Metastatic angiosarcomas: doxorubicin-based regimens, weekly paclitaxel and metastasectomy significantly improve the outcome.

BACKGROUND: Angiosarcomas are a rare but aggressive form of soft tissue sarcoma. At metastatic stage, the clinical benefit of therapeutic intervention remains debatable. PATIENTS AND METHODS: We have carried a retrospective analysis of 149 cases treated between 1996 and 2009 in the French Sarcoma Group. RESULTS: The median age was 60; the sex ratio was 0.80. Sixty-two percentage of cases presented with metastasis at the diagnosis. About 20% arose in irradiated fields. The median overall survival was 11 months. Treatment consisted in metastasectomy (5.4%), doxorubicin-based regimen (46.9%), weekly paclitaxel (Taxol) (31.5%), other chemotherapy regimens (10.7%) or exclusive palliative care (10.9%). Clinical prognostic factors identified by univariate analysis were presence of bone metastasis (P = 0.0107), presence of other metastasis (P = 0.0327) and performance status (P < 0.0001). The Cox model retained a performance status of two or more as the sole independent prognostic factor (HR [hazard ratio] = 2.49, P < 0.0001). After adjustment to the performance status and compared with exclusive palliative care, the following treatments significantly improve the outcome: doxorubicin-based regimen as first-line chemotherapy (HR = 0.38, P = 0.0165), weekly paclitaxel as first-line regimen (HR = 0.36, P = 0.0146) and metastasectomy (HR = 0.09, P = 0.0221). CONCLUSIONS: This retrospective analysis indicates that some therapeutic interventions may significantly improve the outcome of this aggressive disease. Doxorubicin-based regimens and weekly paclitaxel seem to provide the same range of efficacy.

Specific immune landscapes and immune checkpoint expressions in histotypes and molecular subtypes of sarcoma.

Soft tissue sarcomas are a group of rare and aggressive connective tissue neoplasms for which curative therapeutic opportunities are limited in advanced phase. Clinical trials assessing immunotherapy in these tumors have so far reported limited efficacy. The objective of this study is to provide a description of the immunologic landscape of sarcomas to guide the next clinical trials of immunotherapy in these diseases. The gene expression profile of 93 immune checkpoint (ICP) and membrane markers (MM) of immune cells was analyzed in a series of 253 soft tissue sarcoma (synovial sarcoma, myxoid liposarcoma, sarcoma with complex genomic and GIST) using Agilent Whole Human Genome Microarrays. The unsupervised hierarchical clustering of gene expression level was found able to properly group patients according to the histological subgroup of sarcoma, indicating that each sarcoma subgroup is associated with a specific immune signature defined by its gene expression pattern. Using the prognostic impact of CIBERSORT signature on metastatic-free survival in each subgroup, specific target could be proposed for each of the four groups: Treg through ICOS and GITR in GIST, M0 macrophages in all four sarcoma subtypes, OX40 in SS, CD40 in GIST and SS. The immune landscape of sarcoma was found to be as heterogeneous as the histotypes and molecular subtypes, but strongly correlated to the histotype. Histotype adapted immunotherapeutic approaches in each sarcoma subtypes must be considered in view of these results, consistently with the already reported specific response of histotypes of ICPs.

Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group.

BACKGROUND: There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). PATIENTS AND METHODS: Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. RESULTS: The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. CONCLUSION: As for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial setting.

Soft tissue sarcomas of the trunk wall (STS-TW): a study of 343 patients from the French Sarcoma Group (FSG) database.

