External Fixator Usage and Delayed MRI Scans: A National Survey Study.

OBJECTIVE: To report the current state of institutional protocols regarding the use of MRI in patients with external fixation devices (EFDs) in the United States. DESIGN: National Survey Study. PARTICIPANTS: Practicing orthopaedic surgeons frequenting the Orthopaedic Trauma Association website were invited to participate in this study. RESULTS: Sixty-two eligible orthopaedic surgeons completed the survey. No respondents reported any known harmful complications of MRI use with an EFD. Eight respondents (13%) reported at least one early scan termination because of mild warmth or vibration without any lasting complications. Fifty-six respondents (90%) reported delays to care related to MRI-EFD compatibility labeling, and 27 respondents (48%) reported delayed MRI scans in every patient with an EFD who needed one. Twenty-six surgeons (42%) had modified their practice in some way in response to these barriers. Examples include delaying EFD placement until after MRI, relying on CT arthrograms over MRI for surgical planning, and taking patients to the operating room to remove EFDs temporarily and then replace them. Nineteen respondents (31%) had developed formal protocols to address this issue, but having a written protocol was not associated with any decrease in delays ( P = 0.119). Eighty-nine percent of respondents thought there was a need for a national consensus guideline on this issue. CONCLUSION: Despite no previous reports of harmful complications, MRI utilization is frequently delayed or prevented in patients with EFDs in place. This is a pervasive problem nationally, which persists despite the implementation of written institutional protocols. Additional research is needed, potentially at the national level, to address this common issue. LEVEL OF EVIDENCE: V.

Gait Analysis in Orthopaedic Surgery: History, Limitations, and Future Directions.

Gait analysis has expanding indications in orthopaedic surgery, both for clinical and research applications. Early work has been particularly helpful for understanding pathologic gait deviations in neuromuscular disorders and biomechanical imbalances that contribute to injury. Notable advances in image acquisition, health-related wearable devices, and computational capabilities for big data sets have led to a rapid expansion of gait analysis tools, enabling novel research in all orthopaedic subspecialties. Given the lower cost and increased accessibility, new gait analysis tools will surely affect the next generation of objective patient outcome data. This article reviews the basic principles of gait analysis, modern tools available to the common surgeon, and future directions in this space.

Indications for and Risks Associated With Implant Removal After Pediatric Trauma.

A wide range of implants are used in the treatment of pediatric fractures, including wires, plates, screws, flexible rods, rigid rods, and external fixation devices. Pediatric bones differ from adult bones both mechanically and biologically, including the potential for remodeling. Implants used in pediatric trauma patients present a unique set of circumstances regarding indications, risks, timing of implant removal, weight-bearing restrictions, and long-term sequelae. Indications for implant removal include wire/pin fixation, when substantial growth remains, and infection. When considering implant removal, the risks and benefits must be assessed. The primary risk of implant removal is refracture. The timing of implant removal varies widely from several weeks to a year or more with the option of retention depending on the fracture, type of implant, and skeletal maturity of the patient.

Clinical and Radiographic Predictors of Nonunion in Open Tibial Shaft Fractures.

Open fracture is a risk factor for nonunion of diaphyseal tibia fractures. Compared with closed injuries, there is a relative lack of scientific knowledge regarding the healing of open tibia fractures. The objective of this study was to investigate which patient, injury, and surgeon-related factors predict nonunion in open tibial shaft fractures. A cohort of 98 patients with 104 extra-articular open tibial shaft fractures (OTA/AO 41A2-3, 42A-C, and 43A) were treated surgically between 2007 and 2018 at a single level 1 trauma center and were retrospectively reviewed. Patients underwent irrigation and debridement followed by definitive intramedullary nailing or plate fixation. Patient, injury, and perioperative prognostic factors were analyzed as predictors of nonunion based on anteroposterior and lateral radiographs. The nonunion rate was 27.9% (n=29). There were 12 occurrences of deep infection (11.5%). The median follow-up was 14 months. High-energy mechanism of injury (hazard ratio [HR], 5.76), Gustilo-Anderson class IIIA injury (HR, 3.66), postoperative cortical continuity of 0% to 25% (HR, 2.90), early postoperative complication (HR, 4.20), and deep infection (HR, 2.25) were significant predictors of nonunion on univariable analysis (P<.05). On multivariable assessment, only high-energy mechanism of injury, Gustilo-Anderson class IIIA injury, and early postoperative complication reached significance as predictors of nonunion. These data also indicate that lack of cortical continuity is a significant univariable radiographic predictor of nonunion. This is potentially modifiable, may guide surgeons in selecting patients for early bone grafting procedures, and should be assessed carefully in this high-risk population. [Orthopedics. 2021;44(3):142-147.].

Medial Column Support in Pilon Fractures Using Percutaneous Intramedullary Large Fragment Fixation.

