Static spacers play a crucial role in the treatment of complex periprosthetic joint infections of the knee.

PURPOSE: To determine the superior spacer design, a growing number of studies are comparing treatment results between patients having been treated with articulating and static knee spacers in the setting of two-stage revision for periprosthetic joint infection (PJI). In contrast, the primary objective of this study was to compare preoperative characteristics between patients from both spacer groups and examine whether significant differences were present prior to spacer implantation. METHODS: This retrospective, single-centre, cohort study examined the preoperative situation of 80 consecutive knee PJIs between 2017 and 2020. All patients underwent two-stage revision, with 35 (44%) receiving an articulating and 45 (56%) a static spacer. RESULTS: No significant differences were observed in terms of patient gender (p = 0.083), age (p = 0.666), comorbidity (p = 0.1) and preoperative clinical function (p = 0.246). Static spacers were significantly more often used in the presence of a periarticular fistula (p = 0.033), infection of a revision implant (p < 0.001), higher degree of bone loss (p < 0.001) and infection caused by a difficult-to-treat pathogen (p = 0.038). Complication and revision rates were similar for both spacer types during the interim period, while patients with articulating spacers demonstrated a superior clinical function (p < 0.001) during the interim period and after reimplantation. CONCLUSION: Static spacers are being utilised in significantly more complex and unfavourable preoperative scenarios. Therefore, a preoperative selection bias may be at least partially accountable for any disparities observed in postoperative outcomes. To achieve the best possible results, surgeons should know and respect the distinct indications of static and articulating spacers and consequently understand and use them as complementary surgical options. LEVEL OF EVIDENCE: Level III.

Ten recommendations for sarcoma surgery: consensus of the surgical societies based on the German S3 guideline "Adult Soft Tissue Sarcomas".

PURPOSE: The evidence-based (S3) guideline "Adult Soft Tissue Sarcomas" (AWMF Registry No. 032/044OL) published by the German Guideline Program in Oncology (GGPO) covers all aspects of sarcoma treatment with 229 recommendations. Representatives of all medical specialties involved in sarcoma treatment contributed to the guideline. This paper compiles the most important recommendations for surgeons selected by delegates from the surgical societies. METHODS: A Delphi process was used. Delegates from the surgical societies involved in guideline process selected the 15 recommendations that were most important to them. Votes for similar recommendations were tallied. From the resulting ranked list, the 10 most frequently voted recommendations were selected and confirmed by consensus in the next step. RESULTS: The statement "Resection of primary soft tissue sarcomas of the extremities should be performed as a wide resection. The goal is an R0 resection" was selected as the most important term. The next highest ranked recommendations were the need for a preoperative biopsy, performing preoperative MRI imaging with contrast, and discussing all cases before surgery in a multidisciplinary sarcoma committee. CONCLUSION: The evidence-based guideline "Adult Soft Tissue Sarcomas" is a milestone to improve the care of sarcoma patients in Germany. The selection of the top ten recommendations by surgeons for surgeons has the potential to improve the dissemination and acceptance of the guideline and thus improve the overall outcome of sarcoma patients.

Contrast-enhanced ultrasound reveals perfusion differences between benign lipoma and semi-malignant atypical lipomatous tumors: A prospective clinical study.

