Publications by authors named "Eberhard Stoeckle"

60 Publications

Longitudinal prognostication in retroperitoneal sarcoma survivors: Development and external validation of two dynamic nomograms.

Eur J Cancer 2021 Sep 20;157:291-300. Epub 2021 Sep 20.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Purpose: The aim of this study was to create and validate dynamic nomograms to predict overall survival (OS) and disease-free survival (DFS) at different time points during follow-up in patients who had undergone resection of primary retroperitoneal sarcoma (RPS).

Methods: Patients with primary RPS operated upon between 2002 and 2017 at four and six referral centres comprised the development and external validation cohorts, respectively. Landmark analysis and multivariable Cox models were used to develop dynamic nomograms. Variables were selected using two backward procedures based on the Akaike information criterion. The prediction window was fixed at 5 years. Nomogram performances were tested in terms of calibration and discrimination on the development and validation cohorts.

Results: Development and validation cohorts totalled 1357 and 487 patients (OS analysis), and 1309 and 452 patients (DFS analysis), respectively. The final OS model included age, landmark time (T), tumour grade, completeness of resection and occurrence of local/distant recurrence. The final DFS model included T, histologic subtype, tumour size, tumour grade, multifocality and the interaction terms between T and size, grade and multifocality. For OS, Harrell C indices were higher than 0.7 in both cohorts, indicating very good discriminative capability. For DFS, Harrell C indices were between 0.64 and 0.72 in the development cohort and 0.62 and 0.68 in the validation cohort. Calibration plots showed good agreement between predicted and observed outcomes.

Conclusion: Validated nomograms are available to predict the 5-year OS and DFS probability at different time points throughout the first 5 years of follow-up in RPS survivors.
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http://dx.doi.org/10.1016/j.ejca.2021.08.008DOI Listing
September 2021

Implementing a Machine Learning Strategy to Predict Pathologic Response in Patients With Soft Tissue Sarcomas Treated With Neoadjuvant Chemotherapy.

JCO Clin Cancer Inform 2021 Sep;5:958-972

Bordeaux University, Bordeaux, France.

Purpose: Neoadjuvant chemotherapy (NAC) has been increasingly used in patients with locally advanced high-risk soft tissue sarcomas in the past decade, but definition and prognostic impact of a good histologic response (GHR) are lacking. Our aim was to investigate which histologic feature from the post-NAC surgical specimen independently correlated with metastatic relapse-free survival (MFS) in combination with clinical, radiologic, and pathologic features using a machine learning approach.

Methods: This retrospective study included 175 consecutive patients (median age: 59 years, 75 women) with resectable disease, treated with anthracycline-based NAC between 1989 and 2015 in our sarcoma reference center, and with quantitative histopathologic analysis of the surgical specimen. The outcome of interest was the MFS. A multimodel, multivariate survival analysis was used to define GHR. The added prognostic value of GHR was investigated through the comparisons with the standard model (including histologic grade, size, and depth) and SARCULATOR nomogram using concordance indices (c-index) and Monte-Carlo cross-validation.

Results: Seventy-two patients (72 of 175, 41.1%) had a metastatic relapse. Stepwise Cox regression, random survival forests, and least absolute shrinkage and selection operator-penalized Cox regression all converged toward the same definition for GHR, ie, < 5% stainable tumor cells. The five-year MFS probability was 1 (95% CI, 1 to 1) in patients with GHR versus 0.73 (95% CI, 0.65 to 0.81) in patients without GHR (log-rank = .0122). The final prognostic model incorporating the GHR was significantly better than the standard model and SARCULATOR (average c-index in testing sets = 0.72 [95% CI, 0.61 to 0.82] 0.57 [95% CI, 0.44 to 0.70] and 0.54 [95% CI, 0.45 to 0.64], respectively; = .0414 and .0091).

Conclusion: Histologic response to NAC improves the prediction of MFS in patients with soft tissue sarcoma and represents a possible end point in future studies exploring innovative regimens in the neoadjuvant setting.
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http://dx.doi.org/10.1200/CCI.21.00062DOI Listing
September 2021

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

Ann Surg Oncol 2021 Apr 27. Epub 2021 Apr 27.

Department of Surgery, Mayo Clinic, Jacksonville, FL, USA.

Background: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes.

Methods: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis.

Results: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.
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http://dx.doi.org/10.1245/s10434-021-10024-yDOI Listing
April 2021

Management of Primary Retroperitoneal Sarcoma (RPS) in the Adult: An Updated Consensus Approach from the Transatlantic Australasian RPS Working Group.

Ann Surg Oncol 2021 Apr 14. Epub 2021 Apr 14.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document.

Methods: The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation.

Results: Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies.

Conclusions: Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
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http://dx.doi.org/10.1245/s10434-021-09654-zDOI Listing
April 2021

Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

Ann Surg Oncol 2021 Oct 19;28(11):6882-6889. Epub 2021 Mar 19.

Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Background: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS.

Methods: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes.

Results: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042).

Conclusion: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.
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http://dx.doi.org/10.1245/s10434-021-09739-9DOI Listing
October 2021

Reconstruction of elbow flexion after sarcoma excision by a unipolar pedicled latissimus dorsi flap.

Acta Chir Belg 2021 Feb 3:1-21. Epub 2021 Feb 3.

Sarcoma Surgery Unit, Bergonié Institute, 229 cours de l'Argonne, 33000, Bordeaux, France.

Introduction: The latissimus dorsi flap is widely used in plastic surgery for covering the upper limb but also for reconstruction the function of the elbow or shoulder. We describe a case of a sarcoma of the anterior compartment of the arm, the surgical removal then the covering and reconstruction of the elbow flexion. This case was carried out by a unipolar pedicled flap of the latissimus dorsi.

Material And Methods: Three steps were performed (excision, flap preparation and flap fixation). The functional results (muscle strength, MRC scale) and range of motion (ROM) were analyzed. We performed a small literature review to compare the results.

Results: A complete excision (R0) was carried out with a good vitality of the latissimus dorsi flap. A rapid scarring was obtained, allowing an early start of adjuvant radiotherapy. Muscular strength was 33% less compared to preoperative, MRC scale was classified 4. ROM of the elbow were rated at -10/0/130. One year after the operation, the patient is still in remission.

Conclusion: Our functional results are comparable to those found in the literature. The muscle strength in our case appears to be superior, probably linked to a brachio-radialis muscle still functional. No difference in function has been found in the literature between a unipolar or a bipolar transfer of the latissimus dorsi. This case report confirms the reliable and effective nature of the latissimus dorsi flap. The use of this flap for reconstruction after sarcoma surgery has only few reports in the literature.
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February 2021

Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG).

Ann Surg Oncol 2021 May 2;28(5):2705-2714. Epub 2021 Jan 2.

Department of Surgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Background: This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking.

Methods: Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used.

Results: The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis.

Conclusions: A surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.
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http://dx.doi.org/10.1245/s10434-020-09445-yDOI Listing
May 2021

Has the Outcome for Patients Who Undergo Resection of Primary Retroperitoneal Sarcoma Changed Over Time? A Study of Time Trends During the Past 15 years.

Ann Surg Oncol 2021 Mar 18;28(3):1700-1709. Epub 2020 Oct 18.

Department of Surgical Oncology, Princess Margaret Cancer Centre/Mount Sinai Hospital, Toronto, Canada.

Background: This study aimed to investigate changes in treatment strategy and outcome for patients with primary retroperitoneal sarcoma (RPS) undergoing resection at referral centers during a recent period.

Methods: The study enrolled consecutive adult patients with primary non-metastatic RPS who underwent resection with curative intent between 2002 and 2017 at 10 referral centers. The patients were grouped into three periods according to date of surgery: t1 (2002-2006), t2 (2007-2011), and t3 (2012-2017). Five-year overall survival (OS), disease-specific survival (DSS), and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were calculated. Multivariable analyses for OS and DSS were performed.

Results: The study included 1942 patients. The median follow-up period after resection varied from 130 months (interquartile range [IQR], 124-141 months) in t1 to 37 months (IQR, 35-39 months) in t3. The 5-year OS was 61.2% (95% confidence interval [CI], 56.4-66.3%) in t1, 67.0% (95 CI, 63.2-71.0%) in t2, and 71.9% (95% CI, 67.7-76.1%) in t3. The rate of macroscopically incomplete resection (R2) was 7.1% in t1 versus 4.7% in t3 (p = 0.066). The median number of resected organs increased over time (p < 0.001). In the multivariable analysis resection during t3 was associated with better OS and DSS. The 90-day postoperative mortality improved over time (4.3% in t1 to 2.3% in t3; p = 0.031). The 5-year CCI of LR and DM did not change significantly over time.

Conclusions: The long-term survival of patients who underwent resection for primary RPS has increased during the past 15 years. This increased survival is attributable to better patient selection for resection, quality of surgery, and perioperative patient management.
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http://dx.doi.org/10.1245/s10434-020-09065-6DOI Listing
March 2021

Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2020 10 14;21(10):1366-1377. Epub 2020 Sep 14.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival.

Methods: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018.

Findings: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events.

Interpretation: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma.

Funding: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
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http://dx.doi.org/10.1016/S1470-2045(20)30446-0DOI Listing
October 2020

Patterns of recurrence and survival probability after second recurrence of retroperitoneal sarcoma: A study from TARPSWG.

Cancer 2020 11 14;126(22):4917-4925. Epub 2020 Aug 14.

Division of General Surgery, Mount Sinai Hospital, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR).

Methods: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence.