BACKGROUND: Soft tissue sarcomas of the trunk wall (STS-TW) are usually studied together with soft tissue sarcomas of other locations. We report a study on STS-TW forming part of the French Sarcoma Group database. PATIENTS AND METHODS: Three hundred and forty-three adults were included. We carried out univariate and multivariate analysis for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). RESULTS: Tumor locations were as follows: thoracic wall, 82.5%; abdominal wall, 12.3% and pelvic wall, 5.2%. Median tumor size was 6.0 cm. The most frequent tumor types were unclassified sarcoma (27.7%) and myogenic sarcoma (19.2%). A total of 44.6% of cases were grade 3. In all, 21.9% of patients had a previous medical history of radiotherapy (PHR). Median follow-up was 7.6 years. The 5-year OS, MFS and LRFS rates were 60.4%, 68.9% and 58.4%, respectively. Multivariate analysis retained PHR and grade for predicting LRFS and PHR, size and grade as prognostic factors of MFS. Factors influencing OS were age, size, PHR, depth, grade and surgical margins. The predictive factors of incomplete response were PHR, size and T3. CONCLUSIONS: Our results suggest similar classical prognostic factors as compared with sarcomas of other locations. However, a separate analysis of STS-TW revealed a significant poor prognosis subgroup of patients with PHR.

Adjuvant management of operated uterine sarcomas: A single institution experience.

PURPOSE: The purpose of this study was to describe the adjuvant management of high grade uterine sarcoma and highlight prognostic factors for overall survival and progression-free survival. MATERIAL AND METHODS: Between 01/2000 and 01/2015, 91 patients undergoing surgery were presented at the multidisciplinary team meeting of our institution. The type of surgery, the anatomopathological features, adjuvant treatments, dates and sites of recurrence were collected. The prognostic value of the various factors was evaluated with the multivariate Cox model. RESULTS: A total of 50 women with uterine sarcoma were identified and lesions included 43 leiomyosarcomas (86%) and seven high grade sarcomas (14%). Eighteen patients received adjuvant pelvic radiotherapy (36%) and six adjuvant systemic therapy (12%). The median follow-up time was 63 months. Thirty-nine patients (78%) had a recurrence: 22 had only metastatic recurrence (58%), two had isolated pelvic recurrence (5%) and 15 had pelvic and metastatic recurrence (38%). Adjuvant radiotherapy was associated with survival without pelvic recurrence in univariate analysis (P=0.005, hazard ratio [HR]=0.15); age greater than 55 years and adjuvant radiotherapy were associated with metastatic free survival in multivariate analysis (P=0.015, HR=2.37, and P=0.013, HR=0.41 respectively) CONCLUSION: According to the results of our series, there is a benefit of radiotherapy after surgery in terms of local control of uterine sarcoma. It is necessary to identify the subgroup of patients who will benefit from an adjuvant radiotherapy in order to provide them with more optimal care.

Prognostic factors for adult sarcomas of head and neck.

The optimal management of adult soft-tissue sarcomas is not clearly established. To assess prognostic factors and survival, the experience of 45 recent successive cases was reviewed. Data were collected from a retrospective database (1993-2005) and statistically analyzed. Rhabdomyosarcomas were excluded. The mean age was 50.1 years; there were 24 men and 21 women. The main histological subtypes were undifferentiated sarcoma (14) and angiosarcoma (10); 21 tumours were grade 3 (46%). The most frequent primary sites were neck muscles (15, 33%) and scalp (11, 24%). At presentation, 5 (20%) cases with lymph-node involvement and another 11 cases (24%) with distant metastasis were observed. The treatment was with curative intent in 33 cases (73%). This entailed surgery, with adjuvant radiotherapy in 15 cases and adjuvant chemotherapy in 5 cases. The 5-year overall survival was 52% (+/-8%). In univariate analysis, the poor prognostic factors were high grade, initial metastasis or lymph nodes, absence of surgery, and number of surgical procedures. In multivariate analysis, two factors remained significant: grade (P=0.006) and absence of surgery (P=0.005). After taking into account grade and metastasis at presentation, quality of surgery has prognostic value. The primary aim of a multidisciplinary approach to these tumours must favour complete resection.

Perfusion MR imaging at 3-Tesla: Can it predict tumor grade and histologic necrosis rate of musculoskeletal sarcoma?

