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

Double row fixation is more costly and does not have clinical benefit over single anchor for insertional achilles tendon surgery

Surgical repair of insertional Achilles tendinosis is indicated in the face of failed conservative measures. Several methods for this repair have been described, and the optimal method is not universally agreed upon. In addition, the cost of medical care is important, and should be considered when determining the surgical repair for each patient. The purpose of this study is to compare implant costs between a single anchor or 4 anchor, double row repair, and evaluate associated outcomes. A retrospective comparative trial was performed for this purpose. The entire study encompassed 110 patients, 78 with a single anchor repair, and 32 with a double row repair. The average implant cost of the single anchor repair was $391.18 ±$272.10 and the double row repair was $1811.2 9 ±$169.47, p \u3c .001. The groups did not have a statistically significant difference in complications (9% with single anchor vs 6.3% with double row, p = 1.0) or revisions 6.4% with single anchor vs 3.1% with double row, p = .67). The only difference in demographics between the groups was that the single anchor group had a higher percentage of female patients (p = .04). While the double row repair has been shown to have favorable biomechanical results, the present study did not show a benefit in complications or revisions and was a more costly repair technique. Surgeons should take these findings in consideration when choosing the repair technique when surgery is indicated

Effect of preoperative coronal plane alignment on actual vs predicted alignment using patient specific instrumentation in total ankle replacement

Alignment in total ankle replacement is important for success and implant survival. Recently there has been the introduction and adoption of patient specific instrumentation for implantation in total ankle replacement. Current literature does not evaluate the effect of preoperative deformity on accuracy of patient specific instrumentation. A retrospective radiographic analysis was performed on 97 consecutive patients receiving total ankle replacement with patient specific instrumentation to assess the accuracy and reproducibility of the instrumentation. Subgroup analysis evaluated the effect of preoperative deformity. All surgeries were performed by fellowship trained foot and ankle surgeons without industry ties to the implants used. Preoperative and postoperative films were compared to plans based on computerized tomography scans to assess how closely the plan would be implemented in patients. Overall postoperative coronal plane alignment was within 2° of predicted in 87.6% (85 patients). Similarly, overall postoperative sagittal plane alignment was within 2° of predicted in 88.7% (86 patients). Tibial implant size was accurately predicted in 81.4% (79 patients), and talus implant size was correct in 75.3% (73 patients). Patients with preoperative varus deformity had a higher difference between predicted and actual postoperative alignment compared to valgus deformity (1.1° compared to 0.3°, p=0.02). A higher average procedure time was found in varus patients, and more adjunctive procedures were needed in patients with varus or valgus deformity, but these were not significant, p\u3e0.5. Surgeons can expect a high degree of accuracy when using patient specific instrumentation overall, but less accurate in varus deformity

Current techniques in total ankle arthroplasty

Total ankle replacement (TAR) continues to increase in popularity as a motion-preserving option to ankle arthrodesis. TAR is indicated for primary, posttraumatic and inflammatory arthropathies as an alternative procedure to tibiotalar arthrodesis. Proper patient selection is paramount to a successful outcome in TAR. Contraindications to TAR include the presence of neuropathy, active infection, severe peripheral arterial disease, inadequate bone stock, and severe uncorrectable coronal plane deformity. This article is a brief overview of techniques and PEARLS on how to address a well-aligned ankle joint, varus deformity as well as valgus deformities as well as the authors\u27 experience with single versus staging coronal plane deformities

Soft tissue reconstruction and osteotomies for pes planovalgus correction

The correction of the flexible pes planovalgus foot and ankle is a complicated and somewhat controversial topic. After conservative methods fail, there is a wide range of possible soft tissue and bony procedures. The appropriate work up and understanding of the pathomechanics are vital to the correct choice of procedures to correct these deformities. Once the work up and procedure selection are done, the operation must also be technically performed well and with efficiency, as most often the condition is corrected with a variety of procedures. This article discusses some of the most common procedures necessary to fully correct the pes planovalgus foot and discusses the authors\u27 technique and pearls

Deformity correction of the midfoot/hindfoot/ankle

The correction of the deformed arthritic foot and ankle is a complicated and somewhat controversial topic. After conservative methods fail, there is a wide range of possible bony procedures and arthrodesis that maybe performed. The appropriate work up and understanding of the pathomechanics is vital to the correct choice of procedures to correct these deformities. Once the work up and procedure selection is done, the operation must also be technically performed well and with efficiency, as most often the condition is corrected with a variety of procedures. This article discusses some of the most common procedures necessary to fully correct deformity of the midfoot, hindfoot, and ankle. This article will also discuss the authors\u27 technique and pearls