The Value of Video Rasterstereography in the Detection of Alterations in Posture as a Marker of Pain Relief after Targeted Infiltrations of the Lumbar Spine.

BACKGROUND: Targeted infiltrations to the lumbar spine are used to identify the correct scope for surgery in patients with chronic lumbar back pain (CLBP) and multi-segmental pathologies, where radiologic imaging and clinical presentation do not match. Conclusions from that method have so far been based on individual statements of pain relief. The main principle for the infiltrations is the assumption that by locally administering an analgesic agent to possible surgical target areas, the effect of surgery can be temporarily simulated. The aim was to investigate the use of rasterstereographic posture measurements to substantiate reported pain reduction after infiltrations. METHODS: In this case-control study (Level II), rasterstereography was performed on 57 patients and 28 reference subjects to evaluate changes in posture during 1 week of injections under fluoroscopic guidance and correlated with changes in the Numeric Pain Rating Scale (NRS). Statistical analysis was performed with SPSS (α = .05, two-sided) and presented in the form of box, scatter, and Bland-Altman plots. RESULTS AND CONCLUSION: The CLBP patients' trunk inclination (median 6°) and absolute lateral tilt were significantly increased (p < .01 each) compared to the reference group. No significant difference was observed for trunk length, kyphotic/lordotic angle, or lateral deviation. During infiltration, no significant difference in posture could be observed. A subgroup analysis of patients reporting the highest pain improvement indicated no significant difference. No correlation was observed with pain improvement reported by the patients during injections. Subsequent rasterstereography does not seem to be able to verify results of injections in the diagnostics of lumbar spine pathologies, as patients' reported pain relief does not correlate with a relevant alteration in posture. The short-term effect of the targeted infiltrations may not suffice to change false posture being developed over years.

FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity.

PURPOSE: Although programmed death-ligand 1 (PD-L1) antibody-based therapy has improved the outcome of patients with cancer, acquired resistance to these treatments limits their clinical efficacy. FS118 is a novel bispecific, tetravalent antibody (mAb2) against human lymphocyte activation gene-3 (LAG-3) and PD-L1 with the potential to reinvigorate exhausted immune cells and overcome resistance mechanisms to PD-L1 blockade. Here, using FS118 and a murine surrogate, we characterized the activity and report a novel mechanism of action of this bispecific antibody. EXPERIMENTAL DESIGN: This study characterizes the binding activity and immune function of FS118 in cell lines and human peripheral blood mononuclear cells and further investigates its antitumor activity and mechanism of action using a surrogate murine bispecific antibody (mLAG-3/PD-L1 mAb2). RESULTS: FS118 demonstrated simultaneous binding to LAG-3 and PD-L1 with high affinity and comparable or better activity than the combination of the single component parts of the mAb2 in blocking LAG-3- and PD-L1-mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb2 significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb2, whereas LAG-3 expression increased upon treatment with the combination of mAbs targeting LAG-3 and PD-L1. Moreover, following binding of mLAG-3/PD-L1 mAb2 to target-expressing cells, mouse LAG-3 is rapidly shed into the blood. CONCLUSIONS: This study demonstrates a novel benefit of the bispecific approach over a combination of mAbs and supports the further development of FS118 for the treatment of patients with cancer.

Using inpatient gradual diagnostics to identify the treatment strategy for lumbar back pain-Can treadmill gait analysis objectify the patients' declaration of pain relief?

BACKGROUND: Patients with chronic lumbar back pain (CLBP) often present with an altered gait profile, which is a crucial element of good functioning in everyday life. In patients with multisegmental spinal pathologies and incongruity between radiologic imaging and clinical presentation, inpatient gradual diagnostics (IGD) is performed to determine the precise origin of the disabling pain. The underlying principle of IGD is the assumption that by locally administering an analgesic and anti-inflammatory agent to possible surgical target areas, the surgical effect can be temporarily simulated. The conclusions drawn from IGD are, however, mostly based on the patients' subjective feedback about pain relief. RESEARCH QUESTION: The aim of this study was to evaluate whether reported pain relief during IGD can be objectified by gait analysis. We hypothesized that patients with greater pain relief during IGD would show greater improvement in their pathologic gait and stance. METHODS: Treadmill gait and stance analyses were prospectively performed on CLBP patients before and after a one-week IGD. Self-report measures included the numeric pain rating scale (NRS) and the Oswestry Disability Index (ODI). RESULTS AND SIGNIFICANCE: Compared with a reference group (n = 28), IGD patients (n = 57) at admission showed reduced velocity, cadence, step length, and swing phase (p < .01 each). Their stance phase was increased by 5% of the gait cycle, and a more asymmetrical total load distribution during stance was observed. No difference was seen in stride width or foot rotation. While many patients reported good pain relief during IGD, no correlation was observed between subjective improvement and treadmill measures. We can thus confirm a pathologic gait profile in patients with CLBP. Based on our findings, gait analysis would not yet seem suitable to objectify IGD results. The short time interval between admission and discharge may not suffice to change a pathological gait that has developed over years.

Epitope-Specific Tolerance Modes Differentially Specify Susceptibility to Proteolipid Protein-Induced Experimental Autoimmune Encephalomyelitis.

Immunization with myelin components can elicit experimental autoimmune encephalomyelitis (EAE). EAE susceptibility varies between mouse strains, depending on the antigen employed. BL/6 mice are largely resistant to EAE induction with proteolipid protein (PLP), probably a reflection of antigen-specific tolerance. However, the extent and mechanism(s) of tolerance to PLP remain unclear. Here, we identified three PLP epitopes in PLP-deficient BL/6 mice. PLP-sufficient mice did not respond against two of these, whereas tolerance was "leaky" for an epitope with weak predicted MHCII binding, and only this epitope was encephalitogenic. In TCR transgenic mice, the "EAE-susceptibility-associated" epitope was "ignored" by specific CD4 T cells, whereas the "resistance-associated" epitope induced clonal deletion and Treg induction in the thymus. Central tolerance was autoimmune regulator dependent and required expression and presentation of PLP by thymic epithelial cells (TECs). TEC-specific ablation of PLP revealed that peripheral tolerance, mediated by dendritic cells through recessive tolerance mechanisms (deletion and anergy), could largely compensate for a lack of central tolerance. However, adoptive EAE was exacerbated in mice lacking PLP in TECs, pointing toward a non-redundant role of the thymus in dominant tolerance to PLP. Our findings reveal multiple layers of tolerance to a central nervous system autoantigen that vary among epitopes and thereby specify disease susceptibility. Understanding how different modalities of tolerance apply to distinct T cell epitopes of a target in autoimmunity has implications for antigen-specific strategies to therapeutically interfere with unwanted immune reactions against self.