Case Report: Long-Term Survival of a Patient with Cerebral Metastasized Ovarian Carcinoma Treated with a Personalized Peptide Vaccine and Anti-PD-1 Therapy.

Ovarian cancer is one of the most common cancers among women and the most lethal malignancy of all gynecological cancers. Surgery is promising in the early stages; however, most patients are first diagnosed in the advanced stages, where treatment options are limited. Here, we present a 49-year-old patient who was first diagnosed with stage III ovarian cancer. After the tumor progressed several times under guideline therapies with no more treatment options available at that time, the patient received a fully individualized neoantigen-derived peptide vaccine in the setting of an individual healing attempt. The tumor was analyzed for somatic mutations via whole exome sequencing and potential neoepitopes were vaccinated over a period of 50 months. During vaccination, the patient additionally received anti-PD-1 therapy to prevent further disease progression. Vaccine-induced T-cell responses were detected using intracellular cytokine staining. After eleven days of in vitro expansion, four T-cell activation markers (namely IFN-É£, TNF-α, IL-2, and CD154) were measured. The proliferation capacity of neoantigen-specific T-cells was determined using a CFSE proliferation assay. Immune monitoring revealed a very strong CD4+ T-cell response against one of the vaccinated peptides. The vaccine-induced T-cells simultaneously expressed CD154, TNF, IL-2, and IFN-É£ and showed a strong proliferation capacity upon neoantigen stimulation. Next-generation sequencing, as well as immunohistochemical analysis, revealed a loss of Beta-2 microglobulin (B2M), which is essential for MHC class I presentation. The results presented here implicate that the application of neoantigen-derived peptide vaccines might be considered for those cancer stages, where promising therapeutic options are lacking. Furthermore, we provide more data that endorse the intensive investigation of B2M loss as a tumor escape mechanism in clinical trials using anti-cancer vaccines together with immune-checkpoint inhibitors.

Surgical Management of Periprosthetic Joint Infections in Hip and Knee Megaprostheses.

Periprosthetic joint infection is a feared complication after the megaprosthetic reconstruction of oncologic and non-oncologic bone defects of including the knee or hip joint. Due to the relative rarity of these procedures, however, optimal management is debatable. Considering the expanding use of megaprostheses in revision arthroplasty and the high revision burden in orthopedic oncology, the risk of PJI is likely to increase over the coming years. In this non-systematic review article, we present and discuss current management options and the associated results focusing on studies from the last 15 years and studies from dedicated centers or study groups. The indication, surgical details and results in controlling infection are presented for debridement, antibiotics, irrigation and retention (DAIR) procedure with an exchange of the modular components, single-stage implant exchange, two-stage exchanges and ablative procedures.

The Potential for Foreign Body Reaction of Implanted Poly-L-Lactic Acid: A Systematic Review.

Poly-L-lactic acid (PLLA) implants have been used for bone fixation for decades. However, upon insertion, they can cause a foreign body reaction (FBR) that may lead to complications. On 15 December 2023, a systematic review was conducted to search for articles on the PubMed, MeSH term, and Scopus databases using the keywords 'PLLA' and 'foreign body reaction'. The articles were reviewed not only for the question of FBR, its severity, and the manifestation of symptoms but also for the type of implant and its location in the body, the species, and the number of individuals included. A total of 71 original articles were identified. Of these, two-thirds reported on in vivo trials, and one-third reported on clinical applications. The overall majority of the reactions were mild in more than half of the investigations. Symptoms of extreme and extensive FBR mainly include osteolysis, ganglion cysts, and swelling. The localization of PLLA implants in bone can often result in osteolysis due to local acidosis. This issue can be mitigated by adding hydroxyapatite. There should be no strong FBR when PLLA is fragmented to 0.5-4 µm by extracorporeal shock wave.

Evaluation of time to reimplantation as a risk factor in two-stage revision with static spacers for periprosthetic knee joint infection.