PURPOSE: Soft tissue tumors (STT) are difficult to diagnose accurately, and distinguishing between benign and malignant tumors is challenging. Lipoma is the most common STT, while atypical lipomatous tumors (ALT) can dedifferentiate into malignant lipomatous tumors like grade 1 liposarcoma and require more radical therapy. This study aims to investigate the potential of contrast-enhanced ultrasound (CEUS) to differentiate between lipoma and ALT based on tumor perfusion. MATERIALS AND METHODS: We prospectively examined 52 patients who were scheduled for biopsy for suspected lipoma or ALT. The CEUS examination was performed using SonoVue as a contrast agent to quantify tumor perfusion using VueBox V7.1 software. Peak enhancement (PE), rise time (RT), wash-in perfusion index (WiPI), and wash-out rate (WoR) were used to assess contrast enhancement inside the STT. RESULTS: Among 50 tumors examined, 30 were lipomas, and 20 were ALTs. We found significant differences in perfusion between lipomas and ALTs (PE: 49.22 ± 45.75 a.u. vs. 165.67 ± 174.80; RT: 23.86 ± 20.47s vs. 10.72 ± 5.34 s; WiPI: 33.06 ± 29.94 dB vs. 107.21 ± 112.43 dB; WoR: 2.44 ± 3.70 dB/s vs. 12.75 ± 15.80 dB/s; p<.001). ROC analysis of PE resulted in a diagnostic accuracy of 74% for the detection of an ALT, and 77% for the detection of a lipoma. CONCLUSION: CEUS may enhance the differential diagnosis of benign lipomas and ALTs, with ALTs showing higher levels of perfusion. If larger prospective studies confirm these findings, CEUS could enhance diagnostic accuracy, guide surgical planning, and potentially reduce unnecessary treatments for patients presenting with ambiguous lipomatous tumors like lipoma or ALT.

Enhanced antibiotic release from bone cement spacers utilizing dual antibiotic loading with elevated vancomycin concentrations in two-stage revision for periprosthetic joint infection.

PURPOSE: Antibiotic loaded bone cement spacers provide high local antibiotic concentrations, preserve bone stock, and reduce soft tissue contractions. The objective of this in-vitro study was to compare antibiotic release from spacers, aiming to discover the most optimal preparation and identify modifiable factors that can further enhance antibiotic release. METHODS: Six distinct spacer preparation were created using three different bone cements and manual incorporation of antibiotics. During a six-week period, the release of antibiotics from each spacer was measured individually at ten predetermined time points using a chemiluminescent immunoassay. RESULTS: Manually adding 4 g of vancomycin to every 40 g of "Palacos R + G" yielded the most favorable release profile. Throughout all preparations, antibiotic release consistently and significantly decreased over the six-week period. When incorporating a higher concentration of vancomycin, a significantly higher cumulative release of vancomycin was observed, with varying effects on the release of gentamicin. The choice of bone cement had a significant impact on antibiotic release. CONCLUSION: To enhance antibiotic release from spacers, surgeons should manually incorporate high antibiotic concentrations into the most appropriate bone cement and keep the interim period as short as possible. Specifically, we suggest manual incorporation of 4 g of vancomycin to every 40 g of gentamicin premixed "Palacos R + G" to create bone cement spacers.

Quality of life, infection control, and complication rates using a novel custom-made articulating hip spacer during two-stage revision for periprosthetic joint infection.

INTRODUCTION: Two-stage revision remains the gold standard treatment for most chronically infected and complex total hip arthroplasty infections. To improve patient outcome and reduce complication rates, we have developed a novel custom-made articulating hip spacer technique and present our short-term results. MATERIALS AND METHODS: Between November 2017 and November 2019, 27 patients (mean age 70 years) underwent two-stage revision for periprosthetic joint infection of the hip using the articulating spacer design described here. We retrospectively analyzed spacer-related complications as well as rates for complication, infection control, and implant survivorship after final reimplantation. Furthermore, we prospectively collected patient-reported health-related quality of life (HRQoL) scores prior to spacer implantation, with the spacer and after reimplantation of the new prosthesis. RESULTS: An additional round of spacer exchange was performed in two patients (8.3%), persistent wound discharge was the reason in both cases. We had one (4.2%) spacer-related mechanical complication, a dislocation that was treated with closed reduction. After reimplantation, infection control was achieved in 96% with an implant survivorship of 92% after a mean follow-up time of 19 (range 7-32, SD 7.2) months. While the scores for VR-12 MCS, VAS hip pain and patient-reported overall satisfaction significantly improved after first stage surgery, the scores for WOMAC, UCLA and VR-12 PCS significantly improved after second stage surgery. CONCLUSIONS: Our two-stage approach for periprosthetic joint infection shows high infection eradication and implant survivorship rates at short-term follow-up. Spacer-related complication rates were low, and we achieved high patient satisfaction rates and low pain levels already during the spacer period. To further simplify comparison between different spacer designs, we propose a new hip spacer classification system.