PURPOSE: To identify quantitative perfusion parameters that are best associated with tumor grade and tumor necrosis at magnetic resonance (MR) imaging at 3-Tesla. METHODS: MR perfusion studies of 31 patients with a musculoskeletal sarcoma were retrospectively evaluated by two readers. There were 18 men and 13 women with a mean age of 34.9±24.4 (standard deviation [SD] years) (range: 6-87 years). All patients underwent carcinologic tumor resection less than 3 months after MR imaging. For all patients six perfusion parameters (three semi-quantitative and three permeability parameters) were analyzed. The percentage of tumor necrosis was estimated using MR imaging. Perfusion data were compared between groups of tumors with different grades and necrosis ratios. Interobserver variability was calculated using intraclass correlation coefficient (ICC). RESULTS: Interobserver variability among the perfusion parameters was good to excellent (ICC: 0.72-0.9). The area under the curve and maximum slope values showed a significant association with the degree of tumor necrosis (P=0.02-0.04). When tumors with low necrosis ratios were compared to those with high ratios the former parameter was 80% lower. In the same groups, the imaging necrosis index was 56.9-59.8% higher in patients with grade 2 necrosis (P=0.01). Extracellular space volume (Ve) was 31.4% to 55.8% lower in tumors with high grade while the backflow constant (Kep) was 33.6% to 40.1%% higher in tumors with high grade. CONCLUSION: Semi-quantitative MR perfusion parameters have an excellent reproducibility and are associated with the degree of histologic tumor necrosis in musculoskeletal sarcomas. The utility of permeability parameters for determining tumor grade needs further investigations.

Surgical implications of sentinel node with micrometastatic disease in invasive breast cancer.

AIM: To assess the rate of positive axillary clearance (AC) when the sentinel node biopsy (SNB) contains micrometastatic disease in invasive breast cancer and to evaluate the factors that could predict positivity. PATIENTS AND METHODS: This is a prospective study carried out on 542 successive women undergoing SNB for unifocal T0-T1 N0 invasive breast cancer without previous treatment. RESULTS: Five hundred and twenty-five sentinel nodes (SN) were found, 142 contained metastases. Fifty-five of the positive SN contained micrometastatic disease only. Of them, 40 patients underwent completion of AC. Six out of 40 patients who had micrometastatic SN had a positive AC, five for micrometastasis between 0.2 and 2 mm (5/34), one for isolated cells in the SN (1/6). None of the studied factors (age, histological tumour size, histological grade, estradiol receptor (ER), histological tumour type, size and method of micrometastasis detection) could significantly predict the status of the AC. CONCLUSION: As long as the results of ongoing prospective randomised studies are unknown, it remains necessary to perform AC when the SNB contains micrometastatic disease, whatever the size or the detection mode of the metastasis.

Renal tubular dysgenesis-like lesions and hypocalvaria. Report of two cases involving indomethacin.

We describe a case of twins with twin-to-twin transfusion syndrome (TTS) who were found to have renal tubular dysgenesis (TRD)-like lesions and hypocalvaria attributed to indomethacin treatment of the mother for acute polyhydramnios. History of pregnancy, postnatal clinical course, pathological findings of the kidneys, and the skulls are presented and discussed. These findings include incompletely differentiated proximal tubules in the kidneys and hypoplastic calvaria in both twins. The renal tubular lesions were more marked in the donor than in the transfused twin, probably due to the greater degree of ischemia in that twin. This seems to be in favor of a vascular etiology of the renal defects. However, the fact that similar renal lesions and hypocalvaria were also present in the transfused twin seems to indicate that indomethacin played a role in their onset. This so-called kidney-skull connection has never been reported in conjunction with indomethacin therapy.

Pure flat epithelial atypia: is there a place for routine surgery?

