31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Anatomical Study of the Descending Genicular Artery Chimeric Flaps

Purpose: With increasing use of the chimeric flap of the descending genicular artery, the authors systematically investigated the anatomy of its branches in cadavers. Methods: Fifteen fresh cadaveric thighs were studied by anatomical dissection. The branches of the descending genicular arteries were skeletonized along their courses to the femoral arteries. Branches’ lengths and diameters were measured to simulate the combined application of the skin, muscle, bone, osteochondral and osteocutaneous flaps with tendon enthesis. Results: The descending genicular artery was noted in 11 thighs, with an average diameter of 1.94 ± 0.36 mm and an average length of 10.69 ± 4.41 mm. In addition, the saphenous artery was noted in all 15 thighs, and the average diameter of the original part was 1.35 ± 0.18 mm. Branches arose from the saphenous artery to supply the skin above the knee, the anterior of tibia, the sartorius muscle and the pes anserinus. The average diameter of the osteoarticular artery was 1.80 ± 0.46 mm which divaricated into a periosteal branch to supply the bone above the medial femoral epicondyle and a few articular branches to supply the bone and the cartilage of the medial femoral condyle. Conclusions: This study systematically investigated the anatomy of the descending genicular artery and its branches. Based on the anatomical features of descending genicular artery, chimeric flap offers combination therapy with other tissue flaps. Besides, considering its long chimeric arm, chimeric flap could be used to repair not only local complex injuries but also defects in different locations. Clinical Relevance: The descending genicular artery chimeric flap is a clinical option for reconstructing compound tissue defects of limbs

Additional file 1: of Which level is responsible for gluteal pain in lumbar disc hernia?

LDH_GP.sav. (SAV 31 kb

CT and MRI Determination of Intermuscular Space within Lumbar Paraspinal Muscles at Different Intervertebral Disc Levels

<div><p>Background</p><p>Recognition of the intermuscular spaces within lumbar paraspinal muscles is critically important for using the paramedian muscle-splitting approach to the lumbar spine. As such, it is important to determine the intermuscular spaces within the lumbar paraspinal muscles by utilizing modern medical imaging such as computed tomography (CT) and magnetic resonance imaging (MRI).</p><p>Methods</p><p>A total of 30 adult cadavers were studied by sectional anatomic dissection, and 60 patients were examined using CT (16 slices, 3-mm thickness, 3-mm intersection gap, <i>n</i> = 30) and MRI (3.0T, T2-WI, 5-mm thickness, 1-mm intersection gap, <i>n</i> = 30). The distances between the midline and the superficial points of the intermuscular spaces at different intervertebral disc levels were measured.</p><p>Results</p><p>Based on study of our cadavers, the mean distances from the midline to the intermuscular space between multifidus and longissimus, from intervertebral disc levels L1–L2 to L5–S1, were 0.9, 1.1, 1.7, 3.0, and 3.5 cm, respectively. Compared with the upper levels (L1–L3), the superficial location at the lower level (L4–S1) is more laterally to the midline (<i>P</i><0.05). The intermuscular space between sacrospinalis and quadratus lumborum, and that between longissimus and iliocostalis did not exist at L4–S1. The intermuscular spaces in patients also varied at different levels of the lumbar spine showing a low discontinuous density in CT and a high signal in MRI. There were no significant differences between the observations in cadavers and those made using CT and MRI.</p><p>Conclusion</p><p>The intermuscular spaces within the paraspinal muscles vary at different intervertebral disc levels. Preoperative CT and MRI can facilitate selection of the muscle-splitting approach to the lumbar spine. This paper demonstrates the efficacy of medical imaging techniques in surgical planning.</p></div

Illustration showing transverse sections at different levels of the lumbar region.

<p>(a) At the upper level of the lumbar spine, three cleavage planes within the paraspinal muscles were found: ML, SQ and LI, which are the entries used in the Wiltse, Watkins and Weaver approaches, respectively. (b) At the lower level of the lumbar spine, only ML was found, and its superficial location lied more laterally to the midline than the location at the upper level. The Wiltse approach through ML may be the best choice for protecting muscle integrity and its neurovascular supply. <i>Arrow</i>: incision site; <i>M</i>: multifidus; <i>L</i>: longissimus; <i>I</i>: iliocostalis; <i>IS</i>: iliac spine; <i>QL</i>: quadratus lumborum; <i>PS</i>: psoas major.</p

Transverse CT images at different disc level.

<p>(a) L1-L2 intervertebral disc level; (b) L2-L3 intervertebral disc level; (c) L3-L4 intervertebral disc level; (d) L4-L5 intervertebral disc level; (d) L5-S1 intervertebral disc level</p

Horizontal views of the posterior lumbar spine in anatomical sections obtained from cadavers.

<p>(a) Through the upper level of the lumbar spine (L1), the muscles in the posterior lumbar region were divided into three parts: the medial part (multifidus), middle part (longissimus) and lateral part (iliocostalis). The longissimus and iliocostalis were the two parts of the sacrospinalis. The red arrows point to the ML, which is a natural corridor filled with adipose tissue between the multifidus and longissimus. The blue arrows show the LI, which is a thin fascia between the longissimus and iliocostalis. The white arrows point to SQ between the sacrospinalis and quadratus lumborum. (b) Through the lower level of the lumbar spine (L5), the ML was well defined, and slightly more lateral to the midline. LI and SQ could not be identified. <i>M</i>: multifidus; <i>L</i>: longissimus; <i>I</i>: iliocostalis; <i>IS</i>: iliac spine; <i>QL</i>: quadratus lumborum; <i>PS</i>: psoas major.</p

Horizontal views of the posterior lumbar spine in MRI images.

<p>(a) Through the upper level of the lumbar spine (L1), ML (red arrows), SQ (white arrows) and LI (blue arrows) were identified by lines of high signal intensity inserted into the paraspinal muscles. (b) Through the lower level of the lumbar spine (L5), only the ML was identified. <i>M</i>: multifidus; <i>L</i>: longissimus; <i>I</i>: iliocostalis; <i>IS</i>: iliac spine; <i>QL</i>: quadratus lumborum; <i>PS</i>: psoas major.</p

Horizontal views of the posterior lumbar spine in CT images.

<p>(a) Through the upper level of the lumbar spine (L1), ML (red arrows), SQ (white arrows) and LI (blue arrows) were identified by line-shaped low densities within the paraspinal muscles. (b) Through the lower level of the lumbar spine (L5), only the ML was identified. <i>M</i>: multifidus; <i>L</i>: longissimus; <i>I</i>: iliocostalis; <i>IS</i>: iliac spine; <i>QL</i>: quadratus lumborum; <i>PS</i>: psoas major.</p