MRI patterns indicate treatment success and tumor relapse following radiofrequency ablation of osteoblastoma.

Purpose: To explore the typical magnetic resonance imaging (MRI) pattern of osteoblastoma (OB) after radiofrequency ablation (RFA) treatment and to identify signs indicating treatment success or relapse.Materials and methods: Forty-four follow-up MRI examinations of 15 patients with OB who had undergone 19 RFA procedures were analyzed retrospectively. An early follow-up group (1-4 months after RFA) and a late follow-up group (8-131 months after RFA) were established. The groups were further subdivided according to treatment success. Images were analyzed for the presence of central nidus enhancement (CNE), peripheral nidus enhancement (PNE), perifocal bone marrow edema (PBME) and fatty nidus conversion (FNC).Results: The early follow-up MRI image from every patient in the treatment success group exhibited a target-like appearance with negative CNE and positive PNE or PBME. PNE and PBME were observed in 93% and 71% of the early follow-up images, respectively. A target-like appearance was observed in 25% of the late follow-up images, and PNE and PBME were each observed in 20% of these images. FNC was not observed in the early follow-up images, but was seen in 55% of the late follow-up images. All three MRI images of the patients exhibiting clinical recurrence demonstrated strong CNE, PNE and extensive PMBE, which was in contrast to the images of the patients exhibiting treatment success.Conclusion: A target-like appearance of OB in early follow-up MRI examination indicates treatment success. PNE and PBME typically reduce over time and can lead to FNC in successfully treated patients. CNE recurrence, PNE and extensive PBME are signs of relapse.

What Is the Long-term (27- to 32-year) Survivorship of an Uncemented Tapered Titanium Femoral Component and Survival in Patients Younger Than 50 Years?

BACKGROUND: Uncemented femoral components in primary THA are in widespread use, especially in patients younger than 50 years, but few studies have evaluated their survival into the late third and early fourth decade. QUESTIONS/PURPOSES: We evaluated (1) survivorship using femoral revision for any reason as the endpoint, (2) survivorship using femoral revision for aseptic loosening as the endpoint, (3) survival in patients younger than 50 years, (4) cumulative incidence of stem revision for periprosthetic femoral fracture and (5) the overall risk of revision (change of any part of the implanted components) at a minimum of 27 years of follow-up with an uncemented tapered titanium stem still in clinical use today. METHODS: We reviewed the clinical and radiographic results of 326 THAs performed in 326 patients (for 28 patients with bilateral THA, only the first hip was included in the analysis to ensure independent observations) using an uncemented grit-blasted, tapered collarless titanium alloy (TiAl6Nb7) stem between January 1985 and December 1989. In that same timeframe, we performed 1038 primary THAs. During that time, we used cementless stems in patients without severe femoral canal deformity and adequate bone stock for uncemented femoral fixation as determined by using the indication criteria described by the developer. In all, 34% (354 of 1038) were cementless; all cementless stems implanted during that time were the stem being studied here. No others were used. The mean (range) age at the time of surgery was 56 years (13-81 years). Sixty-seven patients were younger than 50 years at the time of primary THA. A competing risk survivorship analysis was used to estimate long-term survival. The minimum follow-up was 27 years (mean 28 years; range 27-32 years); at that time, 169 patients had died, and four patients were lost to follow-up. RESULTS: Survivorship at 28 years with revision of the femoral component for any reason as the endpoint was 87% (95% CI 83 to 90). Survivorship for femoral revision for aseptic loosening as the endpoint was 94% at 28 years (95% CI 90 to 96). Survival in patients younger than 50 years at the time of primary THA was 89% (95% CI 78 to 95) and 95% (95% CI 86 to 98) at 28 years for the endpoints of all stem revisions and aseptic stem loosening, respectively. The overall cumulative incidence of stem revision for periprosthetic femoral fracture was 4% (95% CI 2 to 7) at 28 years. The overall THA survival rate at 28 years with revision for any reason as the endpoint was 57% (95% CI 51 to 62). CONCLUSIONS: Uncemented femoral fixation of a tapered collarless titanium alloy stem was reliable into the early fourth decade, especially in patients younger than 50 years. Late stem failures in the third and early fourth decade were mainly because of periprosthetic femoral fracture, while aseptic loosening occurred in undersized stems during the early second decade. LEVEL OF EVIDENCE: Level IV, therapeutic study.