PURPOSE: To determine whether it is appropriate to routinely undertake surgery if flat epithelial atypia (FEA) or pure flat epithelial atypia (pFEA) is found on large-core biopsy. PATIENTS AND METHODS: Between 2005 and 2010, 1678 large-core biopsy procedures were carried out, which led to 136 FEA sites being identified, 63 of which across 59 patients were pFEA (four patients had two sites of pFEA each). Forty-eight patients underwent further surgical excision, equating to 52 excised sites of pFEA. RESULTS: Of the 52 operated sites, there were 20 benign lesions (38%), 26 borderline lesions (56%), and three ductal carcinomas in situ (6%). The rate of histologic underestimation was put at 3.8%. Of the three cases that were underestimated, one was discarded because the definitive histology was not representative of the site from which microcalcifications had initially been taken. The other two cases that were underestimated were found in patients with an increased individual risk of breast cancer. CONCLUSION: In patients with no personal or first-degree family history of breast cancer, after complete or subtotal excision under radiology of the radiological lesion, and while excluding images fitting BI-RADS 5, annual monitoring may be offered as an alternative to surgical excision in view of the absence of underestimation found in our study.

[Intraoperative molecular assessment of sentinel nodes in the breast cancer using the Gene Search BLN Assay technique: our experience about 126 patients]. / Évaluation de l'analyse peropératoire des ganglions "sentinelle" par biologie moléculaire (technique Gene Search BLN Assay) dans le cancer du sein: à propos de 126 patientes.

INTRODUCTION: Intraoperative molecular assay Gene Search BLN Assay (BLN) detects sentinel lymph node (SLN) metastasis in breast cancer. Our objective was to compare BLN to the definitive conventional histologic methods and to experiment the management of BLN in routine. MATERIAL AND METHODS: Each SLN was cut into alternate slabs. Half slabs were analysed with the intraoperative BLN molecular method, and the other slabs with the definitive histologic method. RESULTS: Two hundred and thirty four SLN have been analysed (124 patients). Thirty-five SLN had metastasis for 29 patients (23.4%). BLN correctly identified 28 patients. Two cases of discordance between BLN and standard method were found, probably explained by a sample bias. The sensibility of BLN is 96.4%, the sensitivity is 99%, the predictive positive value is 96.4%, the predictive negative value is 99% and the concordance is 98.4%. The surgery time increases and there is a need to adapt the theatre organization accordingly. CONCLUSION: The Gene Search BLN Assay gives a great interest for the patient, the surgeon and the pathologist because it increases the quality of the intraoperative analysis by comparison with the intraoperative conventional histology.

[Intraoperative determination of axillary node metastasis by RT-PCR]. / Utilisation d'une méthode PCR en temps réel pour l'étude des ganglions sentinelles dans les carcinomes mammaires : expérience des centres anticancéreux de Lille et de Clermont-Ferrand.

UNLABELLED: The intraoperative determination of axillary node micrometastasis according to the Rapid GeneSearch Breast Lymph Node (BLN) is based on RT-PCR (mRNA of mammaglobine and CK19) detects metastases > 0.2 mm. PATIENTS AND METHODS: Eighty-three pts between November 2007 and June 2008 were included (33 from Centre Jean-Perrin and 50 from Centre Oscar-Lambret). Lymph nodes were cut in 2 mm slices, and 1 out of 2 was examined with BLN; the others were examined by imprints then histological exam with immunohistochemistry. RESULTS: Forteen pts had micro- or macrometastasis. Seven were positive with intraoperative imprints including six macrometastasis and one micrometastasis; seven were positive with BLN and seven at histological exam with two cases of discordance. Sensitivity was 92%, specificity 98%. Positive predictive value 92%, and negative predictive value 98%. The median time for intraoperative determination was 40 minutes for 2 SLN. DISCUSSION: Half each lymph node is study by each method. This explains the discordances observed. Limit of BLN is the absence of CTI detection; however there is no consensus about the necessity of axillary clearance in such a case. CONCLUSION: In this series BLN reduces axillary clearance and improves comfort patients.