Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort.

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.

Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study.

PURPOSE: There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. PATIENTS AND METHODS: This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. RESULTS: Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7-40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1-negative tumour. CONCLUSION: Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02406781.

Homogeneous myxoid liposarcomas mimicking cysts on MRI: A challenging diagnosis.

OBJECTIVES: Myxoid liposarcoma (M-LPS) is the second most frequent subtype of liposarcoma. Foci of fat on MRI are strongly suggestive of this diagnosis. The aims of this study are to (i) assess the prevalence of perfectly homogeneous M-LPS-mimicking cyst and characterize their associated clinical and pathological features and to (ii) identify helpful clues to prevent misdiagnosis when encountered with a cyst-like lesion in soft tissue parts. METHODS: MR images from 32 consecutive pathologically proven M-LPS and round cell liposarcomas (RC-LPS) were retrospectively reviewed independently by two radiologists at our institution. Location, morphology, signals, lesion architecture, heterogeneity, margins and periphery were systematically assessed in each case. Medical records were checked for initial and definitive histopathological diagnosis, therapeutic managements and outcomes. Histopathological specimens of cyst-like M-LPS were reviewed for the study. RESULTS: We have identified seven perfectly homogeneous well-defined cyst mimickers (21.9%) located on the limbs, all but one being deep-seated. These tumors were significantly smaller than the conventional M-LPS (p = 0.0005). Six lesions were initially diagnosed as benign; 4 patients underwent marginal surgical resection without prior diagnosis and 2 cases were put under medical surveillance, one of which progressed towards classical RC-LPS on follow-up MRI. No specific pathological features could be identified nor were any clinical adverse outcomes recorded. CONCLUSION: "Cyst" on MRI, without pathological adjacent joint, necessitates ultrasonography with Doppler and intravenous Gadolinium agent injections as subsets of M-LPS can mimic cyst on MRI. Cyst-like M-LPS, due to their smaller size and relative favorable outcome, could have better prognosis.

Pre- and postoperative radiotherapy for extremity soft tissue sarcoma: Evaluation of inter-observer target volume contouring variability among French sarcoma group radiation oncologists.

PURPOSE: The purpose of this study was to evaluate, during a national workshop, the inter-observer variability in target volume delineation for primary extremity soft tissue sarcoma radiation therapy. METHODS AND MATERIALS: Six expert sarcoma radiation oncologists (members of French Sarcoma Group) received two extremity soft tissue sarcoma radiation therapy cases 1: one preoperative and one postoperative. They were distributed with instructions for contouring gross tumour volume or reconstructed gross tumour volume, clinical target volume and to propose a planning target volume. The preoperative radiation therapy case was a patient with a grade 1 extraskeletal myxoid chondrosarcoma of the thigh. The postoperative case was a patient with a grade 3 pleomorphic undifferentiated sarcoma of the thigh. Contour agreement analysis was performed using kappa statistics. RESULTS: For the preoperative case, contouring agreement regarding GTV, gross tumour volume GTV, clinical target volume and planning target volume were substantial (kappa between 0.68 and 0.77). In the postoperative case, the agreement was only fair for reconstructed gross tumour volume (kappa: 0.38) but moderate for clinical target volume and planning target volume (kappa: 0.42). During the workshop discussion, consensus was reached on most of the contour divergences especially clinical target volume longitudinal extension. The determination of a limited cutaneous cover was also discussed. CONCLUSION: Accurate delineation of target volume appears to be a crucial element to ensure multicenter clinical trial quality assessment, reproducibility and homogeneity in delivering RT. radiation therapy RT. Quality assessment process should be proposed in this setting. We have shown in our study that preoperative radiation therapy of extremity soft tissue sarcoma has less inter-observer contouring variability.

The risk of postoperative complications and functional impairment after multimodality treatment for limb and trunk wall soft-tissue sarcoma: Long term results from a monocentric series.