INTRODUCTION: We investigated the time to reimplantation (TTR) during two-stage revision using static spacers with regard to treatment success and function in patients with chronic periprosthetic joint infection (PJI) of the knee. METHODS: 163 patients (median age 72 years, 72 women) who underwent two-stage exchange for chronic knee PJI between 2012 and 2020 were retrospectively analyzed (based on the 2011 Musculoskeletal Infection Society criteria). A cutoff TTR for increased risk of reinfection was identified using the maximally selected log-rank statistic. Infection control, aseptic revisions and overall survival were analyzed using Kaplan-Meier survival estimates. Adjustment for confounding factors-the Charlson Comorbidity Index (CCI) and C-reactive protein (CRP)-was done with a Cox proportional hazards model. RESULTS: When TTR exceeded 94 days, the adjusted hazard of reinfection was increased 2.8-fold (95% CI 1.4-5.7; p = 0.0036). The reinfection-free rate was 67% (95% CI 52-79%) after 2 years and 33% (95% CI 11-57%) after 5 years for a longer TTR compared to 89% (95% CI 81-94%) and 80% (95% CI 69-87%) at 2 and 5 years, respectively, for a shorter TTR. Adjusted overall survival and number of aseptic revisions did not differ between the longer TTR and shorter TTR groups. Maximum knee flexion was 90° (IQR 84-100) for a longer TTR and 95° (IQR 90-100) for a shorter TTR (p = 0.0431), with no difference between the groups in Oxford Knee Score. Baseline characteristics were similar (body mass index, age, previous surgeries, microorganisms) for the two groups, except that there was a higher CCI (median 4 vs. 3) and higher CRP (median 3.7 vs 2.6 mg/dl) in the longer TTR group. CONCLUSION: A long TTR is sometimes unavoidable in clinical practice, but surgeons should be aware of a potentially higher risk of reinfection. LEVEL OF EVIDENCE: III, retrospective comparative study.

Implant retention in a rabbit model of fracture-related infection.

Aims: Fracture-related infection (FRI) is commonly classified based on the time of onset of symptoms. Early infections (< two weeks) are treated with debridement, antibiotics, and implant retention (DAIR). For late infections (> ten weeks), guidelines recommend implant removal due to tolerant biofilms. For delayed infections (two to ten weeks), recommendations are unclear. In this study we compared infection clearance and bone healing in early and delayed FRI treated with DAIR in a rabbit model. Methods: Staphylococcus aureus was inoculated into a humeral osteotomy in 17 rabbits after plate osteosynthesis. Infection developed for one week (early group, n = 6) or four weeks (delayed group, n = 6) before DAIR (systemic antibiotics: two weeks, nafcillin + rifampin; four weeks, levofloxacin + rifampin). A control group (n = 5) received revision surgery after four weeks without antibiotics. Bacteriology of humerus, soft-tissue, and implants was performed seven weeks after revision surgery. Bone healing was assessed using a modified radiological union scale in tibial fractures (mRUST). Results: Greater bacterial burden in the early group compared to the delayed and control groups at revision surgery indicates a retraction of the infection from one to four weeks. Infection was cleared in all animals in the early and delayed groups at euthanasia, but not in the control group. Osteotomies healed in the early group, but bone healing was significantly compromised in the delayed and control groups. Conclusion: The duration of the infection from one to four weeks does not impact the success of infection clearance in this model. Bone healing, however, is impaired as the duration of the infection increases.

Vibration emissions affect the quality of liquid-preserved AI doses in stallions.

