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AimsThe results of irrigation and debridement with component retention (IDCR) in the treatment of acutely infected total knee arthroplasties (TKAs) have been variable. The aim of this study was to assess the outcome after IDCR when combined with chronic antibiotic suppression. We also evaluated survivorship free from subsequent infection, removal of the components, and death, as well as the risk factors for failure.Patients and MethodsThis was a single-centre retrospective review of 134 infected primary TKAs that were treated with IDCR. Infections within four weeks of the procedure were defined as acute postoperative infections, and those occurring more than four weeks after the procedure with symptoms for less than three weeks were defined as acute haematogenous infections. Patients were treated with intravenous antibiotics for four to six weeks, followed by chronic oral antibiotic suppression. Estimates of survival were made using a competing risk analysis. The mean follow-up was five years (2.1 to 13).ResultsThe infection was an acute postoperative infection in 23 TKAs and an acute haematogenous infection in 111 TKAs. The incidence of subsequent infection was 36% in those with an acute postoperative infection and 33% in those with a haematogenous infection, five years postoperatively (p = 0.40). Age < 60 years increased the risk of subsequent infection (hazard ratio (HR) 2.4; p = 0.009) and removal of the components (HR 2.8; p = 0.007). Infection with a staphylococcal species increased the risk of subsequent infection (HR 3.6; p < 0.001), and removal of the components (HR 3.2; p = 0.002). Musculoskeletal Infection Society host type and local extremity grade, body mass index (BMI), the duration of symptoms, gender, and the presence of a monoblock tibial component had no significant effect on the outcome.ConclusionIn a rigorously defined group of acute periprosthetic infections after TKA treated with IDCR and chronic antibiotic suppression, the infection-free survival at five years was 66%. The greatest risk factor for failure was an infection with a staphylococcal species, followed by age of < 60 years. Cite this article: Bone Joint J 2018;100-B:1471–76.

We previously demonstrated that shotgun metagenomic sequencing can detect bacteria in sonicate fluid, providing a diagnosis of prosthetic joint infection (PJI). A limitation of the approach that we used is that data analysis was time-consuming and specialized bioinformatics expertise was required, both of which are barriers to routine clinical use.

The expansion and accumulation of HIV-infected BCL6 + Tfh CD4 + T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4 + T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8 + T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4 + T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.

PurposeProvide an adaptive multicriteria optimization (MCO) method for intensity‐modulated proton therapy (IMPT) utilizing GPU technology. Previously described limitations of MCO such as Pareto approximation and limitation on the number of objectives were addressed.MethodsThe treatment planning process for IMPT must account for multiple objectives, which requires extensive treatment planning resources. Often a large number of objectives (>10) are required. Hence the need for an MCO algorithm that can handle large number of objectives. The novelty of the MCO method presented here lies on the introduction of the adaptive weighting scheme that can generate a well‐distributed and dense representation of the Pareto surface for a large number of objectives in an efficient manner. In our approach the generated Pareto surface is constructed for a set of DVH objectives. The MCO algorithm is based on the augmented weighted Chebychev metric (AWCM) method with an adaptive weighting scheme. This scheme uses the differential evolution (DE) method to generate a set of well‐distributed Pareto points. The quality of the Pareto points’ distribution in the objective space was assessed quantitatively using the Pareto sampling metric. The MCO algorithm was developed to perform multiple parallel searches to achieve a rapid mapping of the Pareto surface, produce clinically deliverable plans, and was implemented on a GPU cluster. The MCO algorithm was tested on two clinical cases with 10 and 18 objectives. For each case one of the MCO‐generated plans was selected for comparison with the clinically generated plan. The MCO plan was randomly selected out of the set of MCO plans that had target coverage similar to the clinically generated plan and the same or better sparing of the organs at risk (OAR). Additionally, a validation study of the AWCM method vs the weighted sum method was performed.ResultsThe adaptive MCO algorithm generated Pareto points on the Pareto hypersurface in a fast (2–3 hr) and efficient manner for 2 cases with 10 and 18 objectives. The MCO algorithm generated a dense and well‐distributed set of Pareto points on the objective space, and was able to achieve minimization of the Pareto sampling metric. The selected MCO plan showed an improvement of the DVH objectives in comparison to the clinically optimized plan in both cases. For case one, the MCO plan showed a 48% reduction of the 50% dose to OARs and a 16% reduction of the 1% dose to OARs. For case 2, the MCO plan showed a 72% reduction of the 50% dose to OARs and a 42% reduction of the 1% dose to OARs. The comparison of AWCM to WS showed that the AWCM method has a dosimetric advantage over WS for both patient cases.ConclusionWe introduced an adaptive MCO algorithm for IMPT accelerated using GPUs. The algorithm is based on an adaptive method for generating Pareto plans in the objective space. We have shown that the algorithm can provide rapid and efficient mapping of the multicriteria Pareto surface with clinically deliverable plans.