[DNVF Memorandum Health Services Research in Oncology]. / DNVF-Memorandum Versorgungsforschung in der Onkologie.

Health services research in oncology deals with all situations which cancer patients face. It looks at the different phases of care, i. e. prevention / early detection, prehabilitation, diagnostics, therapy, rehabilitation and palliative care as well as the various actors, including those affected, the carers and self-help. It deals with healthy people (e. g. in the context of prevention / early detection), patients and cancer survivors. Due to the nature of cancer and the existing care structures, there are a number of specific contents for health services research in oncology compared to general health services research while the methods remain essentially identical. This memorandum describes the subject, illustrates the care structures and identifies areas of health services research in oncology. This memorandum has been prepared by the Oncology Section of the German Network for Health Services Research and is the result of intensive discussions.

Retrospective analysis of 51 intralesionally treated cases with progressed giant cell tumor of the bone: local adjuvant use of hydrogen peroxide reduces the risk for tumor recurrence.

BACKGROUND: Giant cell tumor of the bone (GCT) has high local recurrence rates and the prognosis is hard to predict. We therefore retrospectively analyzed clinical outcome and recurrences of 51 GCT cases focusing on the effects of adjuvant local use of hydrogen peroxide. METHODS: The series enclosed 51 advanced GCT cases of the upper and lower extremities (n = 27 Campanacci grade III; n = 24 grade II; n = 39 surgery at our institution, n = 12 elsewhere). Mean follow-up was 88.3 (± 62.0) months. Surgical details, histology, metastases, recurrences, and interview-based data on satisfaction and function including the Musculoskeletal Tumor Society (MSTS) score were evaluated. It was investigated whether hydrogen peroxide was additionally used or not to clean the tumor cavity after curettage as we hypothesized influence on recurrences. To analyze the underlying mechanisms, GCT-derived stromal cell lines were cultured in vitro and tested for cell viability and apoptosis after treatment with hydrogen peroxide. Statistical analysis was performed with Student's t tests, analysis of variance (ANOVA) with post hoc testing, Mann-Whitney U tests, chi-square tests, Kaplan-Meier analysis, and multivariate Cox regression analysis. RESULTS: The whole series had 21 recurrences (41%). Eleven recurrences were found (28%) after surgery at our institution. Kaplan-Meier analysis of cumulative recurrence-free survival revealed at 2 years follow-up 69% (72%, only our institution) and at 10 years follow-up 54% (68%, only our institution). Intralesional resection was performed by vigorous curettage, burring, and defect filling with either polymethylmethacrylate bone cement (n = 45) or cancellous bone from the iliac crest (n = 6). Univariate chi-square analysis showed significantly lower recurrence rate after bone cement filling (2.3-fold, p = 0.024). Cleaning of the lesion cavity with hydrogen peroxide significantly reduced recurrence rate (whole collective 2.9-fold, p = 0.004; our institution 2.8-fold, p = 0.04) and significantly increased cumulative recurrence-free survival rate (whole collective at 10 years follow-up 74% versus 31%, p = 0.002; our institution 79% versus 48%, p = 0.02) compared to cases without hydrogen peroxide treatment. In multivariate analysis, significant risk factors for recurrence were pathological fracture (hazard ratio 3.7; p = 0.04), high mitosis rate (hazard ratio 15.6; p = 0.01), and lack of hydrogen peroxide use (hazard ratio 6.0; p = 0.02). In vitro cell culture analyses found apoptotic nature of hydrogen peroxide induced GCT cell death. CONCLUSIONS: The present series proved for the first time that additional cleaning of the tumor cavity with hydrogen peroxide before defect filling significantly reduced recurrence rate and significantly increased recurrence-free survival in advanced but intralesionally treated GCT cases.