Artificial insemination (AI) with liquid-preserved stallion semen is a widely used reproductive technology. As the demand for AI doses of high-class stallions is transnational, they are frequently exposed to long-distance transport. Since recent studies in boars indicated that vibration emissions caused by transport negatively affected sperm quality in vitro, this study questioned whether sperm quality in stallions is similarly impaired. Furthermore, we investigated stallion and extender-related differences in the spermatozoa's resistance to transport-related quality loss. Stallion ejaculates (n = 30) were collected at a German AI center, split in half, and subsequently diluted to a final sperm concentration of 50 × 106 sperm/mL using the semen extenders EquiPlus or Gent (both Minitüb GmbH, Germany). Four 12 mL aliquots of each sample were filled in plastic syringes according to a split-sample design and exposed to vibration (Displacement index Di = 3.0 ± 0.1) at 5 °C for 0 h (control), 3 h, 6 h or 9 h. All samples were stored for four days at 5 °C after transport simulation and analyzed for total sperm motility, thermo-resistance, membrane integrity, and mitochondrial activity determined by flow cytometry as well as the pH. After calculating generalized linear mixed models for each sperm quality trait, a negative impact of the duration of transport simulation could be shown on total sperm motility (P = 0.001), thermo-resistance (P = 0.030), and the pH (P = 0.001). Simulated transport for 6 h and 9 h diminished sperm quality (P ≤ 0.01), with 9 h reducing thermo-resistance by 5 ± 2.2% points (PP) for EquiPlus and sperm motility by 2.2 ± 1.7 PP for Gent compared to the control group. In contrast, samples exposed to vibration for 3 h showed no decline in sperm quality (P > 0.05). The individual stallion influenced every semen trait (P < 0.05) and transport-related losses in sperm thermo-resistance of up to 15.9 PP were demonstrated. Furthermore, EquiPlus was superior to Gent in all semen assessments (P < 0.001). We conclude that in vitro sperm quality is impaired by vibration. As the quality loss depends on the transport time, we recommend keeping shipping time as short as possible especially for spermatozoa of stallions that are susceptible to vibration-induced sperm quality loss.

Analytical Performance Evaluation of a 523-Gene Circulating Tumor DNA Assay for Next-Generation Sequencing-Based Comprehensive Tumor Profiling in Liquid Biopsy Samples.

Next-generation sequencing (NGS)-based comprehensive tumor profiling from liquid biopsy samples can significantly improve diagnosis and monitoring of tumors when high-quality tissue material is difficult to obtain. In addition, it offers the potential to capture the entire complexity of the tumor, which is particularly important for highly heterogeneous or metastatic tumors. Here, we report the findings of an analytical performance evaluation of the TruSight Oncology 500 circulating tumor DNA (ctDNA) assay, a 523-gene NGS panel developed for ctDNA-based comprehensive genomic profiling of tumors, using reference and patient samples. Using 30 ng cell-free DNA, the assay showed high sensitivity and low variant detection variability for single-nucleotide variants, insertions and deletions, and fusions down to a variant allele frequency (VAF) of 0.5% in the reference samples and VAFs that were highly concordant with previous digital droplet PCR results in the patient samples. At reduced input amounts (20, 15, and 5 ng) and below VAFs of 0.5%, sensitivity was considerably lower and variant detection variability increased. Covering 523 tumor-associated genes, the assay demonstrated a convincing performance comparable to NGS-based ctDNA assays with smaller gene panels, highlighting its value to screen large numbers of different genes.

Shock Wave-Activated Silver-Loaded Biopolymer Implant Coating Eliminates Staphylococcus epidermidis on the Surface and in the Surrounding of Implants.

Bacterial biofilms on foreign surfaces are considered a primary cause of implant-related infections, which are challenging to treat. A new implant coating was developed, containing anti-infective silver within a biocompatible polymer carrier substance. In addition to its passive effect on the implant surface, highly concentrated anti-infective silver can be released as needed via the application of high-energy shock waves. This intervention could be applied transcutaneously in a clinical setting without the need for additional surgery. We investigated the inhibition of biofilm formation and the effectiveness of eradication after activation of the coating via shock waves in an in vitro biofilm model using Staphylococcus epidermidis RP62A. This was performed via scanning electron microscopy and quantitative microbiology. Additionally, we examined the cytotoxicity of the new coating on normal human fibroblasts and Saos-2 osteoblast-like cells, depending on the silver concentration. All studies were compared to uncoated titanium surfaces Ti6Al4V and a conventional electroplated silver coating. Cytotoxicity toward normal human fibroblasts and Saos-2 osteoblast-like cells increased with higher silver content but remained tolerable at 6%. Compared to uncoated Ti6Al4V and the electroplated silver coating, the new coating with a silver content of 4% and 6% exhibited a significant reduction in adherent bacteria by a factor of approximately 1000. This was also evident via microscopic examination of the surface morphology of the biofilms. Furthermore, following shock wave activation, no bacteria were detectable on either the implant or in the surrounding fluid after a 24 h period.

