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.

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.

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.

Case Report: CD8+ T-Lymphocyte Deficit: A Prerequisite for Pasteurella spp. Infection?

Background: Immunity against Pasteurella spp. is not well-known for humans. Methods: We've tested T CD8+ lymphocytes in a patient with a chronic prosthetic joint infection due to Pasteurella spp. to search for a deficit which could have favored her infection. As this deficit was found, we've searched for such a deficit in other patients with Pasteurella spp. Infections, either acute or subacute. Results: Eight patients were tested and all had a persistent T CD8+ lymphocytes deficit. This is striking as these cells are involved in the response to this type of infection in animal models. Conclusion: The authors suggest that a deficit in CD8+ T lymphocytes can be one of the causes for the onset of infections with P. multocida.

Assessment of resection margins in bone sarcoma treated by neoadjuvant chemotherapy: Literature review and guidelines of the bone group (GROUPOS) of the French sarcoma group and bone tumor study group (GSF-GETO/RESOS).

BACKGROUND: Standardized reports are essential to meeting the bone sarcoma reference center certification requirements of the French National Cancer Institute (INCa). The usual classifications of the Musculoskeletal Tumor Society (MSTS), the American Joint Committee on Cancer (AJCC/IUCC) TNM R classification and the American College of Pathologists, are inexact inasmuch as they fail to include chemotherapy impact on tumor cells in assessing surgical margins. This leads to inconsistent interpretation by teams managing bone sarcoma. The present literature analysis sought to assess the limitations of existing classifications for purposes of standardized reporting of the management of surgical specimens from patients with osteosarcoma or Ewing sarcoma receiving neoadjuvant chemotherapy, by addressing the following questions: 1) What is the prognostic value of margins and chemotherapy response in the classifications? 2) What are the histologic changes induced by chemotherapy, with what impact on interpretation of margins? METHOD: A PubMed literature analysis was performed, targeting the prognostic value of resection margin assessment, in September 2018. French bone pathology group (Groupe français des pathologistes osseux) and international guidelines on bone specimen management were referred to so as select items for a standardized report. Eight of the 523 articles retrieved met the study eligibility criteria. RESULTS: Minimal distance between tumor and surgical margin, with a>2mm threshold, seemed to be the optimal parameter for predicting local recurrence. Good chemotherapy response and appendicular skeletal location were associated with lower risk of local recurrence. None of the available classifications take into account the microscopic changes induced by chemotherapy in interpreting resection margins. DISCUSSION: To standardize practice, GROUPOS developed a standardized report for bone sarcoma specimens, considering the histopathologic changes in the tumor after neoadjuvant chemotherapy. The TNM R system was adapted and a threshold of>2mm was chosen as an acceptable limit to qualify surgical resection as safe (R0). R1 status (≤2mm) was subdivided into subgroups a, b and c, to include margin measurement in relation to the post-chemotherapy scar: R1a, resection within the scar; R1b, resection in healthy tissue,≤2mm from the scar and/or residual viable cells; and R1c, resection within the lesion in contact with viable cells or within coagulation necrosis areas. The GROUPOS members drew up this standardized report so as to ensure a common language, improving bone sarcoma management in specialized centers. Reliable data can thus be established for national and international multicenter studies. LEVEL OF EVIDENCE: IV.

Total femur replacement in non-oncologic indications: Functional and radiological outcomes from a French survey with a mean 6 years' follow-up.

INTRODUCTION: There are few published studies on total femur replacement (TFR) because its indications are rare. Other than malignant diseases, the indications extend to revisions and interprosthetic femur fractures; however, the outcomes of these indications have not been well defined. The aim of this retrospective survey was to analyze the complication rate and functional outcomes of these newer indications. HYPOTHESIS: The morbidity and outcomes after TFR are comparable to those reported in the literature for non-cancer indications. MATERIAL AND METHODS: Between 1997 and 2016, 29 TFR procedures were done at 6 French teaching hospitals in 15 women and 14 men, average age 68±14 years [32-85]. The primary indication was degenerative joint disease in the hip and/or knee in 16 cases, mechanical failure of the implant used after tumor resection in 11 cases and femur fracture in 2 cases. The mean number of surgical procedures before TFR was 3.6 (maximum 5) at the hip and 4.5 (maximum 10) at the knee. Six different models were implanted consisting of a rotational hinge knee (except in one case); 20 patients received a dual mobility system and 9 a standard hip replacement bearing. The femoral shaft was partially conserved 21/29 times and the trochanter 25/29 times. RESULTS: Five patients suffered a general complication and 12 suffered a local complication (including 4 hematomas and 2 hip dislocations). Eight patients (28.6%) suffered a surgical site infection, although three had a prior infection. Among the 12 patients with a history of infection or progressive infection before the TFR, 9 healed and 3 had the infection continue. At a minimum follow-up of 2 years and mean of 6 years, 23 TFR implants were still in place and not infected; the other 6 had been removed or were infected, including one patient who underwent disarticulation. The median survival of the non-infected TFR was 15 years. At 10 years, 70% of TFR implants were still in place and non-infected. Walking was possible with or without a cane in 15 patients (51.7%), with two canes or a walker in 12 patients (41.3%) and impossible in 2 patients. Active knee flexion averaged 79.4°±30.3° [0°-120°]; 17 patients (62.9%) had 90° or more flexion; two patients (7.4%) had no flexion. The extension deficit averaged 3.7°±7°[-20° to 10°] and 20 patients had no flexion deformity. The leg length difference averaged 1.3cm±2.3 [0-10]; 19 patients (67.8%) had no difference in leg length. DISCUSSION: Our starting hypothesis was confirmed for the complication rate and clinical outcomes. The benefits of dual mobility cups are emphasized. While the indications for TFR are rare, they will likely increase in the coming years. LEVEL OF EVIDENCE: IV, Retrospective cohort study….

Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.

Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.

Intra-articular Gentamicin-loaded PLA Microparticle Injection for the Treatment of Septic Arthritis in Rabbits.

BACKGROUND: Because local delivery of drugs induces high concentrations, it could be helpful to apply these delivery systems to the treatment of septic arthritis by antibiotics. Thus, a gentamicin-loaded polymer was tested in a rabbit model of Staphylococcus aureus septic arthritis. METHODS: Thirty New Zealand rabbits were split into five groups: A: infection only; B: infection and systemic gentamicin treatment; C: infection and unloaded polymer and systemic gentamicin treatment; D: infection and gentamicin-loaded polymer only; and E: no infection and unloaded polymer. After inducing nonlethal septic arthritis in the knee joint by injecting 10 colony-forming units (CFUs) of a strain of methicillin-sensitive S aureus in groups A, B, C, and D, rabbits were housed for 15 days, and then the joint capsules were removed and the remaining bacteria were counted. Bacterial load was expressed in CFUs per gram of synovial tissue. In group E, capsules were removed, and a pathologic examination was done. RESULTS: At day 15, the bacterial load was 6 × 10, 2 × 10, 1.8 × 10, and 7 × 10 CFU/g of tissue for groups A, B, C, and D, respectively. Compared with the mean of groups A, B, and C, the bacterial load of group D was 4.94 units of log10 CFU/g lower than that of these groups. The bacterial load of group D was statistically significantly lower than that of the other three groups. Noticeably, two animals of group D had a nil bacterial count. In group E animals, a minimal foreign body reaction was observed around the polymer. DISCUSSION: Gentamicin-containing microparticles were more efficient in reducing bacterial load than systemic injections of gentamicin and thus have an interesting role to play in the treatment of human arthritis. However, inserting microparticles in joints is not easy, and hydrogels might be a good alternative approach.

Antibiotic-loaded Porous Alumina Ceramic for One-stage Surgery for Chronic Osteomyelitis.

The classic treatment of chronic osteomyelitis is usually a two-stage surgery combined with systemic antibiotic therapy for several months. We report the case of a patient presenting a chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus who was treated with a one-stage surgery using an antibiotic-loaded ceramic. We used a porous alumina ceramic loaded with gentamicin to reconstruct the bone removed during débridement and to avoid its colonization. All bacteriological samples performed before and during the surgery revealed the presence of a methicillin-resistant S aureus. Because of the local release of the antibiotic, very high concentrations (more than 50 times the concentration needed) were administered in the surgical wound, thus helping to cure the infection. Owing to the strength of the ceramic, the patient was allowed to walk 10 days after the surgery. After a follow-up at 14 months, the patient is well-being, without any relapse of the infection. The CT-scan follow-up shows an osseointegration of the ceramic. Even, if it is too early to tell that infection is completely cured, these first results are encouraging for the use, in the future, of this antibiotic-loaded ceramic for complex bone infection.

Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone.

BACKGROUND: Giant cell tumours (GCT) of bone are benign neoplasms associated with a high rate of local recurrence after extensive intra-lesional curettage. Recently, understanding of the biological molecular availability of strong anti-osteoclastic drugs has suggested their potential value in reducing local recurrences after curettage. Through a phase II clinical trial, we investigated the effect of a short treatment with zoledronic acid (ZOL) after intra-lesional curettage of GCT, as well as local recurrence and tolerance of the treatment. METHODS AND PATIENTS: Twenty-four patients were enrolled in a multicentre, phase 2 study. The patients were treated with extensive intra-lesional curettage followed by five courses of ZOL (4 mg IV every 3 weeks). The clinical and biological tolerance of each patient was assessed. Patients were reviewed clinically and by X-ray every 6 months until the end of the study (36 months). RESULTS: Eighteen out of 20 patients reported side-effects with ZOL, mainly grade 1 and 2 effects. The local recurrence rate was 15%; three patients had a recurrence, one at 4 months (huge GCT of the sacrum), one at 24 months (patient who discontinued the treatment after the first course of ZOL), and one after the observational period, at 58 months. Finally, local relapse-free survival was 82 ± 9% at 60 months. CONCLUSION: Short adjuvant treatments with ZOL after extensive intra-lesional curettage of GCT were associated with a low rate of recurrence but did not prevent local recurrence in this study. No serious general adverse effects were observed. More studies are needed to evaluate the potential benefit of medical bisphosphonate injections combined with intra-lesional curettage in the treatment of GCTB.