Outcome of conservative and surgical treatment of enchondromas and atypical cartilaginous tumors of the long bones: retrospective analysis of 228 patients.

BACKGROUND: Sufficient data on outcome of patients with clinically and radiologically aggressive enchondromas and atypical cartilaginous tumors (ACT) is lacking. We therefore analyzed both conservatively and surgically treated patients with lesions, which were not distinguishable between benign enchondroma and low-grade malignant ACT based upon clinical and radiologic appearance. METHODS: The series included 228 consecutive cases with a follow-up > 24 months to assess radiological, histological, and clinical outcome including recurrences and complications. Pain, satisfaction, functional limitations, and the musculoskeletal tumor society (MSTS) score were evaluated to judge both function and emotional acceptance at final follow-up. RESULTS: Follow-up took place at a mean of 82 (median 75) months. The 228 patients all had comparable clinical and radiological findings. Of these, 153 patients were treated conservatively, while the other 75 patients underwent intralesional curettage. Besides clinical and radiological aggressiveness, most lesions were histologically judged as benign enchondromas. 9 cases were determined to be ACT, while the remaining 7 cases had indeterminate histology. After surgery, three patients developed a recurrence, and a further seven had complications of which six were related to osteosynthesis. Both groups had excellent and almost equal MSTS scores of 96 and 97%, respectively, but significantly less functional limitations were found in the non-surgery group. Further sub-analyses were performed to reduce selection bias. Sub-analysis of histologically diagnosed enchondromas in the surgery group found more pain, less function, and worse MSTS score compared to the non-surgery group. Sub-analysis of smaller lesions (< 4.4 cm) did not show significant differences. In contrast, larger lesions displayed significantly worse results after surgery compared to conservative treatment (enchondromas > 4.4 cm: MSTS score: 94.0% versus 97.3%, p = 0.007; pain 2.3 versus 0.8, p = 0.001). The majority of lesions treated surgically was filled with polymethylmethacrylate bone-cement, while the remainder was filled with cancellous-bone, without significant difference in clinical outcome. CONCLUSION: Feasibility of intralesional curettage strategies for symptomatic benign to low-grade malignant chondrogenic tumors was supported. Surgery, however, did not prove superior compared to conservative clinical and radiological observation. Due to the low risk of transformation into higher-grade tumors and better functional results, more lesions might just be observed if continuous follow-up is assured.

Intraoperative Electron Radiation Therapy Combined with External Beam Radiation Therapy after Gross Total Resection in Extremity Soft Tissue Sarcoma: A European Pooled Analysis.

INTRODUCTION: We report a pooled analysis evaluating the combination of gross complete limb-sparing surgery, intraoperative electron radiation therapy (IOERT), and external beam radiation therapy (EBRT) in patients with extremity soft tissue sarcoma (STS). METHODS: Individual data of 259 patients (median follow-up 63 months) with extremity STS from three European expert centers were pooled. Median age was 55 years and median tumor size was 8 cm. Eighty percent of patients presented with primary disease, mainly located in the lower limb (81%). Union for International Cancer Control 7th edition stage at presentation was as follows: stage I: 9%; stage II: 47%; stage III: 39%; stage IV: 5%. Most patients showed high-grade lesions (91%), predominantly liposarcoma (31%). Median IOERT dose was 12 Gy, preceeded (17%) or followed (83%) by EBRT, with a median dose of 45 Gy. RESULTS: Surgery resulted in R0 resections in 71% of patients and R1 resections in 29% of patients. The 5-year local control (LC) rate was 86%, and significant factors in univariate analysis were disease status and resection margin. Only margin remained significant in multivariate analysis. The 5-year distant control rate was 69%, and significant factors in univariate analysis were histology, grading, resection margin, and metastases prior to/at IOERT. Only grading and metastases remained significant in multivariate analysis. Actuarial 5-year rates of freedom from treatment failure and OS were 61% and 78%, respectively. Significant factors for OS were grading and metastases prior to/at IOERT (univariate, multivariate). Limb preservation and good functional outcome were achieved in 95% and 81% of patients. CONCLUSIONS: Our pooled analysis confirmed prior reports of encouraging LC and survival, with excellent rates of preserved limb function with this treatment approach. Resection margin remained the most important factor for LC, while grading and metastases prior to/at IOERT mainly predicted survival.