Results: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re-resection (61.9%). The 5-year OS rate varied significantly based on the pattern of failure (P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P < .001]). The 5-year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection.

Conclusions: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease-free survivors were identified after surgery for second LR in patients selected for this intervention.
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http://dx.doi.org/10.1002/cncr.33139DOI Listing
November 2020

Magnetic resonance imaging assessment of chemotherapy-related adipocytic maturation in myxoid/round cell liposarcomas: specificity and prognostic value.

Br J Radiol 2020 Jun 6;93(1110):20190794. Epub 2020 Mar 6.

Department of Radiology, Institut Bergonie, F-33000, Bordeaux, France.

Objective: To investigate the specificity, clinical implication and prognostic value of MRI adipocytic maturation (MAM) in myxoid/round cells liposarcomas (MRC-LPS) treated with neoadjuvant chemotherapy (NAC).

Methods: Of the 89 patients diagnosed with MRC-LPS at our sarcoma reference center between 2008 and 2018, 28 were included as they were treated with NAC, surgery and radiotherapy. All patients underwent contrast-enhanced MRIs at baseline and late evaluation. A control cohort of 13 high-grade pleomorphic and dedifferentiated LPS with same inclusion criteria was used to evaluate the specificity of MAM in MRC-LPS. Two radiologists analyzed the occurrence of MAM, changes in the tumor architecture, shape and surrounding tissues during NAC. Pathological features of tumor samples were reviewed and correlated with MRI. Metastatic relapse-free survival was estimated with Kaplan-Meier curves and Cox models. Associations between prognostic T1-based delta-radiomics features and MAM were investigated with Student -test.

Results: MAM was more frequent in MRC-LPS ( = 0.045) and not specific of any type of chemotherapy ( = 0.7). Regarding MRC-LPS, 14 out of 28 patients (50%) demonstrated MAM. Eight patients showed metastatic relapses. MAM was not associated with metastatic relapse-free survival ( = 0.9). MAM correlated strongly with the percentage of histological adipocytic differentiation on surgical specimen ( < 0.001), which still expressed the tumor marker NY-ESO-1. None of the prognostic T1-based delta-radiomics features was associated with MAM.

Conclusion: MAM seems a neutral event during NAC.

Advances In Knowledge: MAM predominated in MRC-LPS and was not specific of a type of chemotherapy. Occurrence of MAM was not associated with better patients' metastasis free survival.
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http://dx.doi.org/10.1259/bjr.20190794DOI Listing
June 2020

Can radiomics improve the prediction of metastatic relapse of myxoid/round cell liposarcomas?

Eur Radiol 2020 May 17;30(5):2413-2424. Epub 2020 Jan 17.

Department of Radiology, Institut Bergonie, F-33000, Bordeaux, France.

Objective: The strongest adverse prognostic factor in myxoid/round cell liposarcomas (MRC-LPS) is the presence of a round cell component above 5% within the tumor bulk. Its identification is underestimated on biopsies and in the neoadjuvant setting. The aim was to improve the prediction of patients' prognosis through a radiomics approach.

Methods: Thirty-five out of 89 patients with MRC-LPS managed at our sarcoma reference center from 2008 to 2017 were included in this IRB-approved retrospective study as they presented with a pre-treatment contrast-enhanced MRI (median age, 49 years old). Two radiologists reported usual conventional/semantic radiological variables. After signal intensity (SI) normalization, voxel size standardization of T2-WI, and whole tumor volume segmentation, 44 3D-radiomics features were extracted. Using least absolute shrinkage and selection operator penalized Cox regression on prefiltered features, a radiomics score based on 3 weighted radiomics features was generated. Four prognostic multivariate models for MRFS were compared using concordance index: (1) clinical model, (2) semantic radiological model, (3) radiomics model, and (4) radiomics + semantic radiological model.

Results: Twelve patients showed a metastatic relapse. The radiomics score included FOS_Skewness, GLRLM_LRHGE, and SHAPE_Volume and correlated with MRFS (hazard ratio = 19.37, p = 0.0009) and visual heterogeneity on T2-WI (p < 0.0001). A high score indicated a poorer prognosis. After adjustment, the best predictive performances were obtained with model (4) (concordance index = 0.937) and the lowest with model (1) (concordance index = 0.637).

Conclusion: Adding selected radiomics features that quantify tumor heterogeneity and shape at baseline to a conventional radiological analysis improves prediction of MRC-LPS patients' prognosis.

Key Points: • Fourteen radiomics features quantifying shape and heterogeneity of myxoid/round cell liposarcomas on T2-WI were associated with metastatic relapse in univariate analysis. • A radiomics score based on 3 selected and weighted radiomics features was a strong and independent prognostic factor for metastatic relapse-free survival. • The best prediction of metastatic relapse-free survival for myxoid/round cell liposarcomas was achieved by combining the radiomics score to relevant radiological features.
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http://dx.doi.org/10.1007/s00330-019-06562-5DOI Listing
May 2020

The Nanocind Signature Is an Independent Prognosticator of Recurrence and Death in Uterine Leiomyosarcomas.

