Improved Metastatic-Free Survival after Systematic Re-Excision Following Complete Macroscopic Unplanned Excision of Limb or Trunk Soft Tissue Sarcoma.

BACKGROUND: Whether re-excision (RE) of a soft tissue sarcoma (STS) of limb or trunk should be systematized as adjuvant care and if it would improve metastatic free survival (MFS) are still debated. The impact of resection margins after unplanned macroscopically complete excision (UE) performed out of a NETSARC reference center or after second resection was further investigated. METHODS: This large nationwide series used data from patients having experienced UE outside of a reference center from 2010 to 2019, collected in a French nationwide exhaustive prospective cohort NETSARC. Patient characteristics and survival distributions in patients reexcised (RE) or not (No-RE) are reported. Multivariate Cox proportional hazard model was conducted to adjust for classical prognosis factors. Subgroup analysis were performed to identify which patients may benefit from RE. RESULTS: Out of 2371 patients with UE for STS performed outside NETSARC reference centers, 1692 patients were not reviewed by multidisciplinary board before treatment decision and had a second operation documented. Among them, 913 patients experienced re-excision, and 779 were not re-excised. Characteristics were significantly different regarding patient age, tumor site, size, depth, grade and histotype in patients re-excised (RE) or not (No-RE). In univariate analysis, final R0 margins are associated with a better MFS, patients with R1 margins documented at first surgery had a better MFS as compared to patients with first R0 resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53-0.93; p = 0.013). All subgroups except older patients (>70 years) and patients with large tumors (>10 cm) had superior MFS with RE. CONCLUSIONS: RE might be considered in patients with STS of limb or trunk, with UE with macroscopic complete resection performed out of a reference center, and also in originally defined R0 margin resections, to improve LRFS and MFS. Systematic RE should not be advocated for patients older than 70 years, or with tumors greater than 10 cm.

Development of a DNA damage-induced senescence model in osteoarthritic chondrocytes.

Senescent cells (SnCs) have been described to accumulate in osteoarthritis (OA) joint tissues in response to injury, thereby participating in OA development and progression. However, clinical therapeutic approaches targeting SnCs using senolysis, although promising in preclinical OA models, have not yet proven their efficacy in patients with knee OA. This pitfall may be due to the lack of understanding of the mechanisms underlying chondrocyte senescence. Therefore, our study aimed to generate models of chondrocyte senescence. This study used etoposide, to induce DNA damage-related senescence or chronic exposure to IL-1ß to entail inflammation-related senescence in human OA chondrocytes. Several hallmarks of cellular senescence, such as cell cycle arrest, expression of cyclin-dependent kinase inhibitors, DNA damages, and senescence-associated secretory profile were evaluated. Chronic exposure to IL-1ß induces only partial expression of senescence markers and does not allow us to conclude on its ability to induce senescence in chondrocytes. On the other hand, etoposide treatment reliably induces DNA damage-related senescence in human articular chondrocytes evidenced by loss of proliferative capacity, DNA damage accumulation, and expression of some SASP components. Etoposide-induced senescence model may help investigate the initiation of cellular senescence in chondrocytes, and provide a useful model to develop therapeutic approaches to target senescence in OA.

Initial Active Surveillance Strategy for Patients with Peripheral Sporadic Primary Desmoid-Type Fibromatosis: A Multicentric Phase II Observational Trial.

BACKGROUND: Stabilization or spontaneous regressions are demonstrated in more than half of patients affected by primary desmoid-type fibromatosis (DF) in retrospective studies. The objective of this phase II study was to prospectively assess the behavior of primary sporadic DT managed by active surveillance (AS). METHODS: This prospective, multicenter, observational study (NCT01801176) included patients ≥18 years of age with primary sporadic DF located in an extremity or the abdominal/thoracic wall. At inclusion, all patients were initially placed on AS. Follow-up was based on clinical and radiological evaluation by magnetic resonance imaging (MRI) performed at 1, 3, 6, 9, and 12 months, and then every 6 months for 3 years. The primary endpoint was progression-free survival (PFS) at 3 years according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by a Central Review Board. RESULTS: Between 2012 and 2015, 100 patients were enrolled. The female/male ratio was 8 and the median age was 34 years (interquartile range [IQR] 30.8-43.9). Median follow-up was 46.6 months (IQR 36.8-61.1) and the 3-year PFS was 53.4% (95% confidence interval 43.5-63.1%). At progression (48 patients), 23 patients received active treatment. Fifty-eight patients (58%) presented with spontaneous tumor regression (decrease > 0% compared with the initial size) during the first 3 months (n = 35, 35%) or after an initial progression (n = 23, 23%), of whom 26 (26%) had partial responses (PRs). The median time to PR was 31.7 months (25.3-not available). CONCLUSIONS: These data support the use of AS as the primary approach to select patients with peripheral DF who require aggressive treatment.