On-Demand Release of Anti-Infective Silver from a Novel Implant Coating Using High-Energy Focused Shock Waves.

Implant-related infections are a significant concern in orthopedic surgery. A novel anti-infective implant coating made of bioresorbable polymer with silver nitrate was developed. A controlled release of silver ions into the vicinity of the prosthesis can be triggered on-demand by extracorporeal shock waves to effectively combat all clinically relevant microorganisms. Microscopy techniques were used to examine the effects of shock wave application on coated titanium discs. Cytotoxicity was measured using a fibroblast proliferation assay. The anti-infective effect was assessed by monitoring the growth curves of three bacterial strains and by conventional culture. Microscopic analysis confirmed surface disruption of the coatings, with a complete release of silver in the focus area after shock wave application. Spectrometry detected an increase in silver concentration in the surrounding of the discs that surpassed the minimum inhibitory concentration (MIC) for both S. epidermidis RP62A and E. coli ATCC 25922. The released silver demonstrated an anti-infective effect, significantly inhibiting bacterial growth, especially at 6% and 8% silver concentrations. Cytotoxicity testing showed decreasing fibroblast viability with increasing silver concentration in the coating, with 6% silver maintaining viability above 25%. Compared to a commonly used electroplated silver coating on the market, the new coating demonstrated superior antimicrobial efficacy and lower cytotoxicity.

Two-Stage Revision Arthroplasty for Resistant Gram-Positive Periprosthetic Joint Infections Using an Oral Linezolid-Based Antibiotic Regime.

BACKGROUND: Increasing antibiotic resistance has been reported as an issue in the systemic treatment of periprosthetic joint infection (PJI). Linezolid offers the advantages of high oral bioavailability and little resistance; however, efficacy in the treatment of PJI varies considerably, and studies reporting consistent surgical treatment are scarce. METHODS: This is a retrospective, single-center analysis of two-stage revisions performed between 2008 and 2017. We identified 111 patients who met the inclusion criteria. Oral linezolid was given for 28 days following 14 days of intravenous tailored antibiotics in resistant gram-positive PJI. A total of 64% of the patients had methicillin-resistant coagulase-negative staphylococci. The median follow-up was 43 (interquartile range (IQR) 30-57) months. RESULTS: 22% (24/111) of the patients underwent surgery for subsequent infection. The 5-year infection-free survival probability was 77% (95% confidence interval (CI) 69-85). A total of 5% of the patients (6/111) had the same organism at the time of reinfection. The patients with infections caused by other organisms than Coagulase-negative staphylococci tended to have a worse reinfection-free survivorship at five years (70% vs. 81%, p = 0.09). Furthermore, the patients with obesity tended to have reduced reinfection-free survivorship at five years (69% vs. 84%, p = 0.08). Overall, 5% (6/111) of the patients had blood count abnormalities with no treatment discontinuations. CONCLUSION: Two-stage revision arthroplasty with systemic oral linezolid treatment for resistant gram-positive PJI results in an infection control of 77% at the mid-term.

Sperm concentration of boar semen doses and sperm quality: Novel perspectives based on the extender type and sperm resilience.

This study evaluated the effect of sperm concentration of boar semen doses on their capacity to maintain its motility over the thermo-resistance test (TRT; sperm resilience) and verified if the extender type (short or long-term) could influence this effect. Thirty ejaculates from five crossbred mature PIC® boars were used, and a factorial design was followed to produce semen doses with 1.5 billion cells in 45 or 90 mL, using Beltsville Thawing Solution (BTS) or Androstar® Plus (APlus). Then, low-concentration doses (16.7 × 106 cells/mL in 90 mL) and higher-concentration doses (33.3 × 106 cells/mL in 45 mL) with BTS or APlus were produced and stored at 17 °C for 168 h. At 72 h, during the TRT, the low-concentration doses (16.7 × 106 cells/mL) lost three-fold less motility than doses with 33.3 × 106 cells/mL (P < 0.01), regardless of the extender type (11. 5% vs. 30.5% of initial motility, respectively). Similar results were found when the TRT was carried out at 168 h, with low-concentration doses losing two-fold less motility (11.4%) than highly concentrated doses (25.9%; P < 0.01). No sperm concentration effect was observed on membrane integrity or mitochondrial membrane potential (P ≥ 0.23). The osmolarity was not affected by the sperm concentration (P = 0.56), only by the extender and the storage time (P < 0.01). In conclusion, the sperm concentration effect on sperm quality was not influenced by extender type, and the data suggest that a low concentration of semen doses positively affects sperm resilience.