Clin Cancer Res 2020 02 3;26(4):855-861. Epub 2019 Dec 3.

Oncosarc, INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.

Purpose: Uterine leiomyosarcoma, which accounts for 7% of all soft-tissue sarcomas and 1%-3% of all uterine malignancies, is an aggressive tumor responsible for a significant proportion of uterine cancer-related deaths. While Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage is the most important prognostic factor, metastatic and relapse rates at stage I exceed 50% so it is currently impossible to predict the clinical outcome of stage I leiomyosarcomas. In 2010, our team published a transcriptomic signature composed of 67 genes related to chromosome biogenesis, mitosis control, and chromosome segregation. It has demonstrated its prognostic value in many cancer types and was recently successfully applied to formalin-fixed, paraffin-embedded sarcomas by NanoCind on NanoString technology, making another step forward toward its use in routine practice.

Experimental Design: Sixty uterine leiomyosarcomas at any stage, including 40 localized in the uterus (stage I), were analyzed with the NanoCind (CINSARC with NanoString) signature. Its prognostic value was evaluated for overall survival and relapse-free survival and compared in multivariate analysis with other prognostic markers like FIGO staging and genomic index.

Results: The NanoCind signature was able to split the heterogeneous group of uterine leiomyosarcomas of any stage including stage I into two distinct groups with different relapse-free survival and overall survival. These results were validated on an independent cohort of uterine leiomyosarcomas in The Cancer Genome Atlas consortium.

Conclusions: The NanoCind signature is a powerful prognosticator that outperforms FIGO staging and the genomic index. The CINSARC signature is platform independent and "ready to use" and should now be used for randomization in future therapeutic trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2891DOI Listing
February 2020

Quality of surgery and surgical reporting for patients with primary gastrointestinal stromal tumours participating in the EORTC STBSG 62024 adjuvant imatinib study.

Eur J Cancer 2019 10 31;120:47-53. Epub 2019 Aug 31.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

Background: EORTC (European Organisation of Research and Treatment of Cancer) 62024 is a phase III randomised trial evaluating adjuvant imatinib in patients with gastrointestinal stromal tumours (GISTs) and no evidence of residual disease after surgery in 908 patients from 11 countries participated. As surgical treatment aspects (tumour rupture and incomplete resection) contribute to the risk of recurrence, the data of primary surgery were reviewed.

Methods: The surgical record, local pathology report and a surgical questionnaire on details of the operation had to be completed when patients entered the study. Surgeons from 5 countries, covering 8 languages, reviewed the full set of data being available from 793 patients (87.3%).

Results: A known GIST was the reason for surgery in only 58% of the cases, and 12% of the patients were treated as an emergency. The R0-resection rate was 87%. The extent of resection was local excision in 17%, segmental resection in 59%, full-organ resection in 11% and multivisceral resection in 11%, with lymphadenectomy performed in 24% of the patients. Shelling out of the tumour was performed in 9.7%, and the proportion of tumours removed in parts was higher in the endoscopy/laparoscopy group. The incidence of tumour rupture (representing M1) was 9%. The consistency between preoperative and intraoperative findings was 82%. The postoperative complication rate was 7.3%.

Conclusion: The standardisation of surgery in this study was inferior. Given the review data, 18% of the patients should not have participated in the trial. Quality of surgery and improperly reported intraoperative details might influence the trial results. A detailed surgical questionnaire filled out by the surgeon is mandatory before entering the patient in an adjuvant trial in GIST.
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http://dx.doi.org/10.1016/j.ejca.2019.07.028DOI Listing
October 2019

Watch and Wait Approach for Re-excision After Unplanned Yet Macroscopically Complete Excision of Extremity and Superficial Truncal Soft Tissue Sarcoma is Safe and Does Not Affect Metastatic Risk or Amputation Rate.

Ann Surg Oncol 2019 Oct 23;26(11):3526-3534. Epub 2019 Jul 23.

Department of Medical Oncology and Surgery, Gustave Roussy Institute, Villejuif, France.

Background: The benefits of systematic re-excision (RE) after initial unplanned excision (UE) of soft tissue sarcoma (STS) are unknown.

Objective: The aim of this study was to evaluate the impact of delayed RE versus systematic RE after UE on overall survival (OS), metastatic relapse-free survival (MRFS), local relapse-free survival (LRFS), and rate of amputation.

Methods: Patients who underwent complete UE, without metastasis or residual disease, for primary extremity or superficial STS between 2007 and 2013 were analyzed. The amputation rate, LRFS, MRFS, and OS were assessed in cases of systematic RE in sarcoma referral centers (Group A), systematic RE outside of community centers (Group B), or without RE (Group C).

