary layer thickness δ was of the order of 5 cm, of which the lower 3 cm was imaged. At free stream velocities of 10.3, 14.9 and 19.8 m/s between 90 and 100 PIV image pairs were recorded. The evaluation of the recordings were made without windows shifting and window deformation which were not available at that time

Boundary Layers "Turbulent Boundary Layers"

The following PIV application in a turbulent boundary layer at the wall of a flat plate illustrates two problems: obtaining PIV data close to a wall and recovering PIV data even in a flow with gradients (due to the velocity profile of the boundary layer)

Generation and control of tracer particles for optical velocity measurements in air

The production of monodisperse tracer particles with suitable properties for optical flow investigations, such as small size, spherical shape, smooth surface, appropriate density and diffraction index, non-evaporating and agglomerating, electrically neutral, non-toxic and easily removable, is a challenging task. It is shown that high concentrations of narrow band particle size distributions, with a mean diameter below 1 µm, can easily be generated by means of multi-hole nozzles under overcritical pressure conditions