BACKGROUND AND OBJECTIVES: Conservative surgery for soft-tissue sarcoma (STS) within multimodality treatment attempts to reconcile two contradictory requirements: assuring a good oncological outcome through a wide resection and preserving the function. The aim of our study is to verify whether our conservative approach to STS met these objectives. METHODS: A retrospective database analysis was performed in adults with primary limb or trunk wall STS operated in a single center from 1989 to 2012. Predictive factors for postoperative complications and functional impairment were tested in a multivariate analysis. RESULTS: 728 patients were operated (resection R0: 68%). Neoadjuvant chemotherapy (NAC) was given to 28%, postoperative radiotherapy to 70% of patients. Median follow-up was 103 months. At five years, overall survival was 80% and local recurrences 11%. Major postoperative complications occurred in 8% and functional impairment in 13% of the patients. Independent predictive factors for postoperative complications were American Society of Anesthesiologist classes 2 and 3 (OR: 2.3, CI: 1.2-4.5 and 4.0 CI: 1.7-9.3), tumor size >80 mm (OR: 2.5, CI: 1.3-4.9), tumor site (trunk wall/lower limb, OR: 4.1, CI: 1.3-13.6) and multifocal/multicompartmental spread (OR: 2, CI: 1.1-3.6). Independent predictive factors for function impairment were postoperative complications (OR: 5.3, CI: 2.8-10.1), NAC (OR: 3.6, CI: 2.2-5.8), and bone or neurovascular involvement (OR 3.3, CI 2.0-5.3), whereas Early Rehabilitation after Surgery (ERAS) improved outcome (OR: 0.5, CI: 0.3-0.9). CONCLUSION: Postoperative complications induced functional impairment. They may be reduced by acting on comorbidity factors and careful tumor evaluation prior to surgery. Furthermore, ERAS measures improved function.

Precision of manual two-dimensional segmentations of lung and liver metastases and its impact on tumour response assessment using RECIST 1.1.

BACKGROUND: Response evaluation criteria in solid tumours (RECIST) has significant limitations in terms of variability and reproducibility, which may not be independent. The aim of the study was to evaluate the precision of manual bi-dimensional segmentation of lung, liver metastases, and to quantify the uncertainty in tumour response assessment. METHODS: A total of 520 segmentations of metastases from six livers and seven lungs were independently performed by ten physicians and ten scientists on CT images, reflecting the variability encountered in clinical practice. Operators manually contoured the tumours, firstly independently according to the RECIST and secondly on a preselected slice. Diameters and areas were extracted from the segmentations. Mean standard deviations were used to build regression models and 95% confidence intervals (95% CI) were calculated for each tumour size and for limits of progressive disease (PD) and partial response (PR) derived from RECIST 1.1. RESULTS: Thirteen aberrant segmentations (2.5%) were observed without significant differences between the physicians and scientists; only the mean area of liver tumours (p = 0.034) and mean diameter of lung tumours (p = 0.021) differed significantly. No difference was observed between the methods. Inter-observer agreement was excellent (intra-class correlation >0.90) for all variables. In liver, overlaps of the 95% CI with the 95% CI of limits of PD or PR were observed for diameters above 22.7 and 37.9 mm, respectively. An overlap of 95% CIs was systematically observed for area. No overlaps were observed in lung. CONCLUSIONS: Although the experience of readers might not affect the precision of segmentation in lung and liver, the results of manual segmentation performed for tumour response assessment remain uncertain for large liver metastases.

Soft tissue masses with myxoid stroma: Can conventional magnetic resonance imaging differentiate benign from malignant tumors?