Results: Groups A, B, and C included 300 (48.2%), 71 (11.4%), and 251 (40.4%) patients, respectively. Median follow-up was 61 months and 5-year OS was 88.4%, 87.3%, and 88% in Groups A, B, and C, respectively (p = 0.22), while 5-year MFRS was 85.4%, 86.2%, and 84.9%, respectively (p = 0.938); RE (p = 0.55) did not influence MRFS. The 5-year LRFS was 83%, 73.5%, and 63.8% in Groups A, B and C, respectively (p = 0.00001). Of the 123 local recurrences observed, 0/28, 1/15, and 5/80 patients in Groups A, B, and C, respectively, required amputation (p = 0.41). Factors influencing LRFS were adjuvant radiotherapy [hazard ratio (HR) 0.21; p = 0.0001], initial R0 resection (HR 0.24, p = 0.0001), and Group A (HR 0.44; p = 0.01).

Conclusion: Systematic RE in sarcoma centers offers best local control but does not impact OS. Delayed RE at the time of local relapse, if any, could be an option.
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http://dx.doi.org/10.1245/s10434-019-07494-6DOI Listing
October 2019

Local and Metastatic Relapse Features in Patients After a Primary Soft Tissue Sarcoma: Advocating for a Better-Tailored Follow-Up.

Front Oncol 2019 2;9:559. Epub 2019 Jul 2.

Department of Medical Oncology, Institut Bergonié, Bordeaux, France.

No consensus exists on how to follow patients after complete remission of a primary Soft Tissue Sarcoma (STS). Studying relapse features could help tailor guidelines for follow-up. Patients in complete remission after initial management of a localized STS at Institut Bergonié who presented a first local and/or metastatic relapse between January 1995 and July 2015 were eligible. Characteristics of relapse diagnosis were retrospectively collected. 359 patients met inclusion criteria. 197 and 187 patients presented a local relapse and a metastatic relapse, respectively. In group 1 (limbs/trunk wall) and 2 (trunk/gynecological/other location), local relapse was diagnosed on clinical symptoms in 89 and 44% of cases, first detected by the patient himself in 68.5 and 34% of cases, and outside a planned visit in 67 and 36% of cases, respectively. In patients with metastatic relapse, diagnosis was made during a planned visit in 63% of cases, and by imaging in 62% of cases. Median survival after relapse was not different whether the first local relapse was diagnosed clinically or by imaging (44 [95%CI: 28-69.8] vs. 57 months [95%CI: 33.9-84.5], = 0.35) but was longer if diagnosis of metastatic relapse was made on planned chest-CT scan rather than chest X-ray (58 [95%CI: 35.5-103.9] vs. 25 months [95%CI: 16.5-32.6], < 0.05). Patient's education for regular clinical examination can be recommended for follow-up of local relapses after a primary STS of the limbs or superficial trunk. Modeling studies aiming at better understanding and predicting tumor biology to improve tailoring STS patients' follow-up are warranted.
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http://dx.doi.org/10.3389/fonc.2019.00559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614176PMC
July 2019

Abnormal vascularization of soft-tissue sarcomas on conventional MRI: Diagnostic and prognostic values.

Eur J Radiol 2019 Aug 11;117:112-119. Epub 2019 Jun 11.

Department of Radiology, Institut Bergonié, Comprehensive Cancer Center, F-33076, Bordeaux, France; University of Bordeaux, F-33000, Bordeaux, France; INSERM U1218, Action, Institut Bergonié, Bordeaux, France. Electronic address:

Purpose: To assess the prevalence of abnormal vessels inside and surrounding soft-tissue sarcomas (STS) on conventional MRIs so as to evaluate their correlations with particular histotypes, histological grades, and prognosis.

Method: This single-center retrospective study included 157 adult patients (median age: 61) with histologically-proven non-metastatic STS. All had pre-treatment conventional contrast-enhanced MRI. Two radiologists reported: presence of abnormal flow-voids, number and distribution (peri-tumoral and/or intra-tumoral), percentage of tumor circumference it covered, maximal diameter. The radiological findings were correlated with histopathology. Associations were evaluated with Chi-2 or t-tests. Survival analysis (for metastasis-free survival (MFS) and overall survival (OS)) included log-rank tests and multivariate Cox-model.

Results: Twenty-nine of 157 (18.5%) STS showed abnormal flow-voids that were peri-tumoral (9/157, 5.7%), intra-tumoral (5/157, 3.2%) or both intra- and peri-tumoral (15/157, 9.6%). Ten STS had more than 5 flow-voids, all being grade II-III, namely: 4 undifferentiated sarcomas, 2 solitary fibrous tumors, 1 alveolar soft-part sarcoma (ASPS), 2 leiomyosarcomas and 1 pleomorphic liposarcoma. The distribution of flow-voids was associated with survivals in the univariate analysis: patients with abnormal peritumoral flow-voids (APTFV) showed poorer OS and MFS (p = 0.039 and 0.014, respectively). These associations did not remain significant in multivariate analysis. Radio-pathological correlations revealed large tortuous tumoral neo-vessels with intra-vascular thrombi of tumor cells in ASPS and in one case of undifferentiated sarcoma displaying enrichment in genes involved in neo-angiogenesis at transcriptional level.

