Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

Neoadjuvant irradiation of retroperitoneal soft tissue sarcoma with ions (Retro-Ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: Following surgery for soft tissue sarcoma of the retroperitoneum, the predominant pattern of failure is local recurrence, which remains the main cause of death. Radiotherapy is utilized to reduce recurrence rates but the efficacy of this strategy has not been definitely established. As treatment tolerability is more favorable with preoperative radiotherapy, normofractionated neoadjuvant treatment is the current approach. The final results of the prospective, randomized STRASS (EORTC 62092) trial, which compared the efficacy of this combined treatment to that of surgery alone, are still awaited; preliminary results presented at the 2019 ASCO Annual Meeting indicated that combined treatment is associated with better local control in patients with liposarcoma (74.5% of the cohort, 11% benefit in abdominal progression free survival after 3 years, p = 0.049). Particles allow better sparing of surrounding tissues at risk, e.g., bowel epithelium, and carbon ions additionally offer biologic advantages and are preferred in slow growing tumors. Furthermore, hypofractionation allows for a significantly shorter treatment interval with a lower risk of progression during radiotherapy. METHODS AND DESIGN: We present a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the retroperitoneum will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the safety and feasibility based on the proportion of grade 3-5 toxicity (CTCAE, version 5.0) in the first 12 months after surgery or discontinuation of treatment for any reason related to the treatment. Local control, local progression-free survival, disease-free survival, overall survival, and quality of life are the secondary endpoints of the study. DISCUSSION: The aim of this study is to confirm that hypofractionated, accelerated preoperative radiotherapy is safe and feasible. The rationale for the use of particle therapy is the potential for reduced toxicity. The data will lay the groundwork for a randomized phase III trial comparing hypofractionated proton and carbon ion irradiation with regard to local control. TRIAL REGISTRATION: ClinicalTrials.gov NCT04219202 . Retrospectively registered on January 6, 2020.

[Periprosthetic joint infections : Latest developments, strategies and treatment algorithms]. / Periprothetische Früh- und Spätinfektionen : Neuste Entwicklungen, Strategien und Behandlungsalgorithmen.

BACKGROUND: Due to their multidimensional consequences, periprosthetic joint infections are a serious complication in arthroplasty. There are disagreements in the literature regarding their classification. At the same time, a consequence for the practical procedure cannot always be derived. THERAPEUTIC PROCEDURES: In addition to debridement with antibiotics and implant retention, there are options for a one or two-stage change in the therapeutic procedure. Although the preservation of implants is only possible in the case of acute infections with a short duration of symptoms, prosthesis changes are indicated with a longer symptom duration. For both procedures, there are interinstitutional deviating indication criteria, weighing pros and cons. Both have specific problems, such as, in particular, the duration of the antibiotics course, the question of anchoring the prosthesis and, in the case of a two-stage procedure, the shape of the spacer.

[Low-grade-infections after spondylodeses-A chameleon? : Current findings and therapeutic strategies]. / Low-Grade-Infektionen in der Wirbelsäulenchirurgie ­ Ein Chamäleon? : Neuste Erkenntnisse und Behandlungsstrategien.

BACKGROUND: Low-grade infections are caused by low-virulence pathogens. The course of these infections is often mild, which is why they are often delayed or not recognized at all. Chronic infections can lead to osteolysis and implant loosening. The rate of complications requiring revision, such as implant loosening or material failure, is known from the literature. However, the rate of low-grade infections in patients requiring spinal revision surgery remains unclear. PURPOSE: The aim of this review is to present the latest treatment strategies for low-grade infections. The diagnostic and therapeutic options are summarized in the form of algorithms. The aim of this work is to raise an awareness of the possibility of a low-grade infection in patients undergoing spinal revision surgery. MATERIALS AND METHODS: Review of the literature RESULTS: The detection of low-grade infections is difficult from both a clinical and a radiological point of view. In the event of unexplained implant loosening or failure despite the lack of local inflammatory signs and often normal laboratory parameters, a low-grade infection must be considered. Multiple microbiological sampling must be requested as part of the revision surgery. A histological examination is recommended for all revision surgery, especially if a low-grade infection is suspected. The diagnosis should ideally be completed by sonicating the implants with subsequent microbiological incubation of the preserved samples. If a low-grade infection is suspected, the biofilm-covered implant should be removed or replaced if instability/no fusion is present. The use of topical antibiotics could be useful, but its effectiveness in treating low-grade infections has not yet been sufficiently demonstrated. DISCUSSION: An algorithm for clinical decision-making in terms of diagnostic and therapeutic options is suggested.