Enchondromas and atypical cartilaginous tumors at the proximal humerus treated with intralesional resection and bone cement filling with or without osteosynthesis: retrospective analysis of 42 cases with 6 years mean follow-up.

BACKGROUND: Enchondromas and atypical cartilaginous tumors (ACT) are often located at the proximal humerus. Most lesions can be followed conservatively, but surgical resection may alleviate pain, avoid pathological fractures, and prevent transformation into higher grade chondrosarcomas. Rigorous intralesional resection and filling with polymethylmethacrylate bone cement has been proposed for enchondromas but also for ACT, as an alternative for extralesional resection. We intended to analyze radiological, clinical, and functional outcome of this strategy and compare bone cement without osteosynthesis to bone cement compound osteosynthesis, which has not been analyzed so far. METHODS: We retrospectively analyzed 42 consecutive patients (mean follow-up 73 months; range 8-224) after curettage and bone cement filling with or without osteosynthesis. Exclusion criteria were Ollier's disease and cancellous bone filling. Twenty-five patients only received bone cement. Seventeen patients received additional proximal humerus plate for compound osteosynthesis to increase stability after curettage. Demographics and radiological and clinical outcome were analyzed including surgery time, blood loss, hospitalization, recurrences, and complications. An additional telephone interview at the final follow-up assessed postoperative satisfaction, pain, and function in the quick disabilities of the arm, shoulder, and hand (DASH) score and the Musculoskeletal Tumor Society (MSTS) score. Statistics included the Student T tests, Mann-Whitney U tests, and chi-square tests. RESULTS: No osteosynthesis compared to compound osteosynthesis showed smaller tumors (4.2 (± 1.5) cm versus 6.6 (± 3.0) cm; p = 0.005) and smaller bone cement fillings after curettage (5.7 (± 2.1) cm versus 9.6 (± 3.2) cm; p = 0.0001). A score evaluating preoperative scalloping and soft-tissue extension did not significantly differ (1.9 (± 0.9) versus 2.0 (± 1.0); rating scale 0-4; p = 0.7). Both groups showed high satisfaction (9.2 (± 1.5) versus 9.2 (± 0.9); p = 0.5) and low pain (1.0(±1.7) versus 1.9(±1.8); p = 0.1) in a rating scale from 0 to 10. Clinical and functional outcome was excellent for both groups in the DASH score (6.0 (± 11.8) versus 11.0 (± 13.2); rating scale 0-100; p = 0.2) and the MSTS score (29.0 (± 1.7) versus 28.7 (± 1.1); rating scale 0-30; p = 0.3). One enchondroma recurrence was found in the group without osteosynthesis. Complications (one fracture and one intra-articular screw) were only detected after osteosynthesis. Osteosynthesis had longer surgery time (70 (± 21) min versus 127 (± 22) min; p < 0.0001), more blood loss (220 (± 130) ml versus 460 (± 210) ml; p < 0.0001), and longer stay in the hospital (6 (± 2) days versus 8 (± 2) days; p = 0.004). CONCLUSIONS: Intralesional tumor resection was oncologically safe and clinically successful with or without osteosynthesis. Osteosynthesis did not reduce the risk for fracture but was more invasive.

[Infections after reconstructive spinal interventions : How do I deal with them?] / Infektionen nach rekonstruktiven Wirbelsäuleneingriffen : Wie gehe ich damit um?