Conclusions: APTFV on conventional MRIs may be associated with a higher risk of metastatic relapse and poorer OS in STS patients.
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http://dx.doi.org/10.1016/j.ejrad.2019.06.007DOI Listing
August 2019

Soft-Tissue Sarcomas: Assessment of MRI Features Correlating with Histologic Grade and Patient Outcome.

Radiology 2019 06 9;291(3):710-721. Epub 2019 Apr 9.

From the Departments of Diagnostic and Interventional Radiology (A.C., P.J.M., X.B., M.K.), Oncologic Surgery (E.S.), Clinical Epidemiology Research (V.B.), Medical Oncology (A.I.), and Pathology (F.L.L.), Bergonié Institute, Regional Comprehensive Cancer Center, Bordeaux, France; National Institute for Research in Digital Sciences (INRIA) Bordeaux-Sud-Ouest, Modeling in Oncology Team, National Center for Scientific Research (CNRS) Multidisciplinary Research Unit 5251, Talence, France (A.C.); and University of Bordeaux, Bordeaux, France (A.C., A.I., F.L.L.).

Background Managing soft-tissue sarcoma (STS) relies on histologic grade, which is the strongest prognostic factor and a routine assessment at biopsy. However, underestimation of histologic grade may occur because of tumor heterogeneity. Purpose To identify MRI features that are associated with high-grade STS (grade III) and to determine the relationship between MRI features and patient survival. Materials and Methods In this retrospective single-center study, patients (age ≥16 years) were included if they presented with STS diagnosed between 2008 and 2015, had a baseline contrast material-enhanced MRI study, had a pathologic grade assessed on the whole surgical specimen, and had no history of neoadjuvant treatment. Visceral sarcomas, well-differentiated liposarcomas, and angiosarcomas were excluded. Images were evaluated for size, heterogeneity, architecture, margins, and surrounding tissue at T2-weighted, T1-weighted precontrast, and T1-weighted postcontrast MRI. χ tests, Fisher tests, and multivariable binary logistic regression were performed to identify features associated with a final grade of III. The associations between combinations of these features and overall survival and metastasis-free survival were investigated with Kaplan-Meier curves and multivariable Cox models. Results A total of 130 patients were included (53 women [mean age ± standard deviation, 60.7 years ± 19.2]); 72 of the 130 (55.4%) STSs were grade III. At multivariable analysis, three MRI features were associated with grade III STS: peritumoral enhancement (odds ratio [OR], 3.4; = .003), presence of an area compatible with necrosis (OR, 2.4; = .03), and heterogeneous signal intensities greater than or equal to 50% at T2-weighted imaging (OR, 2.3; = .04). The presence of at least two of these three features was an independent predictor of metastasis-free survival (hazard ratio, 4.5; = .01) and overall survival (hazard ratio, 4.2; = .04). Conclusion MRI features including necrosis, heterogeneity, and peritumoral enhancement of soft-tissue sarcomas were associated with grade III tumors, metastasis-free survival, and overall survival. © RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019181659DOI Listing
June 2019

Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG.

Clin Cancer Res 2019 04 5;25(8):2664-2671. Epub 2019 Feb 5.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: The role of surgery for first relapse locally recurrent retroperitoneal sarcoma (RPS-LR1) is uncertain. We report outcomes of the largest RPS-LR1 series and propose a new prognostic nomogram.

Experimental Design: Patients with consecutive RPS-LR1 without distant metastases who underwent resection at 22 centers (2002-2011) were included. Endpoints were disease-free and overall survival (DFS, OS) and crude-cumulative-incidence (CCI) of local/distant recurrence from second surgery. Nomograms predicting DFS and OS from second surgery were developed and validated (calibration plots); discrimination was assessed (Harrell C index).

Results: Of 684 patients identified, full prognostic variable data were available for 602. Initial surgery for primary RPS was performed at our institutions in 188 patients (31%) and elsewhere in 414 (69%). At a median follow-up of 119 months [Interquartile range (IQR), 80-169] from initial surgery and 75 months (IQR 50-105) from second surgery, 6-year DFS and OS were 19.2% [95% confidence interval (CI), 16.0-23.0%] and 54.1% (95% CI, 49.8-58.8%), respectively. Recurrence patterns and survival probability were histology-specific, with liposarcoma subtypes having the highest 6-year CCI of second local recurrence (LR, 60.2%-70.9%) and leiomyosarcoma (LMS) having higher 6-year CCI of distant metastasis (DM, 36.3%). Nomograms included age at second surgery, multifocality, grade, completeness of second surgery, histology, chemotherapy/radiotherapy at first surgery, and number of organs resected at first surgery. OS and DFS nomograms showed good calibration and discriminative ability (C index 0.70 and 0.67, respectively).