Osteoarthritic chondrocytes undergo a glycolysis-related metabolic switch upon exposure to IL-1b or TNF.

BACKGROUND: Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes. METHODS: Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays. RESULTS: We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF. CONCLUSION: These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract.

French translation and validation of the cross-cultural adaptation of the MSTS functional assessment questionnaire completed after tumor surgery.

INTRODUCTION: Malignant tumors of the extremities are uncommon. Their surgical treatment, whether conservative or not, may cause sequelae. Functional assessment of patients is essential for research purposes, but also follow-ups and adaptation of treatments. The Musculoskeletal Tumor Society Rating Scale (MSTS) is a disease-specific functional scoring system often used in English literature. Currently, no studies have been published on a valid French translation of the MSTS, whether for the lower or upper extremities. We, therefore, conducted a prospective study to answer the following questions: (1) Are the proposed adapted French versions of the MSTS valid? (2) Do the psychometric properties of the two versions obtained make their use relevant? MATERIALS AND METHODS: The translation and cross-cultural adaptation were carried out following the recommendations of Beaton and Guillemin to obtain two versions: one for patients who had undergone upper extremity surgery (MSTS-UE) and one for those who had undergone lower extremity surgery (MSTS-LE). A prospective multicenter cohort study was then carried out to analyze the psychometric properties of these two versions. RESULTS: A total of 250 patients from 3 referral centers were enrolled in this study. A confirmatory factor analysis (CFA) demonstrated that the two French versions of the MSTS (MSTS-LE and MSTS-UE) were a good fit with a root mean square error of approximation (RMSEA)<0.08 and a comparative fit index (CFI)>0.90. The psychometric properties of the two versions were validated with internal consistency (Cronbach alpha>0.7), convergent validity of each item with its score (> 0.4), and sufficient criterion validity (Pearson correlation coefficient>0.4). The discriminant validity analysis showed that there was a significant correlation between each version and the performance status (PS) (p<0.05). CONCLUSION: This study produced a French version of the MSTS scoring system and validated the psychometric properties of the two versions obtained (MSTS-UE and MSTS-LE). Therefore, the French MSTS scoring system is a valid measurement that can be used in international studies. LEVEL OF EVIDENCE: I.

Overall survival in patients with re-excision of positive microscopic margins of limb and trunk wall soft tissue sarcoma operated outside of a reference center: a nationwide cohort analysis.

BACKGROUND: This French nationwide NETSARC exhaustive prospective cohort aims to explore the impact of systematic re-excision (RE) as adjuvant care on overall survival (OS), local recurrence free survival (LRFS), and local and distant control (RFS) in patients with soft tissue sarcoma (STS) with positive microscopic margins (R1) after initial resection performed outside of a reference center. METHODS: Eligible patients had experienced STS surgery outside a reference center from 2010 to 2017, and had R1 margins after initial surgery. Characteristics and treatment comparisons used chi-square for categorical variables and Kruskall-Wallis test for continuous data. Survival distributions were compared in patients reexcised (RE) or not (No-RE) using a log-rank test. A Cox proportional hazard model was used for subgroup analysis. RESULTS: A total of 1,284 patients had experienced initial STS surgery outside NETSARC with R1 margins, including 1,029 patients with second operation documented. Among the latter, 698 patients experienced re-excision, and 331 were not re-excised. Characteristics were significantly different regarding patient age, tumor site, tumor size, tumor depth, and histotype in the population of patients re-excised (RE) or not (No-RE). The study identified RE as an independent favorable factor for OS (HR 0.36, 95%CI 0.23-0.56, p<0.0001), for LRFS (HR 0.45, 95%CI 0.36-0.56, p<0.0001), and for RFS (HR 0.35, 95%CI 0.26-0.46, p<0.0001). CONCLUSION: This large nationwide series shows that RE improved overall survival in patients with STS of extremities and trunk wall, with prior R1 resection performed outside of a reference center. RE as part of adjuvant care should be systematically considered.

A novel and secure technique of stemmed acetabular cup implantation in complex hip reconstructions: a comparative study and technical note.