SUMMARY: Pilon fractures are complex injuries to the tibial plafond requiring stable fixation in the setting of effective soft tissue management, particularly in high-energy injuries, open fractures, or in geriatric individuals. Medial column support of the distal tibial metaphysis is often an essential component when applying balanced fixation. However, the biologic implications of multiple surgical approaches in the setting of damaged tissue, devitalized bone, or significant bone loss may contribute to increased complications. Percutaneous intramedullary large fragment screws offer both stability and a soft tissue-friendly approach for stabilizing the medial column. Here, we present our technique and indications for medial column support in pilon fractures using percutaneous large fragment fixation, along with our early clinical experience in a case series of 7 patients. At minimum 6-month follow-up, all patients healed their injuries with maintained alignment and without complications or further reoperation. Medial column support with percutaneous large fragment fixation in pilon fractures is a viable option to provide mechanical stability while effectively managing tenuous soft tissue envelopes.

Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay.

Monitoring functional competence of immune cell populations in clinical routine represents a major challenge. We developed a whole-blood assay to monitor functional competence of peripheral innate immune cells including NK cells, dendritic and monocyte cell subsets through their ability to produce specific cytokines after short-term stimulation, detected through intra-cytoplasmic staining and multi-parametric flow-cytometry. A PMA/ionomycin T cell activation assay complemented this analysis. Comparing cohorts of healthy women and breast cancer (BC) patients at different stages, we identified significant functional alteration of circulating immune cells during BC progression prior to initiation of treatment. Of upmost importance, as early as the localized primary tumor (PT) stage, we observed functional alterations in several innate immune populations and T cells i.e. (i) reduced TNFα production by BDCA-1+ DC and non-classical monocytes in response to Type-I IFN, (ii) a strong drop in IFNγ production by NK cells in response to either Type-I IFN or TLR7/8 ligand, and (iii) a coordinated impairment of cytokine (IL-2, IFNγ, IL-21) production by T cell subpopulations. Overall, these alterations are further accentuated according to the stage of the disease in first-line metastatic patients. Finally, whereas we did not detect functional modification of DC subsets in response to TLR7/8 ligand, we highlighted increased IL-12p40 production by monocytes specifically at first relapse (FR). Our results reinforce the importance of monitoring both innate and adaptive immunity to better evaluate dysfunctions in cancer patients and suggest that our whole-blood assay will be useful to monitor response to treatment, particularly for immunotherapeutic strategies.

ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients.

BACKGROUND: Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points. PATIENT AND METHODS: This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed. RESULTS: When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS. CONCLUSION: In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01362107.

Calcium-dependent interaction of S100B with the C-terminal domain of the tumor suppressor p53.

In vitro, the S100B protein interacts with baculovirus recombinant p53 protein and protects p53 from thermal denaturation. This effect is isoform-specific and is not observed with S100A1, S100A6, or calmodulin. Using truncated p53 proteins in the N-terminal (p53(1-320)) and C-terminal (p53(73-393)) domains, we localized the S100B-binding region to the C-terminal region of p53. We have confirmed a calcium-dependent interaction of the S100B with a synthetic peptide corresponding to the C-terminal region of p53 (residues 319-393 in human p53) using plasmon resonance experiments on a BIAcore system. In the presence of calcium, the equilibrium affinity of the S100B for the C-terminal region of p53 immobilized on the sensor chip was 24 +/- 10 nM. To narrow down the region within p53 involved in S100B binding, two synthetic peptides, O1(357-381) (residues 357-381 in mouse p53) and YF-O2(320-346) (residues 320-346 in mouse p53), covering the C-terminal region of p53 were compared for their interaction with purified S100B. Only YF-O2 peptide interacts with S100B with high affinity. The YF-O2 motif is a critical determinant for the thermostability of p53 and also corresponds to a domain responsible for cytoplasmic sequestration of p53. Our results may explain the rescue of nuclear wild type p53 activities by S100B in fibroblast cell lines expressing the temperature-sensitive p53val135 mutant at the nonpermissive temperature.

Central nervous system prophylaxis. Studies showing impairment in verbal skills and academic achievement.

School attendance and school achievement were the parameters studied to assess the pediatric cancer patient's ability to learn and keep pace with their peers. Effects of CNS prophylaxis, as either intrathecal methotrexate (IT) alone or intrathecal methotrexate given in addition to cranial radiation (CRT), were studied in two groups. A third group of cancer patients who received no CNS prophylaxis, and two comparison groups, siblings and a matched sample of children, also participated in the study. Impairment in central nervous system function was measured by means of psychological testing, neurological examination, and computer-assisted tomography. Patients who received central nervous system prophylactic treatments at an early age had poorer performance on verbal IQ scores, with comprehension and arithmetic subscores being most affected. Patients who received both cranial radiotherapy plus intrathecal methotrexate showed a decrease in six out of seven categories of instruction when grades from the year prior to diagnosis were compared to those obtained 3 years after diagnosis. The combined groups of patients with leukemia had a lower grade point average and poorer school attendance than did the comparison groups.