Conclusions: We developed nomograms to predict DFS and OS for patients undergoing RPS-LR1 resection. Nomograms provide individualized, disease-relevant estimations of survival for RPS-LR1 patients and assist in clinical decisions.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2700DOI Listing
April 2019

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

J Surg Oncol 2019 Mar 4;119(4):479-488. Epub 2019 Jan 4.

Faculté de Médecine de la Timone, Génétique Médicale et génomique fonctionnelle, UMR S910 Inserm, Université Aix-Marseille 2, Marseille, France.

Background And Objectives: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS).

Methods: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included. Demographics, tumor type, treatment modalities, and latest follow-up status were collected. Primary endpoints were overall survival and local/metastatic recurrence incidences.

Results: Two hundred five DESTS and 3001 OLSTS were included. The patients were younger, with more female and smaller tumors in DESTS. There were more clear cell/epithelioid sarcomas, synovial sarcomas, and myxoid liposarcomas vs more dedifferentiated liposarcomas in OLSTS. DESTS tumors were less irradiated and more often amputated (24.3% vs 3.4%). The five-year survival rate was 78.2% compared to 68.6% in OLSTS and after multivariate analysis, STS localization did not impact survival or local/metastatic recurrence.

Conclusion: Though rare and smaller than other limb localizations, DESTS are to be considered as aggressive. Despite a higher amputation rate, the prognosis remains the same as in OLSTS. Limb sparing vs amputation should be carefully assessed in DESTS, especially if grade 3 or of a poor prognosis histological subtype.
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http://dx.doi.org/10.1002/jso.25359DOI Listing
March 2019

MRI assessment of surrounding tissues in soft-tissue sarcoma during neoadjuvant chemotherapy can help predicting response and prognosis.

Eur J Radiol 2018 Dec 5;109:178-187. Epub 2018 Nov 5.

Department of Radiology, Institut Bergonie, F-33000, Bordeaux, France.

Objectives: To determine if changes in surrounding tissues of soft-tissue sarcomas (STS) evaluated by MRI during neoadjuvant chemotherapy (NAC) are associated with the histological response and satellite tumorous cells beyond the pseudocapsule on surgical specimen, disease-free survival (DFS) and overall survival (OS).

Methods: Fifty-seven adult patients with locally advanced high-grade STS of extremities and trunk wall were included in this single-centre retrospective study. All were uniformly treated by 5-6 cycles of anthracycline-based NAC, curative surgery and adjuvant radiotherapy and had available MRI with a gadolinium-chelates administration at baseline and after 2 cycles. Thirty-seven patients also had a pre-operative MRI. Two senior radiologists evaluated MRI growth pattern, oedema, contrast-enhanced oedema, aponeurotic enhancement, and their qualitative changes during NAC. An expert pathologist reviewed all surgical specimens. A good histological response was defined as <10% viable cells. Associations with pathological findings were estimated with Fisher and Chi-square tests and multivariate analysis with binary logistic regression. Survival analyses included log-rank tests.

Results: Forty-two patients had poor responses and 25 had satellite tumorous cells on surgical specimen. Changes in surrounding oedema and in contrast-enhanced oedema were associated with responses (p = 0.008 and 0.011, respectively). Diffuse infiltrative growth pattern (IGP) on baseline MRI, changes in margin definition and in contrast-enhanced oedema at early evaluation were associated with satellite tumorous cells (p = 0.039, 0.011 and 0.009, respectively). Diffuse IGP on baseline MRI and stable or increased oedema during treatment were predictors of DFS (p = 0.009 and 0.040, respectively).

Conclusion: Surrounding tissues of STS during NAC should be carefully evaluated as they may steer treatment efficacy and patient prognosis.
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http://dx.doi.org/10.1016/j.ejrad.2018.11.004DOI Listing
December 2018

Localized Myxofibrosarcomas: Roles of Surgical Margins and Adjuvant Radiation Therapy.

Int J Radiat Oncol Biol Phys 2018 10 2;102(2):399-406. Epub 2018 Jun 2.

Department of Surgery, Curie Institute, Paris, France.

Purpose: The objective of this study was to describe the outcome and prognostic factors for adults treated for localized myxofibrosarcoma.

Methods And Materials: We conducted a retrospective multicenter study of 425 nonmetastatic patients who underwent surgery between January 1996 and December 2015 in French National Group and were enrolled in the Conticabase. Pathologic diagnosis was systematically reviewed by expert pathologists. The endpoints were relapse-free and metastasis-free survival. Log-rank tests and Cox models have been used to identified prognostic factors.