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

OBJECTIVES: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. DESIGN: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. RESULTS: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. CONCLUSIONS: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

Blood-saving dissection with monopolar tungsten needle electrodes and Teflon-coated spatula electrodes in tumor orthopedics.

INTRODUCTION: Resection of musculoskeletal tumors and reconstruction with tumor endoprostheses often results in blood loss requiring transfusion of blood products. We assessed the blood-saving potential of using monopolar tungsten needle electrodes and polytetrafluoroethylene (PTFE)-coated spatula electrodes (intervention) compared with conventional dissection with sharp instruments and coagulation with uncoated steel electrodes (control). METHODS: We retrospectively analyzed data of 132 patients (79 interventions, 53 controls) undergoing surgery by one single experienced surgeon in our tertiary referral center between 2012 and 2021. RESULTS: Intraoperative blood loss in the intervention group was reduced by 29% [median (IQR): 700 (400-1200) vs 500 (200-700) ml; p = 0.0043]. Postoperative wound drainage decreased by 41% [median (IQR): 1230 (668-2041) vs 730 (450-1354) ml; p = 0.0080]. Additionally, patients in need of PRBCs during surgery declined from 43% to 15% (23/53 vs 12/79; p = 0.0005), while the transfusion rate after surgery did not change notably. The number of patients in need of revision surgery due to wound healing disorders was low in both groups (control group: 4/53 vs intervention group: 4/79). Only one patient in the control group and two patients in the intervention group underwent revision surgery due to hemorrhage. Baseline characteristics were similar between groups (sex, Charlson Comorbidity score, tumor entity). CONCLUSION: Dissection with tungsten needle electrodes and PTFE-coated spatula electrodes appears an effective surgical blood-saving measure without increased risk of wound healing disorders. LEVEL OF EVIDENCE: III, retrospective comparative study. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov. Identifier: NCT05164809.

Is long time to reimplantation a risk factor for reinfection in two-stage revision for periprosthetic infection? A systematic review of the literature.

The two-stage revision arthroplasty is a common treatment option for chronic periprosthetic infection (PJI). The time to reimplantation (TTR) reported in the literature varies substantially from a few days to several hundred days. It is hypothesized that longer TTR could be associated with worse infection control after second stage. A systematic literature search was performed according to Preferred Reporting items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in Pubmed, Cochrane Library and Web of Science Core Collection in clinical studies published until January 2023. Eleven studies investigating TTR as a potential risk factor for reinfection met the inclusion criteria (ten retrospective and one prospective study, published 2012-2022). Study design and outcome measures differed notably. The cutoff points above which TTR was regarded as "long" ranged from 4 to 18 weeks. No study observed a benefit for long TTR. In all studies, similar or even better infection control was observed for short TTR. The optimal TTR, however, is not yet defined. Larger clinical studies with homogeneous patient populations and adjustment for confounding factors are needed.

Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.

Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data. Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients. Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

What Is the Risk of Dislocation and Revision in Proximal Femoral Replacement with Dual-mobility Articulation After Two-stage Revision for Periprosthetic Hip Infection?