Radiotherapy in the treatment of aggressive fibromatosis: experience from a single institution.

BACKGROUND: Desmoid-type fibromatosis is a rare, potentially locally aggressive disease. Herein we present our experience in the treatment with radiotherapy. METHODS AND MATERIALS: In total 40 patients who received 44 treatments from 2009 to 2018 at the Heidelberg University Hospital with photons (N = 28) as well as protons (N = 15) and carbon ions (N = 1) were investigated. The median age at radiotherapy was 41 years [range 8-78]. Familial adenomatous polyposis (FAP) was confirmed for nine patients and 30 had a unifocal desmoid tumor. The localizations were abdominal wall, abdominopelvic cavity, thoracic wall, extremity, head and neck and trunk. The median prescribed dose was 54 Gy/ Gy (RBE) [range 39.6-66, IQR 50-60]. Eleven treatments were performed at the time of first diagnosis; 33 at the time of progression or recurrence. Post-operative radiotherapy was performed in 17 cases. The median planning target volume was 967 ml [84-4364 ml, IQR 447-1988]. Survival analysis was performed by the Kaplan-Meier Method. RESULTS: The median follow-up time was 32 months [1-153]. At the end of the follow-up interval all patients but one were alive. The estimated local progression free survival of the treated lesion in 3 and 5 years was 76.4% and 63,8%, respectively. The progression-free survival in 3 and 5 years was 72.3 and 58.4% and the overall survival was 97.4 and 97.4%, respectively. In case of macroscopic tumor (N = 31) before radiotherapy a partial remission was observed in 12 cases (38.7%) and a complete remission in 4 cases (12.9%). Progression was observed in 13 (29.5%) cases, predominantly at the margin of the planning target volume (PTV, N = 5, 38,4%) followed by progression within the PTV (N = 4, 30.8%). In univariate analysis multifocal localization was associated with impaired progression-free survival (p = 0.013). One patient developed a grade V gastrointestinal bleeding, otherwise no acute toxicity >°III was observed. Late toxicity was depending on the localization of the desmoid tumor and was especially severe in patients with FAP and abdominopelvine desmoids including gastrointesinal fistula, perforation and abscess. CONCLUSION: Radiotherapy in the treatment of desmoids can lead to long term control. Treatment of patients with abdominopelvine desmoids should be avoided, as the risk of higher-grade complications is substantial.

[Specific intraoperative and secondary complications of biological reconstructions following extralesional tumour resections of malignant bone tumours]. / Operationstypische und sekundäre Komplikationen biologischer Rekonstruktionsverfahren nach extraläsionaler Tumorresektion bei malignen Knochentumoren.

BACKGROUND: The treatment of primary malignant bone tumours is interdisciplinary and individually adapted to the patient. Nowadays, limb salvage surgery is usually possible, and the subsequent reconstruction is carried out either by implantation of modular tumour megaprostheses or by biological reconstruction procedures. Special surgical and secondary complications have to be considered. OBJECTIVES: Indication and explanation of various biological reconstruction procedures and presentation of specific peri- and postoperative complications. MATERIALS AND METHODS: An adapted literature review and the contribution of our own therapy experiences and case studies for the presentation of biological reconstructions and their complication management was performed. RESULTS: In biological reconstructions, autografts, allografts or a combination of autografts and allografts are used. Stabilization is achieved with screw and plate osteosyntheses. The most common secondary complications are pseudarthrosis, interponate fracture, graft necrosis and secondary malpositions. CONCLUSION: In selected cases, particularly at the upper extremities and in dia- or metaphyseal tumour sites, biological reconstruction after extralesional tumor resection is the surgical therapy of choice. The rate of long-term revision interventions is significantly lower compared to modular tumour megaprostheses. Biological reconstructions and the treatment of specific complications have to be performed in specialized centres for musculoskeletal surgical oncology/tumor orthopedics.