Results: Median age was 66 years; 53% were males; 85% of cases occurred in limbs or superficial trunk; median size was 60 mm; 47% and 39% were grades 2 and 3, respectively; 66% had R0 resection and 34% R1 resection. Adjuvant radiation therapy was given to 65% of patients, neoadjuvant radiation therapy to 3%, neoadjuvant chemotherapy to 7%, and adjuvant chemotherapy to 13%. The median follow-up was 51 months. The 5-year local relapse-free survival was 67%; independent prognostic factors for local relapse were R1 resection (hazard ratio [HR] = 1.26; P = .001) and adjuvant radiation therapy (HR = 0.35; P = .0001) (ie, R1 resection and no adjuvant radiation therapy increase the hazard ratio). In stratified analysis, adjuvant radiation therapy was beneficial after R0 resection (P = .0020) and after R1 resection (P = .0001). The 5-year overall survival was 80%. The 5-year metastasis-free survival was 83%. Independent prognostic factors for metastatic relapse were grade 3 disease (HR = 1.975; P = .0001) and tumor size (HR = 1.006; P = .001).

Conclusions: This large series of myxofibrosarcoma confirms the high rate of local relapse. Combination of R0 resection and adjuvant radiation therapy provided the best local control. In parallel with an increasing rate of R0 resection and adjuvant radiation therapy, we observed a constant improvement in both metastatic and local relapse-free survival during the study.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.055DOI Listing
October 2018

Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors.

Mod Pathol 2018 05 12;31(5):816-828. Epub 2018 Jan 12.

Department of Biopathology, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France.

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.
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http://dx.doi.org/10.1038/modpathol.2017.185DOI Listing
May 2018

Clinical activity of eribulin in advanced desmoplastic small round-cell tumor.

Anticancer Drugs 2017 10;28(9):1053-1055

Departments of aMedical Oncology bRadiology cPathology dSurgery, Institut Bergonie, Bordeaux, France.

Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy - that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them.
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http://dx.doi.org/10.1097/CAD.0000000000000536DOI Listing
October 2017

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BMC Med 2017 Apr 10;15(1):78. Epub 2017 Apr 10.

Department of Medicine, Institut Bergonié, Bordeaux, France.

Background: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.

Methods: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.

Results: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.

Conclusions: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.
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http://dx.doi.org/10.1186/s12916-017-0831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385590PMC
April 2017

First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas.

Clin Cancer Res 2017 Feb 6;23(4):908-917. Epub 2016 Oct 6.

Gustave Roussy Cancer Campus, Villejuif, France.

This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS). Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion. Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible. A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1297DOI Listing
February 2017

Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group.

Radiother Oncol 2016 07 17;120(1):156-62. Epub 2016 May 17.

Department of Radiation Oncology, Institut Bergonié, Bordeaux, France.

Purpose: The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS).

Methods And Materials: Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model.

Results: The median TI was 82days (range, 18-346). With a median follow-up of 235months (range, 2-296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19-39days, 40-79days, 80-119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% (p=0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% (p=0.347), respectively. After adjustment for the factors significantly (p⩽0.05) associated with LRFS and OS, TI did not alter LRFS (p=0.182) either OS (p=0.335).

Conclusions: In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes.
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http://dx.doi.org/10.1016/j.radonc.2016.04.037DOI Listing
July 2016

Are Early Relapses in Advanced-Stage Ovarian Cancer Doomed to a Poor Prognosis?

PLoS One 2016 28;11(1):e0147787. Epub 2016 Jan 28.

Stem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.

Objective: Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients.

Study Design: We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis.

Results: The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5).

Conclusion: ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147787PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731146PMC
July 2016

[A critical assessment of morcellation in case of uterine malignancies and its impact on gynecologic surgery: From "precautionary principle" to "realism"].

Bull Cancer 2016 Jan 3;103(1):96-103. Epub 2015 Dec 3.

Centre regional de lutte contre le cancer Bordeaux-Aquitaine, institut Bergonié, département de chirurgie oncogynécologique, 229, cours de l'Argonne, 33076 Bordeaux cedex, France.

Minimally invasive surgery has demonstrated benefits that include improved pain control, decreased infection risk, and faster surgical recovery and return to work. Morcellation is an integral part of making laparoscopic surgery possible for the removal of large uterine leiomyomata, and the development of power morcellation has increased efficiency during these procedures. Morcellation may expose patients to increased morbidity in certain circumstances. This is particularly true in cases of unrecognized malignancy, where intra-abdominal dissemination of cancer may worsen the prognosis (overall survival and disease free survival). A critical review of published data supports that tissue morcellation can be performed safely in screened and selected patients.
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http://dx.doi.org/10.1016/j.bulcan.2015.10.013DOI Listing
January 2016
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