PURPOSE: The stemmed acetabular cup (SAC) can be considered in several complicated situations. This type of prosthesis uses the iliac isthmus, which is most often preserved, thus allowing solid anchorage. Its implantation is prone to mechanical complications intraoperatively, such as extra-isthmic effraction, fracture, and early aseptic loosening. The aim of our study was to compare a new technique using a flexible motorized reamer combined with isthmus catheterization (Group A) versus the standard technique deploying a rigid reamer alone (Group B). MATERIALS AND METHODS: A retrospective analysis was carried out of the SACs implanted at our hospital. The main evaluation criterion was visualization of extra-isthmic effraction (EIE) of the stem. RESULTS: Fifty-six SACs (Integra Lepine®, Genay, France) were implanted, 31 in group A and 25 in group B. The mean follow-up was 21.6 months ± 22.3. This study found fewer EIEs using a flexible motorized reamer (0 versus 5, p = 0.014), less perioperative bleeding (p = 0.054), and less aseptic loosening in group A (p = 0.034). There was no difference in terms of infection or other mechanical complications post-operatively between the two groups. CONCLUSION: Using iliac catheterization combined with a flexible motorized reamer when implanting a SAC helps to avoid EIE and it also appears to reduce complications such as peri-operative bleeding and early aseptic loosening. We recommend use of this surgical technique rather than a rigid reamer alone, and this new technique should allow widespread and more accessible use of this specific type of implant.

A Short-Course Antibiotic Prophylaxis Is Associated with Limited Antibiotic Resistance Emergence in Post-Operative Infection of Pelvic Primary Bone Tumor Resection.

Resections of primary pelvic bone tumors are frequently complicated by surgical site infections (SSIs), thereby impairing the functional prognosis of patients, especially in case of implant removal. Although prophylactic antibiotics play an essential role in preventing SSIs, there are presently no recommendations that support their appropriate use. This study aimed to assess the impact of a 24 h prophylactic protocol on the bacterial ecology, the resistance pattern, and the SSI healing rate. We hypothesized that this protocol not only limits the emergence of resistance but also results in a good cure rate with implant retention in case of SSI. A retrospective study was performed that included all patients with an SSI following a pelvic bone tumoral resection between 2005 and 2017 who received a 24 h antibiotic prophylaxis protocol. Twenty-nine patients with an SSI were included. We observed a 75.9% rate of polymicrobial infection, with a high prevalence of digestive flora microorganisms and a majority of wild-type phenotypes. We confirmed that there was no significant emergence of resistant flora. After first-line debridement, antibiotics (DA) if any implant was used, or debridement, antibiotics, and implant retention (DAIR) whenever possible, we obtained a 79.3% cure rate, with implant removal in 20% of cases. The absence of an implant was significantly associated with SSI healing. Early infection management and low resistance profiles may also have a positive effect, but this needs to be confirmed in a larger cohort. In light of this, the use of a 24 h prophylactic protocol in primary pelvic bone tumor resections is associated with a favorable infection cure rate and implant retention in case of SSI, and minimal selection of resistant microorganisms.

Survival and complications in hinged knee reconstruction prostheses after distal femoral or proximal tibial tumor resection: A retrospective study of 161 cases.

INTRODUCTION: Hinged knee megaprostheses are mainly used for reconstruction after tumor resection. They may incur complications, but this has not been assessed in the French literature, except in small series at short follow-up. We therefore conducted a large-scale nationwide multicenter retrospective study with a minimum 5 years' follow-up. The objectives were (1) to compare survival between distal femoral and proximal tibial reconstruction prostheses, and (2) to analyze complications and failure. HYPOTHESIS: Distal femoral hinged reconstruction prostheses show longer survival with fewer complications than proximal tibial prostheses. MATERIAL AND METHODS: One hundred sixty-one patients were included: 118 in the distal femoral group, and 43 in the proximal tibial group. Tumors were mostly osteosarcomas (90 cases) or chondrosarcomas (31 cases). Mean age was 37 years (range, 12-86 years). Complications were assessed on the Henderson classification. Failure was defined by prosthesis anchor exchange or amputation. RESULTS: At a mean 9 years' follow-up (range, 5-23 years), implant survival was longer in the distal femoral group: 5- and 10-year survival, 84% [95% CI, 75-89] and 70% [95% CI, 59-79] versus 74% [95% CI, 69-85] and 43% [95% CI, 23-61] (p=0.02). Revision surgery for complications mainly concerned aseptic loosening (19%, 30 cases) or deep infection (16%, 25 cases) and more often involved the proximal tibia (65% vs. 43%, 28 vs. 51 cases; OR 2.4 [95% CI, 1.2-5.1]; p=0.02). DISCUSSION: Hinged knee reconstruction prosthesis is a solution in tumoral pathology, but with a high risk of complications (loosening and infection) and a higher failure rate in the proximal tibial reconstruction prosthesis. LEVEL OF EVIDENCE: IV, case series.

Clinical and dynamometric results of hip abductor system repair by trochanteric hydroxyapatite plate with modular implant after resection of proximal femoral tumors.

