Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.

The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire's central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

Two-year results of X-stop interspinous implant for the treatment of lumbar spinal stenosis: a prospective study.

STUDY DESIGN: Prospective Observational Study. OBJECTIVE: To prospectively assess the clinical outcome of patients treated for symptomatic spinal stenosis with the X-stop device. SUMMARY OF BACKGROUND DATA: The X-stop device is used in the treatment of symptomatic lumbar spinal stenosis. The preliminary results of this study of 40 patients at 1 year were published in 2007. The 2-year results of 57 patients are reported in this paper. Zucherman et al report 60% significant improvement at 1 year and 48.4% at 2 years. METHODS: Fifty-seven consecutive patients with radiologically confirmed lumbar spinal stenosis were enrolled and treated with the X-stop device. The device was implanted at a maximum of 2 affected levels. Clinical response was evaluated with the Zurich Claudication Questionnaire (ZCQ), Oswestry Disability Index, and Short Form-36 questionnaires preoperatively and 6, 12, and 24 months postoperatively. RESULTS: Of the 57 patients enrolled, 54 completed the ZCQ questionnaire at 1 year and 46 patients at 2 years. Clinically significant improvement was attained by 65% at 1 year and 57% at 2 years and 70% were satisfied with the outcome of the surgery. Single level and double level insertions did not have significant difference in clinical outcome. CONCLUSION: This study demonstrates with the use of ZCQ scores as primary outcome measures that improved clinical outcomes are maintained at 2 years after X-stop implantation.

The increase in dural sac area is maintained at 2 years after X-stop implantation for the treatment of spinal stenosis with no significant alteration in lumbar spine range of movement.

BACKGROUND CONTEXT: The X-stop interspinous process decompression (IPD) device has been used effectively in the management of symptomatic spinal stenosis. This study examines the radiological outcomes at 2 years postoperatively after X-stop implantation. PURPOSE: To measure the effect of X-stop IPD device on the dural sac and foraminal areas at 24 months postoperatively at instrumented level in symptomatic lumbar canal stenosis. We also aimed to assess its effect on change in lumbar spine movement. STUDY DESIGN: Prospective observational study. PATIENT SAMPLE: Forty-eight patients treated with X-stop had preoperative positional magnetic resonance imaging (MRI) scans, 40 of whom had 2 years postoperative positional MRI scans. Complete scans were available for 39 of these patients. OUTCOME MEASURES: Positional MRI scans were performed pre- and postoperatively. Measurements were done on these scans and are presented as the outcome measures. METHODS: All patients had a multipositional MRI scan preoperatively and at 6 and 24 months postoperatively. Foraminal area was measured in flexion and extension. Dural cross-sectional area was measured in standing erect and in sitting neutral, flexion, and extension (sitting) positions. The total range of movement (ROM) of the lumbar spine and individual segments was also measured. RESULTS: Complete scan data for 39 patients' scans were available. An increase in mean dural sac area was found in all positions. At 24 months after surgery, the mean dural sac area increased significantly in all four postures mentioned above. A small increase in mean foraminal area was noted, but this was not statistically significant. Mean anterior disc height reduced from 5.9 to 4.1 mm (p=.006) at 24 months at the instrumented level in single-level cases, from 7.7 to 6.1 mm (p=.032) in double-level cases caudally, and from 8.54 to 7.91 (p=.106) mm cranially. We hypothesize that the reduction in anterior disc heights could be a result of the natural progression of spinal stenosis with aging. There was no significant change in posterior disc heights at instrumented level or adjacent levels. The mean lumbar spine motion was 21.7 degrees preoperatively and 23 degrees at 24 months (p=.584) in single-level cases. This was 32.1 degrees to 31.1 degrees (p=.637) in double-level cases. There was no significant change in the individual segmental range of motion at instrumented and adjacent levels. CONCLUSION: X-stop interspinous device remains effective in decompressing the stenosed spinal segment by increasing the anatomic dural cross-sectional area and foraminal area of spinal canal. It does not significantly alter the ROM of lumbar spine at instrumented and adjacent levels at 24 months postoperatively.