BASICS: Postoperative surgical site infections of the spine have been described in up to 20% of patients and can result in serious consequences for the patient and substantial treatment costs. Typical bacteria often arise from skin or fecal flora. Various risk factors for infection have been described, including obesity, diabetes, high ASA scores, as well as intraoperative factors such as heavy blood loss, dural tears, or several revision procedures. Consequently, the prophylaxis with pre- and postoperative risk minimization is of particular importance. TREATMENT: When an infection has developed, it is important to carry out early operative revision involving tissue debridement, lavage and acquiring microbiological samples for culture. If the infection presents early, the instrumentation can often be retained. Adjuvant measures such as negative pressure wound treatment may improve the outcome. In late-onset infections, due to the biofilm production on the instrument surface or in cases of implant loosening, one should attempt to remove the instrumentation, and in cases of instability replace it. This article deals with the current literature on the subject and provides an overview of the data with regard to peri- and postoperative infections.

[Use of Negative Pressure Wound Therapy with Instillation and Dwell Time for Wound Treatment - Results of an Expert Consensus Conference]. / Einsatz der Vakuuminstillationstherapie für die Wundbehandlung ­ Ergebnis einer Expertenkonsensuskonferenz.

Rinsing wounds with wound cleansing solutions has long been a recognised cornerstone in wound management as a means of removing cell debris and surface pathogens in wound exudates. In combination with surgical debridement and topical negative pressure wound therapy (NPWT), this can facilitate the intended progression from the inflammatory to the proliferative phase of wound healing. Procedures of topical negative pressure wound therapy with instillation and a defined exposure/dwell-time of topical solutions under cyclic compression and decompression with foam dressings (NPWTi-d) can remove cellular remnants and debris that may inhibit the healing process. At the same time, it can aid in reducing the bacterial load in contaminated or infected wounds. Since this newer technique is now commercially available and increasingly widespread, recommendations for the proper use and clinical indications were developed by a panel of interdisciplinary experts in the course of a consensus meeting. Although the level of evidence from expert opinions is low, general guidelines for a safe and effective use of NPWTi-d can be worked out that can be of assistance to the clinician. The consensus recommendations derived from this meeting include the objectives of the treatment, the administration modalities of NPWTi-d, the indications for various wounds, including their contraindications, therapy settings, as well as the use of topical instillation solutions, volume and duration (dwell time) based on current scientific data, optimal treatment duration and future developments of the NPWTi-d.

Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma.

BACKGROUND: Matrix metalloproteinases (MMPs) are crucially involved in the regulation of multiple stages of cancer progression. Elevated MMP levels have been associated with the development of metastases and poor prognosis in several types of cancer. However, the role of MMPs in osteosarcoma and their prognostic value is still unclear. Available data are conflicting, most likely due to different technical approaches. We hypothesized that in contrast to total mRNA or protein levels frequently analyzed in previous studies the enzymatic activities of MMPs and their inhibitors the tissue inhibitors of matrix metalloproteinases (TIMPs) are closer related to their biological functions. We therefore aimed to evaluate the reliability of different zymography techniques for the quantification of MMP and TIMP activities in osteosarcoma biopsies in order to investigate their distribution, possible regulation and prognostic value. METHODS: All analyses were done using cryo-conserved osteosarcoma pretreatment biopsies (n = 18). Gene and protein expression of MMPs and TIMPs were analyzed by RT-qPCR and western blot analysis, respectively. Overall MMP activity was analyzed by in situ zymography, individual MMP activities were analyzed by gelatin zymography. Reverse zymography was used to detect and quantify TIMP activities. RESULTS: Strong overall MMP activities could be detected in osteosarcoma pretreatment biopsies with MMP2 and MMP9 as predominant active MMPs. In contrast to total RNA or protein expression MMP2 and MMP9 activities showed significant quantitative differences between good and poor responders. While MMP9 activity was high in the good responder group and significantly decreased in the poor responder group, MMP2 activity showed a reverse distribution. Likewise, significant differences were detected concerning the activity of TIMPs resulting in a negative correlation of TIMP1 activity with MMP2 activity (p = 0.044) and negative correlations of TIMP2 and TIMP3 with MMP9 activity (p = 0.007 and p = 0.006). CONCLUSION: In contrast to mRNA or protein levels MMP and TIMP activities showed significant differences between the analyzed good and poor responder groups. A shift from MMP9 to predominant MMP2 activity is associated with poor response to chemotherapy suggesting that the ratio of MMP2/MMP9 activity might be a valuable and easily accessible marker to predict the response to chemotherapy in osteosarcoma.