Author Correction: Mapping the world's free-flowing rivers.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mapping the world's free-flowing rivers.

Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.

Knock-down of oncohistone H3F3A-G34W counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells.

Giant cell tumors of bone (GCTB) are semi-malignant tumors associated with extensive osteolytic defects and massive bone destructions. They display a locally aggressive behavior and a very high recurrence rate. Recently, a single mutation has been identified in GCTB affecting the H3F3A gene coding for the histone variant H3.3 (H3.3-G34W). The aim of this study was to investigate whether H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Initially, we confirmed the high frequency of this mutation in 94% of 84 analyzed tissue samples. Using a siRNA based approach we could selectively knockdown H3.3-G34W in primary neoplastic stromal cells isolated from tumor tissue (GCTSC). H3.3-G34W knockdown caused a significant inhibition of cell proliferation, migration and colony formation capacity in vitro. Xenotransplantation of GCTSCs onto the chorioallantoic membrane of fertilized chicken eggs further demonstrated a significant impact of H3.3-G34W knockdown on tumor engraftment and growth in vivo. Our data indicate that H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Apart from the application of H3.3-G34W screening as diagnostic tool, our data suggest that H3.3-G4W represents a promising target for the development of new GCTB therapies.

[Metastatic breast cancer in the spine : Molecular predictors for choosing adequate treatment strategies]. / Spinale Mammakarzinommetastasen aus Sicht der Wirbelsäulenchirurgie : Prädiktoren auf Molekularebene zur Wahl der adäquaten Therapiestrategie.

Breast cancer is the most common malignancy affecting women and the spinal column is most likely affected by metastases. Modern oncologic treatment options have significantly prolonged survival times in the last decade. Therefore, treatment of vertebral metastases has been of special interest in spine surgery. Different scores are described to evaluate prognosis and to choose correct treatment strategies, which however only differentiate tumor entities and not specific tumor phenotypes. Breast cancer has been classified into five intrinsic subtypes with different survival rates since the turn of the millennium. The aim of this review was to describe molecular predictors of breast cancer malignancy and to better estimate expected survival times and invasiveness of therapies with regard to spinal metastases.

[Diagnostics and treatment of benign spinal tumors]. / Diagnostik und Therapie benigner Tumoren der Wirbelsäule.

Benign tumors of the spine are rare and may lead to unspecific back pain. The classification of the lesion is typically achieved with a combination of imaging techniques (MRI and CT scans) and, in some cases, a histological sampling to allow differentiation from malignant processes. Both open and interventional (CT guided) biopsies are possible, depending on the localization of the tumor. Treatment strategies are diverse, require an interdisciplinary approach, and include operative and interventional procedures. The following article gives an overview of the most important benign tumors of the spine, the typical features in imaging, and treatment strategies.

[Mazabraud and McCune-Albright syndromes in association : A case of two very rare orthopaedic tumour entities]. / Mazabraud- und McCune-Albright-Syndrom in Assoziation : Ein Fall zweier sehr seltener tumororthopädischer Entitäten.

We report on a 47-year-old woman with unilateral fibrous dysplasia and three intramuscular masses. Medical imaging revealed possible intramuscular myxomas, so that the suspected diagnosis was Mazabraud syndrome. After biopsy, the suspected diagnosis was verified by histology and molecular pathology. Due to endocrine abnormalities in the patient's medical history, McCune-Albright syndrome has was also verified.