ABSTRACTRevisions TKAs are being completed with uncemented constructs more frequently. We hypothesized that tantalum cones could be an efficient carrier of antibiotics in uncemented procedures. We aimed to compare the release of vancomycin between (i) tantalum and smooth stainless cylinders; (ii) different concentrations of vancomycin; and (iii) different durations of bathing. Specifically designed tantalum cylinders were bathed in a vancomycin solution with various durations of baths. We investigated rinses between each interval as well as the dose of vancomycin. Vancomycin concentrations were determined in each group by fluorescence polarization immunoassay at different intervals (1 h, days 1, 2, 3, 5). At 1 h, the mean vancomycin concentration for the 1‐hour soaking group was 3,172 μg/ml, whereas mean concentration for the smooth stainless steel group was 39.37 μg/ml (p < 0.001). The rinsing group showed a significantly lower concentration at 1 h and 1 day (p < 0.05). The 2‐gram vancomycin group showed no difference at days 1, 2, and 3 compared to the 1‐hour group. The 5, 15, and 30‐minute bathing groups showed significantly lower vancomycin concentrations at all‐time points. All vancomycin concentrations at day 3 were superior to the minimal inhibitory concentration of Staphyloccocus aureus. The mean concentration of vancomycin depends on the material, duration of bathing, the rinsing effect, and the drug dose. Our in‐vitro study is the first to show that porous tantalum cylinders allow antibiotic carriage and progressive release. If appearing in vivo, in a similar extent, this intrinsic property might be useful to prevent and/or treat peri‐prosthetic joint infection. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:308–312, 2019.

Introduction. This case report shows successful treatment of a refractory sternocleidomastoid branch of the superior thyroid artery (SBSTA) pseudoaneurysm using endovascular glue embolization in a patient who refused surgery. Case Presentation. A 63-year-old female with multiple comorbidities presented with a firm 7 cm tender mass located in the right neck. Ultrasound showed pseudoaneurysm and a 7 × 3.3 × 4 cm multilobular hematoma in the location of the previous central line. CTA showed a corresponding heterogeneous mass. Serial imaging demonstrated enlargement over 2 weeks. Angiogram showed contrast blush off of the SBSTA. Management and Outcome. SBSTA was embolized using glue. Repeat angiogram showed embolization and no contrast blush. One month later, the mass was no longer pulsatile but present on physical exam. CTA showed decreased size. 8 months later, her neck was soft without mass. Discussion. Pseudoaneurysms of the external carotid artery are rare and usually due to trauma. Pseudoaneurysms after central line placement are documented, but most are complications of femoral central lines. A handful of cases of superior thyroid artery pseudoaneurysms due to several etiologies are reported, but none involving the SBSTA. Therapeutic options include surveillance, compression, thrombin injection, embolization, and surgery. Endovascular management offers an alternative for patients unwilling or unable to undergo open surgery.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]

Background: Periprosthetic joint infection (PJI) of the knee with concurrent disruption of the extensor mechanism is a devastating complication. Historically, knees with such complications have been salvaged with use of an arthrodesis or amputation. The purpose of this study was to assess the survival and functional outcomes of a 2-stage exchange arthroplasty combined with knitted monofilament polypropylene (Marlex; C.R. Bard) mesh reconstruction of the extensor mechanism. Methods: From 2000 to 2015, 16 patients underwent a 2-stage exchange arthroplasty and Marlex-mesh reconstruction for PJI with an extensor mechanism disruption. The study included 9 male patients and 7 female patients with a mean age at the time of reimplantation and mesh reconstruction of 64 years. The mean follow-up was 4 years. PJI was diagnosed on the basis of the Musculoskeletal Infection Society criteria. Clinical outcomes, including survivorship, Knee Society Score (KSS) results, and complications, were assessed. Results: Of 16 reconstructions, 13 were in place at the time of the latest follow-up. At 2 years, survivorship free of mesh failure was 86%, survivorship free of PJI was 87%, and survivorship free of PJI or mesh failure was 75%. The mean KSS improved from 48 prior to resection to 74 after mesh reconstruction and reimplantation. The mean extensor lag improved from 31° prior to resection to 3° after mesh reconstruction. Two patients required mesh revision, 1 patient required an above-the-knee amputation for complex wound complications related to reinfection, 1 patient developed a reinfection requiring irrigation and debridement, and 1 patient developed a superficial infection that required debridement. Conclusions: Two-stage exchange arthroplasty combined with Marlex-mesh reconstruction of the extensor mechanism is a viable alternative to knee arthrodesis or amputation. At 2 years, 75% of mesh reconstructions were in place and without evidence of PJI. Moreover, the functional outcomes were improved, with a negligible extensor lag. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.