Establishment of a patient-derived orthotopic osteosarcoma mouse model.

BACKGROUND: Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue. METHODS: Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin. RESULTS: A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established. CONCLUSION: We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.

Improved survival in osteosarcoma patients with atypical low vascularization.

BACKGROUND: Osteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30 years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant. METHODS: Computer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan-Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging. RESULTS: We detected high estimated overall (p ≤ 0.008) and relapse-free (p ≤ 0.004) survival in 25 % of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies. CONCLUSION: Low intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.

Clinical long-term outcome, technical success, and cost analysis of radiofrequency ablation for the treatment of osteoblastomas and spinal osteoid osteomas in comparison to open surgical resection.

OBJECTIVE: To assess the clinical success and costs of computed tomography (CT)-guided radiofrequency ablation (RFA) of osteoblastoma (OB) and spinal osteoid osteoma (OO). MATERIALS AND METHODS: Nineteen patients with OB and eight patients with spinal OO were treated with CT-guided RFA. The OBs were localized in the extremities (n = 10), the vertebral column (n = 2), and (juxta-)articular (n = 7). Dedicated procedural techniques included three-dimensional CT-guided access planning in all cases, overlapping RFA needle positions (median, two positions; range, 1-6 RF-electrode positions) within the OB nidus (multiple ablation technique, n = 15), and thermal protection in case of adjacent neural structure in four spinal OO. The data of eight operated OB and ten operated spinal OO patients were used for comparison. Long-term success was assessed by clinical examination and using a questionnaire sent to all operated and RFA-treated patients including visual analogue scales (VAS) regarding the effect of RFA on severity of pain and limitations of daily activities (0-10, with 0 = no pain/limitation up to 10 = maximum or most imaginable pain/limitation). RESULTS: All patients had a clear and persistent pain reduction until the end of follow-up. The mean VAS score for all spinal OO patients and all OB patients treated either with RFA or with surgical excision significantly decreased for severity of pain at night, severity of pain during the day, and both for limitations of daily and of sports activities. CONCLUSIONS: RFA is an efficient method for treating OB and spinal OO and should be regarded as the first-line therapy after interdisciplinary individual case discussion.

On the inflammatory response in metal-on-metal implants.

BACKGROUND: Metal-on-metal implants are a special form of hip endoprostheses that despite many advantages can entail serious complications due to release of wear particles from the implanted material. Metal wear particles presumably activate local host defence mechanisms, which causes a persistent inflammatory response with destruction of bone followed by a loosening of the implant. To better characterize this inflammatory response and to link inflammation to bone degradation, the local generation of proinflammatory and osteoclast-inducing cytokines was analysed, as was systemic T cell activation. METHODS: By quantitative RT-PCR, gene expression of cytokines and markers for T lymphocytes, monocytes/macrophages and osteoclasts, respectively, was analysed in tissue samples obtained intraoperatively during exchange surgery of the loosened implant. Peripheral T cells were characterized by cytofluorometry before surgery and 7 to 10 days thereafter. RESULTS: At sites of osteolysis, gene expression of cathepsin K, CD14 and CD3 was seen, indicating the generation of osteoclasts, and the presence of monocytes and of T cells, respectively. Also cytokines were highly expressed, including CXCL8, IL-1ß, CXCL2, MRP-14 and CXCL-10. The latter suggest T cell activation, a notion that could be confirmed by detecting a small, though conspicuous population of activated CD4+ cells in the peripheral blood T cells prior to surgery. CONCLUSION: Our data support the concept that metallosis is the result of a local inflammatory response, which according to histomorphology and the composition of the cellular infiltrate classifies as an acute phase of a chronic inflammatory disease. The proinflammatory environment, particularly the generation of the osteoclast-inducing cytokines CXCL8 and IL1-ß, promotes bone resorption. Loss of bone results in implant loosening, which then causes the major symptoms of metallosis, pain and reduced range of motion.