OBJECTIVES: To retrospectively evaluate the diagnostic performance of morphological signs observed on conventional magnetic resonance (MR) imaging to differentiate benign from malignant peripheral solid tumors of soft tissue with myxoid stroma. METHODS: MR images from 95 consecutive histopathologically proven tumors (26 benign and 69 malignant) of soft tissues with myxoid components were evaluated in our tertiary referral center. Two radiologists, blind to pathology results, independently reviewed conventional MR sequences including at least a) one T2-weighted sequence with or without fat suppression; b) one T1-weighted sequence without fat suppression; and c) one T1-weighted sequence with gadolinium-complex contrast enhancement and fat suppression. Multiple criteria were defined to analyze morphology, margins, architecture and tumor periphery and evaluated for each lesion. Intra- and inter-observer reproducibility and Odds ratios were calculated for each criterion. RESULTS: The most relevant and reproducible criteria to significantly predict malignancy were: (1) ill-defined tumor margins, (2) a hemorrhagic component, (3) intra-tumoral fat, (4) fibrosis and (5) the "tail sign". A lesion is classified as malignant if any of these 5 criteria is present, and benign if none of them are observed. Therefore, this combination provides a sensitivity of 92.9% and a specificity of 93.3%. CONCLUSION: Conventional MR imaging provides reproducible criteria that can be combined to differentiate between benign and malignant solid tumors of soft tissue with myxoid stroma.

Selection of an early biomarker for vascular normalization using dynamic contrast-enhanced ultrasonography to predict outcomes of metastatic patients treated with bevacizumab.

BACKGROUND: Dynamic contrast-enhanced ultrasonography (DCE-US) has been used for evaluation of tumor response to antiangiogenic treatments. The objective of this study was to assess the link between DCE-US data obtained during the first week of treatment and subsequent tumor progression. PATIENTS AND METHODS: Patients treated with antiangiogenic therapies were included in a multicentric prospective study from 2007 to 2010. DCE-US examinations were available at baseline and at day 7. For each examination, a 3 min perfusion curve was recorded just after injection of a contrast agent. Each perfusion curve was modeled with seven parameters. We analyzed the correlation between criteria measured up to day 7 on freedom from progression (FFP). The impact was assessed globally, according to tumor localization and to type of treatment. RESULTS: The median follow-up was 20 months. The mean transit time (MTT) evaluated at day 7 was the only criterion significantly associated with FFP (P = 0.002). The cut-off point maximizing the difference between FFP curves was 12 s. Patients with at least a 12 s MTT had a better FFP. The results according to tumor type were significantly heterogeneous: the impact of MTT on FFP was more marked for breast cancer (P = 0.004) and for colon cancer (P = 0.025) than for other tumor types. Similarly, the differences in FFP according to MTT at day 7 were marked (P = 0.004) in patients receiving bevacizumab. CONCLUSION: The MTT evaluated with DCE-US at day 7 is significantly correlated to FFP of patients treated with bevacizumab. This criterion might be linked to vascular normalization. AFSSAPS NO: 2007-A00399-44.

The introduction of early patient rehabilitation in surgery of soft tissue sarcoma and its impact on post-operative outcome.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs are implemented in multiple fields of surgery, but not yet in soft-tissue sarcoma (STS) surgery. We wondered whether its introduction into STS surgery might have impacted postoperative outcome. METHODS: Two hundred and fifty seven adult patients with primary limb or trunk wall STS received ERAS from 2008 to 2012 as a part of the intra-operative management. We evaluated, in retrospect, the intra-operative management, post-operative outcomes, functional and oncological results of these patients and compared them with 459 prior patients treated under a standard recovery after surgery (SRAS) program from 1989 to 2007. RESULTS: The most visible change from SRAS to ERAS in the perioperative management was decrease of wound drainage (72% vs. 15%, p < 0.001) and increase of wound bandaging (16% vs. 66%; p < 0.001), underlining the appliance of the ERAS protocol. Post-operatively, hospital stay dropped from nine (0-74) to three (0-22) days (p < 0.001) without affecting major morbidity (8% vs. 5%, NS) or readmission to the hospital (5% vs. 4%, NS). Functional outcome improved (p = 0.009) but whether this change was due to ERAS remains to be proved because complementary treatments changed over time. Tumour control remained unaffected, with an estimated risk of local recurrence at 5 years of 12% in both groups. CONCLUSION: Introducing a rapid recovery program was associated with a shorter hospitalization stay without compromising surgical or oncological outcomes. The program appears to be safe and reliable to use in patients undergoing STS surgery.