BACKGROUND: Dislocation is a major complication of revision THA after two-stage exchange for periprosthetic joint infection (PJI). The likelihood of dislocation can be particularly high if megaprosthetic proximal femoral replacement (PFR) has been performed during a second-stage reimplantation. Dual-mobility acetabular components are an established way of reducing the instability risk in revision THA; however, the likelihood of dislocation for dual-mobility reconstructions in the setting of a two-stage PFR has not been studied systematically, although patients with these reconstructions might be at an increased risk. QUESTIONS/PURPOSES: (1) What is the risk of dislocation and revision for dislocation in patients who underwent PFR with a dual-mobility acetabular component as part of two-stage exchange for hip PJI? (2) What is the risk of all-cause implant revision and what other procedures were performed (apart from revision for a dislocation) in these patients? (3) What potential patient-related and procedure-related factors are associated with dislocation? METHODS: This was a retrospective study from a single academic center including procedures performed between 2010 and 2017. During the study period, 220 patients underwent two-stage revision for chronic hip PJI. Two-stage revision was the approach of choice for chronic infections, and we did not perform single-stage revisions for this indication during the study period. Thirty-three percent (73 of 220) of patients underwent second-stage reconstruction with a single-design, modular, megaprosthetic PFR because of femoral bone loss, using a cemented stem. A cemented dual-mobility cup was the approach of choice for acetabular reconstruction in the presence of a PFR; however, 4% (three of 73) were reconstructed with a bipolar hemiarthroplasty to salvage an infected saddle prosthesis, leaving 70 patients with a dual-mobility acetabular component and a PFR (84% [59 of 70]) or total femoral replacement (16% [11 of 70]). We used two similar designs of an unconstrained cemented dual-mobility cup during the study period. The median (interquartile range) patient age was 73 years (63 to 79 years), and 60% (42 of 70) of patients were women. The mean follow-up period was 50 ± 25 months with a minimum follow-up of 24 months for patients who did not undergo revision surgery or died (during the study period, 10% [seven of 70] died before 2 years). We recorded patient-related and surgery-related details from the electronic patient records and investigated all revision procedures performed until December 2021. Patients who underwent closed reduction for dislocation were included. Radiographic measurements of cup positioning were performed using supine AP radiographs obtained within the first 2 weeks after surgery using an established digital method. We calculated the risk for revision and dislocation using a competing-risk analysis with death as a competing event, providing 95% confidence intervals. Differences in dislocation and revision risks were assessed with Fine and Gray models providing subhazard ratios. All p values were two sided and the p value for significance was set at 0.05. RESULTS: The risk of dislocation (using a competing-risks survivorship estimator) was 17% (95% CI 9% to 32%) at 5 years, and the risk of revision for dislocation was 12% (95% CI 5% to 24%) at 5 years among patients treated with dual-mobility acetabular components as part of a two-stage revision for PJI of the hip. The risk of all-cause implant revision (using a competing-risk estimator, except for dislocation) was 20% (95% CI 12% to 33%) after 5 years. Twenty-three percent (16 of 70) of patients underwent revision surgery for reinfection and 3% (two of 70) of patients underwent stem exchange for a traumatic periprosthetic fracture. No patients underwent revision for aseptic loosening. We found no differences in patient-related and procedure-related factors or acetabular component positioning for patients with dislocation with the numbers available; however, patients with total femoral replacements had a higher likelihood of dislocation (subhazard ratio 3.9 [95% CI 1.1 to 13.3]; p = 0.03) and revision for a dislocation (subhazard ratio 4.4 [95% CI 1 to 18.5]; p = 0.04) than those who received PFR. CONCLUSION: Although dual-mobility bearings might be an intuitive potential choice to reduce the dislocation risk in revision THA, there is a considerable dislocation risk for PFR after two-stage surgery for PJI, particularly in patients with total femoral replacements. Although the use of an additional constraint might appear tempting, published results vary tremendously, and future studies should compare the performance of tripolar constrained implants to that of unconstrained dual-mobility cups in patients with PFR to reduce the risk of instability. LEVEL OF EVIDENCE: Level III, therapeutic study.

NOTCH3 missense mutations as predictor of long-term response to gemcitabine in a patient with epithelioid hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases. METHODS AND RESULTS: Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patient's tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer. CONCLUSION: The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine.

Effect of using liquid semen on fertility in German Holstein Friesian dairy cattle: A randomized controlled clinical trial.

