Search

Introduction/Purpose: Minimally invasive surgical (MIS) treatment of hallux valgus (HV) deformity is increasing in popularity. A 2mm-diameter burr is used to create a distal first metatarsal osteotomy prior to capital fragment translation and fixation. The metatarsal will shorten by the burr’s diameter (2mm). Plantar or dorsal capital fragment displacement may also cause load transference and possibly transfer metatarsalgia. In this study, we examine the effect of MIS HV on forefoot loading mechanics with respect to metatarsal shortening and sagittal plane displacement. Methods: Four lower-limb cadaveric specimens were studied. A pedobarography pressure-sensing mat was used to record forefoot plantar pressure in a controlled weightbearing stance position.10 Control and post-osteotomy measurements were obtained with the capital fragment fixated in 3 possible positions: 0mm, 5mm dorsal, and 5mm plantar displacement. Pedobarography data yielded pressure data within measurable graphical depictions. Raw mean contact pressure measurements were taken under the first and fifth metatarsal heads to establish medial and lateral forefoot loading pressure ratios. A priori power analysis was performed based on previous peer-reviewed pedobarographic data and our study was adequately powered. Results: 40 measurements were recorded and ratios of medial-to-lateral forefoot loading were constructed. Medial forefoot pressure change control versus 0mm displacement, and control versus dorsal displacement was not found to be statistically significant (p=0.525, p=0.55 respectively). Significant medial pressure increase was identified comparing control versus plantar displacement (p=0.006). Lateral pressure increased significantly with dorsal displacement of the osteotomy (p=0.013). Conclusion: MIS hallux valgus correction does not appear to cause increase in lateral forefoot pressure loading when sagittal plane displacements are controlled. Plantar displacement increases medial loading, and dorsal displacement increases lateral loading. The clinician must consider metatarsal head position post-osteotomy, as decrease in medial loading and subsequent increase in lateral loading may lead to lateral forefoot pain and transfer metatarsalgia.

Category: Ankle; Bunion Introduction/Purpose: Using patient-reported outcomes (PRO) to predict which patients may or may not improve from orthopaedic surgery could be valuable for clinical decision making. The Patient Reported Outcome Instrumentation System (PROMIS) utilizes computerized adaptive testing based on item response theory to decrease administration time while maintaining accuracy. However, the data on the relationship between pre- and post-operative PROMIS scores for elective foot and ankle surgical patients and their ultimate PROs is limited, and the literature is conflicting. The purpose of this study is to assess preoperative PROMIS mobility, physical function (PF), and pain interference (PI) scores to determine their accuracy in predicting patient reported surgery success or failure, and to estimate preoperative score domains associated with patient reported surgery success. Methods: A retrospective chart review was used to identify a cohort of adult patients who underwent operative treatment for at least one foot or ankle surgery between 05/01/2020 – 06/01/2022. Descriptive statistics were calculated to describe the study population, clinical factors, PROMIS scores, and outcomes. Bivariate analyses were performed to assess potential associations between PROMIS score differences with other factors, and PROMIS score differences within levels of other factors. Logistic regression analysis was used to assess potential associations with patient-rated surgery success or failure with patient, clinical, and outcomes data. Significance was determined by associated p-values (p < 0.05). Results: We found that preoperative PROMIS scores for mobility, PF, and PI were not significantly associated with patient-rated surgery success (p=0.092, 0.666, 0.869, respectively). Similarly, in a regression to identify individual factors that influenced patient reported surgical failure, preoperative mobility, PF, and PI scores were all not significant (p=0.095, 0.663, 0.626, respectively). However, preoperative cut-points based on 95% confidence intervals for means were estimated locally to determine the probability of optimal patient reported surgery success, and threshold scores for mobility, PF, and PI were chosen as ≥39, ≥47, and ≤55, respectively. We also found that the only preoperative patient factors that showed higher odds of patient reported surgical failure in a multivariate logistic regression model were age of 50-64 (p=0.004) and diabetes (p=0.006). Conclusion: Our study found no significant associations between preoperative PROMIS scores and patient reported success or failure for foot and ankle surgery. This may be encouraging to surgeons when considering that even patients with seemingly unfavorable preoperative scores have a similar chance as other patients for surgical success and improvement from the patient’s perspective. Additionally, identifying optimal patient PROMIS scores for surgery success can provide an ideal baseline score cutoff for surgeons for comparison when assessing an individual’s chances of surgical success for foot and ankle surgery. However, further study is needed to investigate the clinical utility of these estimates.

Background Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.Methods Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by 51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA–IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund’s adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay.Results pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134 controlled outgrowth of a tumor xenograft. The pIRS21097-1105 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3–4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134 peptide in 2/12 patients (17%, 90% CI 3% to 44%).Conclusion This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134 and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses.Trial registration number NCT01846143

Abstract Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.