Hepar lobatum carcinomatosum associated with liver metastases from breast cancer: report of five cases.

BACKGROUNDS AND AIMS: Hepar lobatum carcinomatosum (HLC) is an exceptional acquired hepatic distortion which consists in irregularly lobulated hepatic contours seen in patients with known liver metastases, usually from breast carcinoma. We aimed to describe and analyze five similar cases of HLC resulting from metastatic mammary carcinoma in the liver and associated with rapid hepatic failure. METHODS: Five cases of HLC were investigated. Medical (including blood liver tests), radiological and histological data (2 cases) were collected and retrospectively analyzed. All patients were followed up for metastatic invasive ductal carcinoma of the breast and had a common pattern of treatment with combination of targeted therapies (bevacizumab, AVASTIN) and chemotherapy (paclitaxel, TAXOL). RESULTS: All the patients showed rapid hepatic failure after a mean of 9 courses of bevacizumab/paclitaxel. In all cases, liver imaging revealed liver capsule retraction and an irregular lobular margin. An apparent tumor regression of all liver metastases was showed in two cases. Biopsies were consistent with sinusoidal obstruction syndrome (SOS) and, surprisingly, no tumoral cells were found. CONCLUSION: Although rare, such an unusual pattern of liver metastasis may mimick acute cirrhosis and cause rapid hepatic failure in patients, despite possible apparent tumor regression on imaging. The etiology of this pathology is unclear, and may involve multiple pathogenic factors. Direct or indirect vascular injury plays an important role in the development of HLC.

Standardization of selection criteria for percutaneous image-guided cryoablation of recurrent soft-tissue sarcomas.

PURPOSE: Percutaneous image-guided cryoablation has not been validated for local management of recurrence of soft tissue sarcoma (STS) of the trunk or limbs. This study aims to identify selection criteria for cryoablation in order to standardize indications of this treatment. PATIENTS AND METHODS: Between 2000 and 2010, 46 patients (57 tumors) presenting local recurrences of STS of the trunk or limbs and treated following standards of care were selected from our institutional database. Eligibility for cryoablation was assessed by two radiologists according to predefined criteria: maximal diameter size of the tumor ≤10cm, distance to skin >5mm, distance to neurovascular structures 3mm at least, absence of articular involvement and planned cryoablation covering the entire lesion volume. Characteristics and outcomes were compared. RESULTS: There was nearly perfect agreement for all criteria (k coefficient ranging from 0.83 to 0.98) between both readers. A subgroup of 13patients was identified as eligible for cryoablation. Locations to the trunk, pelvic girdle or shoulder were significantly more present in the cryoablation group (P=0.002). In this group, tumors were mainly located deeply (P=0.002) with great axes ≤5cm (P=0.044). High local tumor aggressiveness (P=0.016) and differentiated myxoid liposarcoma or myxofibrosarcoma (P=0.007) were more frequent in the eligible group. CONCLUSION: Based on these criteria, two groups of patients with local relapse of STS can be identified. These results may improve the standardization of selection of patients who could be candidates for cryoablation.

Percutaneous image-guided cryoablation in inoperable extra-abdominal desmoid tumors: a study of tolerability and efficacy.