Structural changes in the thigh muscles following trans-femoral amputation.

INTRODUCTION: Early ambulation is the principal objective in trans-femoral amputees. Postamputation modifications complicate the rehabilitation process due to a reduced control at the interface between stump and prosthesis. The aim of this study is to determine whether magnetic resonance imaging depicts the amount of fatty degeneration of the thigh muscles after trans-femoral amputation (TFA). METHODS: A total of 12 patients following a TFA on the basis of a bone neoplasm or metastasis with an evaluable postoperative MRI were identified. Using the Goutallier classification, the fatty degeneration of the thigh muscles was analyzed in the middle (M) and at the distal end (E) of the residual limb at T1 (10.6 months) and T2 (25.6 months). RESULTS: Analysis at two different levels showed different grades of fatty degeneration of thigh muscles after TFA at T1 and T2. Comparing fatty degeneration at both levels of the stump, the quadriceps femoris revealed a significant change (p = 0.01) at T1 and M. sartorius and adductor (p = 0.02) at T2. CONCLUSIONS: MRI is an excellent diagnostic tool to evaluate fatty degeneration after TFA. The highest amount of fatty degeneration of the quadriceps muscle was monitored within the first 10 months. Early physiotherapy is important to strengthen the remaining stump muscles during rehabilitation.

Increased antibiotic release and equivalent biomechanics of a spacer cement without hard radio contrast agents.

We compared a novel calcium carbonate spacer cement (Copal® spacem) to well-established bone cements. Electron microscopic structure and elution properties of the antibiotics ofloxacin, vancomycin, clindamycin, and gentamicin were examined. A knee wear simulator model for articulating cement spacers was established. Mechanical tests for bending strength, flexural modulus, and compressive and fatigue strength were performed. The electron microscopic analysis showed a microporous structure of the spacer cement, and this promoted a significantly higher and longer antibiotic elution. All spacer cement specimens released the antibiotics for a period of up to 50days with the exception of the vancomycin loading. The spacer cement showed significantly less wear scars and fulfilled the ISO 5833 requirements. The newly developed spacer cement is a hydrophilic antibiotic carrier with an increased release. Cement without hard radio contrast agents can improve tribological behaviour of spacers, and this may reduce reactive wear particles and abrasive bone defects.

[Osteoidosteoma. From diagnosis to treatment]. / Osteoidosteom. Von der Diagnose zur Behandlung.

An osteoid osteoma is a benign bone-forming tumor which usually presents in childhood and adolescence and is characterized by extensive nocturnal pain. Computed tomography (CT) is used to reveal the typical radiolucent nidus surrounded by a sclerotic reaction and in magnetic resonance imaging (MRI) a nidal enhancement and perifocal edema can confirm the diagnosis. Having shown excellent success rates radiofrequency ablation has become the treatment of choice which allows minimally invasive and precise destruction of nidal tumor tissue. By using thermal protection techniques and multiple ablation positions successful therapy of perineural tumors and niduses with diameters of more than 2 cm are possible.

Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib.

Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met(+) tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB.

[Standards of microbiological diagnostics of spondylodiscitis]. / Standards der mikrobiologische Diagnostik der Spondylodiszitis.

In most cases spondylodiscitis is due to a monomicrobial infection caused by hematogenous dissemination of Staphylococcus aureus. There are, however, many other possible pathogens causing spondylodiscitis and the pathogen responsible can only be identified in approximately 50% of cases. This leads to delayed diagnosis and therapy and an increased morbidity and mortality rate. Failures in planning and performing material recovery are often the reason. As pathogen-specific antimicrobial treatment according to the results of susceptibility testing is the main component of interdisciplinary therapy, all available methods for identification of the pathogen, such as blood cultures, intraoperative and computed tomography (CT) guided biopsies of inflammatory fluids and tissues as well as molecular biological methods should be performed to optimize antimicrobial therapy.