INTRODUCTION: The capacity of the hydroxyapatite-coated trochanteric screwed plates used with modular hip implants to restore abductor system efficacy after proximal femoral tumor resection has never been assessed. We therefore conducted a retrospective study aiming to: (1) quantitatively evaluate abduction conservation on dynamometry according to use of digastric reinsertion, conserving continuity between the gluteus medius and vastus lateralis muscles, or not, and of standard versus small-offset; (2) assess radiographic trochanteric plate fixation; (3) assess functional scores; and (4) assess complications. HYPOTHESIS: Trochanteric reinsertion better conserves abduction strength when reinsertion is digastric. PATIENTS AND METHODS: Thirty-one patients undergoing proximal femoral tumor resection between 2006 and 2016 with reconstruction by Stanmore METS™ modular implant with trochanteric plate were included. Twenty-one had digastric fixation between the gluteus medius and vastus lateralis and 10 had simple trochanteric fixation without digastric continuity. Abduction strength was compared between sides on dynamometer. Sixteen patients had full assessment of muscle strength, by a single observer; there were 8 deaths, 5 patients lost to follow-up, and 2 cases of material removal. RESULTS: Abduction strength conservation versus the contralateral side was 55.2±23.3% (range, 5.8-86.1%): 66.6±13.0% (46.4-86.1) with versus 36.0±24.7% (5.8-63.2%) without digastric continuity (p=0.01); severe limp rate was 4/21 when digastric continuity was preserved (19%) versus 6/10 (60%) (p=0.04), and radiologic trochanteric reinsertion stability rate was 19/21 (90%) versus 4/10 (40%) (p=0.005). Standard femoral offset conserved greater abduction strength: 64.9±20.0% versus small-offset 45.4±23.2% (p=0.05). Toronto Extremity Salvage Score (TESS) was 89±9.4%, and Musculoskeletal Tumor Society (MSTS) score 75.4±5.4%. There were 6 complications (19%): 4 infections, 1 dislocation, and 1 plate removal; the single dislocation (3%) was in the digastric conservation group. TESS (90.7±7.8% vs 88.3±4) and MSTS score (75.6±4.0% vs 75.1±3.7) and complications [4/21 (19%) vs 2/10 (20%)] did not differ according to digastric or non-digastric reinsertion (p=1). CONCLUSIONS: Abduction strength with a modular implant using a hydroxyapatite-coated trochanteric plate was better conserved by digastric trochanteric reinsertion, resulting in less limping, although the complications rate and functional scores were unaffected. Longer term assessment is needed to confirm this conservation of abduction strength. LEVEL OF EVIDENCE: IV, retrospective study without control group.

Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery.

An obese woman was treated with oral tedizolid 200 mg once daily for pseudoarthrosis 10 years after Roux-en-Y bypass surgery. Total plasma peak concentration was 2.12 mg/liter 3 h after intake, and area under the concentration-time curve from 0 to 24 h (AUC0-24) was 28.3 mg/liter · h. The AUC0-24/MIC ratio for unbound concentrations and for sensitive Staphylococcus and Streptococcus strains was ≥10.8, higher than the target ratio of 3. These results support the use of tedizolid without adjustment after bariatric surgery.

The value of adding sciatic block to continuous femoral block for analgesia after total knee replacement.

BACKGROUND AND OBJECTIVES: The benefit of adding a sciatic nerve block to the femoral block to improve analgesia after total knee replacement is controversial. The aim of this study is to address this controversy in a prospective, comparative, and randomized study. METHODS: Patients were allocated randomly to receive a continuous femoral nerve block or continuous blocks of both the femoral and sciatic nerves. Stimulating catheters were used in all cases. A loading dose of 15 mL ropivacaine 0.75% was injected into each catheter, followed by administration of ropivacaine 0.2% (2-5 mL/h infusion via the femoral catheter; bolus 10 mL repeated every 12 hours in the sciatic catheter). The primary outcome was visual analog scale (VAS) scores (0 = no pain, 100 mm = worst pain) in postanesthesia care unit and in the 48-hour period after surgery. The secondary outcomes were amplitude of knee flexion, morphine consumption, and occurrence of postoperative nausea and vomiting (PONV). RESULTS: The VAS scores at rest were significantly higher when there was only continuous femoral nerve block than when there was both continuous femoral and sciatic nerve blocks. This difference progressively decreased and disappeared at 36 hours after surgery. The combined femoral and sciatic blocks decreased the morphine consumption by 81% and significantly decreased the occurrence of PONV. CONCLUSION: During the 36 hours immediately after total knee replacement, the combination of continuous femoral and sciatic nerve blocks improves analgesia while decreasing morphine consumption and PONV.