OBJECTIVE: To determine the tolerability, effectiveness and outcomes of percutaneous image-guided cryoablation on inoperable extra-abdominal desmoid tumors. METHODS: Between 2011 and 2012, 13 patients (mean age 39.3 years, range 15-74) with inoperable extra-abdominal desmoid tumors were consecutively treated with cryoablation (17 tumors treated in 17 procedures), including two patients with Gardner syndrome and nine recurrences after surgery. Disease-free survival (DFS) and local control based on RECIST criteria were calculated on prospective clinical and imaging follow-up until 2013. RESULTS: Cryoablation was performed under ultrasound (n = 8), computed tomography (n = 1), or combined (n = 8) guidance, and under general (n = 15) or local (n = 2) anesthesia. A major complication was observed in one session (5.8%). Mean follow-up was 11.3 months (6-27 months). Among all the patients treated, eight patients (47%) presented residual tumors on the first magnetic resonance follow-up, which were asymptomatic. The DFS rate was stable at 82.3% (95% confidence interval 0.55-0.94) at 6, 12, and 24 months. The local tumor progression rate was 0% at 6, 12, and 24 months. Two patients (12%) presented an in situ recurrence. CONCLUSIONS: Despite high rates of partial ablation, percutaneous image-guided cryoablation appears to be safe and effective for local control for patients with inoperable extra-abdominal desmoid tumors.

Adherence to consensus-based diagnosis and treatment guidelines in adult soft-tissue sarcoma patients: a French prospective population-based study.

BACKGROUND: Soft-tissue sarcomas (STSs) are rare tumors with varied histological presentations. Management and treatment are thus complex, but crucial for patient outcomes. We assess adherence to adult STS management guidelines across two French regions (10% of the French population). We also report standardized incidence. PATIENTS AND METHODS: STS patients diagnosed from 1 November 2006 to 31 December 2007 were identified from pathology reports, medical hospital records, and cancer registries. Guideline adherence was assessed by 23 criteria (validated by Delphi consensus method), and age and sex-standardized incidence rates estimated. Associations between patient, treatment, and institutional factors and adherence with three major composite criteria relating to diagnostic imaging and biopsy as well as multidisciplinary team (MDT) case-review are reported. RESULTS: Two hundred and seventy-four patients were included (57.7% male, mean age 60.8 years). Practices were relatively compliant overall, with over 70% adherence for 10 criteria. Three criteria with perfect Delphi consensus had low adherence: receiving histological diagnosis before surgery, adequacy of histological diagnosis (adherence around 50% for both), and MDT discussion before surgery (adherence <30%). Treatment outside of specialized centers was associated with lower adherence for all three composite criteria, and specific tumor sites and/or features were associated with lower adherence for diagnostic imaging, methods, and MDT meetings. STS standardized incidence rates were 4.09 (European population) and 3.33 (World) /100 000 inhabitants. CONCLUSIONS: Initial STS diagnosis and treatment across all stages (imaging, biopsy, and MDT meetings) need improving, particularly outside specialized centers. Educational interventions to increase surgeon's sarcoma awareness and knowledge and to raise patients' awareness of the importance of seeking expert care are necessary.

GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study.

BACKGROUND: Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. METHODS: This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. RESULTS: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. CONCLUSIONS: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01267955.

Clinical outcome of leiomyosarcomas of vascular origin: comparison with leiomyosarcomas of other origin.

BACKGROUND: There are no data about the natural history of leiomyosarcoma of vascular origin (vLMS) in comparison with leiomyosarcoma (LMS) of other origin and about the management of advanced disease. METHODS: Among 1472 patients diagnosed with sarcoma from January 1980 to December 2008 at our institution, 195 patients (13%) had LMS. LMS had a vascular origin in 14 cases (7%). RESULTS: Patients with vLMS had a significantly worse median metastasis-free survival (MFS) (0.25 versus 9.6 years, P = 0.001) and overall survival (OS; 2.1 versus 7 years, P < 0.0001) than patients with LMS of other origin. On multivariate analysis, grade and vascular origin were the sole independent adverse prognostic factors for OS. Eight metastatic patients with vLMS received a first-line anthracycline chemotherapy regimen. Two patients had partial response, four had stable disease and two had progressive disease. OS of patients with metastatic vLMS was not significantly different from that observed in patients with metastatic LMS of other origin (22.1 versus 16.5 months, P = 0.84). CONCLUSIONS: Vascular origin is an independent adverse prognostic factor for MFS and OS in patients with LMS. Patients with metastatic vLMS had a similar outcome than patients with metastatic LMS of other origin.