Low fertility rates in lactating dairy cows as well as restricted availability of semen doses of young bulls with high genetic merit are two major problems in the reproduction of dairy cows. By using liquid semen (LS), the number of doses per ejaculate can be increased. One of the challenges of optimizing the reproductive performance of dairy cows is the phenomenon of variable estrus lengths. The objective of this study was to determine whether the use of LS affects pregnancy outcome of dairy cows with delayed ovulation, when compared with frozen semen (FS). A randomized controlled clinical trial was implemented. In a split-sample procedure, 131 ejaculates were processed into LS (Caprogen, LIC, New Zealand) and FS (BioXcell, IMV, France). Both semen types of each ejaculate were inseminated under the same field conditions to cows showing natural or induced heat. Cows and semen type were allocated according to the last digit of the cows identification number (even = frozen semen, odd = liquid semen). Inseminations (n = 667) were conducted after localization of the pre-ovulatory follicle. Determination of ovulation was performed 24 h post AI per transrectal ultrasonographic examination. Ovulations were classified as delayed when the pre-ovulatory follicle was still present at ovulation control. The prevalence of delayed ovulations was 25.2%. Data of 667 inseminations were analyzed with a generalized linear mixed model including semen type (P = 0.016), parity (P = 0.014), backfat thickness (P = 0.006), estrus induction (P = 0.010), ovulation (P = 0.265) and the interaction term 'semen type by ovulation' (P = 0.094). Overall, a higher pregnancy per AI (P/AI) of LS (45.4%) than P/AI of FS (33.7%) was found. In cases of delayed ovulations, use of LS resulted in higher P/AI (46.8%) compared with FS (27.7%; P = 0.017). We concluded that the fertilizing capacity of LS in prolonged intervals from AI to ovulation might be greater when compared with FS and could be an efficient tool to improve fertility of lactating dairy cows with delayed ovulations.

Impact of agitation time of boar semen doses on sperm traits in short- and long-term extenders.

Transport of extended boar semen doses is a common practice in the swine industry. This study aimed to verify the effect of agitation time on sperm parameters during storage in two semen extenders. One normospermic ejaculate from each boar (n = 20) was diluted in a split sample design with long-term (LONG, Androstar® Plus) and short-term (SHORT, Beltsville Thawing Solution) extenders. Extended semen doses were filled with a total volume of 45 mL and 1.5 billion sperm cells and submitted to 0, 3, 6, and 12 h of agitation in an orbital shaker at 70 rpm. The samples were stored at 17 °C for 120 h. Sperm parameters were evaluated for sperm motility, plasma membrane integrity, pH, thermo-resistance test (TRT), oxidative stress status, and mitochondrial membrane potential. Total and progressive motility were affected by the interaction between the agitation time and the extender, with a linear reduction in sperm motility as the agitation time increased for LONG extender (P ≤ 0.05). Semen doses diluted with SHORT showed a higher pH (P < 0.01), and agitation time had a positive quadratic effect with the highest pH observed after 6 h of agitation, regardless of the extender used (P < 0.01). Sperm motility after TRT and plasma membrane integrity potential were not affected by agitation time (P > 0.05). Mitochondrial membrane potential and oxidative stress status quadratically decreased as agitation time increased (P ≤ 0.05). Based on the results, long transport durations of AI doses under mild vibration emissions affect boar semen quality.

Relations between the time of ovulation and fecal estrogen concentration in sows.

Artificial insemination (AI) is the most important biotechnology in pig reproduction. To achieve the best possible fertility results, appropriate timing of the insemination is essential. The optimal time for AI is 12 h before to 4 h after ovulation. This time-frame, unlike in estrus, is not recognizable through external indicators. It would, therefore, be beneficial to find simple and economical methods that support manual estrus checks and are able to determine the time of ovulation more accurately. On this basis, starting 80 h after weaning, 14 DanBred sows (parity: 5.2 ± 2.4) were checked for ovulation via ultrasound scans every 8 h over a period of 72 h. Additionally, rectal fecal samples were taken and analyzed for their estrogen concentration to assess possible relations to ovulation time. On average, sows ovulated 121 ± 10 h after weaning and 16 ± 9 h after onset of heat. There was a prominent drop in fecal estrogen levels 4 h before ovulation when compared to almost all other points in time (before ovulation: 20 h (P = 0.056), 12 h (P = 0.006); after ovulation: 4 h and 12 h (P < 0.001)). There are, however, significant differences in the sow-individual fecal estrogen concentrations for which several influencing factors must be considered.