Evaluation of two modalities of perioperative treatment in the management of extremity and truncal soft tissue sarcomas: neoadjuvant concurrent chemoradiotherapy and sequential treatment.

PURPOSE: Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS: We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS: A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p < 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days, p < 0.01), with no impact on the surgical procedure or postoperative complications. CONCLUSION: cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.

Expression and prognostic significance of PDGF ligands and receptors across soft tissue sarcomas.

BACKGROUND: While the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear. PATIENTS AND METHODS: We analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2). RESULTS: Complex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10-9), PDGFB and C levels were lower in GIST (P < 2 × 10-15 and P < 3 × 10-9) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis. CONCLUSIONS: The expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse.

In vitro - in vivo correlation of intranasal drug deposition.

In vitro - in vivo correlation (IVIVC) allows prediction of in vivo drug deposition from a nasally inhaled drug based on in vitro drug measurements. In vitro measurements include physical particle characterization and, more recently, deposition studies using anatomical models. Currently, there is a lack of IVIVC for deposition measurements in anatomical models, especially for deposition patterns in various nasal cavity regions. Therefore, improvement of in vitro and in vivo measurement methods and knowledge about nasal deposition mechanisms should help IVIVC in the future.

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.

[Development of sarcoma on a ectopic extramedullary hematopoiesis secondary to hereditary spherocytosis: Case report and literature review]. / Développement d'un sarcome sur foyer ectopique hématopoïétique secondaire à une sphérocytose héréditaire : à propos d'un cas et revue de la littérature.

INTRODUCTION: Extramedullary hematopoiesis is a complication of myeloproliferative neoplasms or of chronic hemolysis. The more frequent localizations are splenic, ganglionic or paraspinal. Rarely, extramedullary hematopoiesis is associated with solid cancer. CASE REPORT: We report an original case of sarcoma located in an extramedullary hematopoiesis mass in a 72-year-old woman suffering from hereditary spherocytosis. An asymptomatic right paravertebral mass was found in 2004; the biopsy confirmed extramedullary hematopoiesis. In 2016, the patient was hospitalized due to paravertebral pain. Computed tomography showed the extension of the right paraspinal mass to pleura and mediastinum as well as vertebral bone lysis. Positron emission tomography showed an intense hypermetabolism. The biopsy showed undifferentiated sarcoma. CONCLUSION: This case report illustrates the risk of neoplastic transformation of extramedullary hematopoiesis, and the need for a biopsy when confronted to atypical aspect.

Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft-tissue sarcomas.

Background: Prediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management. Methods: A code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n = 124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n = 67) and matching frozen and FFPE samples (n = 45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated. Results: CINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI: 1.23-6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared with FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI: 1.25-15.72). Conclusion: CINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind®) in routine clinical practice on FFPE blocks to predict metastatic outcome.

Management and prognosis of malignant peripheral nerve sheath tumors: The experience of the French Sarcoma Group (GSF-GETO).

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of soft tissue sarcoma. They can arise in irradiated fields, in patients with type 1 neurofibromatosis (NF1), or sporadically. MPNST exhibit an aggressive behaviour, and their optimal management remains controversial. An unsolved issue is whether NF1-related and sporadic forms of MPNST have a different prognosis, and should be managed differently. MATERIAL AND METHODS: Adult and paediatric patients with histologically confirmed MPNST treated between 1990 and 2013 in French cancer centres of the GSF/GETO network, were included in this retrospective study. RESULTS: A total of 353 patients (37% with NF1 and 59% with sporadic tumours) were analysed. Median age at diagnosis was 42 years (range 1-94). The majority of tumours developed in the limbs, were deep-seated and of high grade. Two hundreds and ninety four patients underwent a curative intent surgery. Among them, 60 patients (21%) had neoadjuvant treatment (mainly chemotherapy), and 173 (59%) had adjuvant treatment (mainly radiotherapy). For operated patients, median progression free and overall survival (OS) were 26.3 months and 95.8 months, respectively. In multivariate analysis, poor-prognosis factors for OS were high grade, deep location, locally advanced stage at diagnosis, and macroscopically incomplete resection (R2). NF1 status was not negatively prognostic, except in the recurrence or metastatic setting, where NF1-related MPNST patients treated with palliative chemotherapy showed worse survival than patients with sporadic forms. CONCLUSION: To our knowledge, our series is the largest study of patients with MPNST reported to date. For operated patients, we showed a worse prognosis for NF1-related MPNST, due to different clinical features at diagnosis, more than NF1 status itself. The French sarcoma group is now conducting correlative analyses on these patients, using the latest molecular tools.

Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group.

BACKGROUND: Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs. METHODS: Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m(2), q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1). RESULTS: Eleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11-4.12). CONCLUSION: Trabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.

[Radiotherapy as conservative therapy for sarcomas within the irradiated field]. / Place de la radiothérapie dans le traitement conservateur des sarcomes en territoire irradié

PURPOSE: To describe long-term outcome after combined-modality treatment including radiation therapy in patients with localized sarcoma within irradiated field. PATIENTS AND METHODS: Individual clinical data from all consecutive patients diagnosed and treated for a localized sarcoma within irradiated field between January 2000 and October 2011 at the Institut Claudius-Regaud, Toulouse, France, were retrospectively reviewed. RESULTS: Twenty-seven patients were eligible for this study. Ten patients were re-irradiated with a rate of unresectable, gross or microscopically positive margins disease significantly higher than the rest of the cohort (90% vs. 12%; P<0.001). After a median follow-up of 3.8 years, there is a non-significant trend toward longer 4-year relapse free survival in the subgroup of patients who received adjuvant or definitive radiation therapy compared to the rest of the cohort (53% vs. 27%; P=0.09) with an acceptable toxicity profile allowing conservative management. CONCLUSION: The complete surgical resection sarcoma within irradiated field is often difficult to achieve enhancing the risk of relapse. Radiation therapy should be discussed when faced with an unresectable tumour or after suboptimal surgery as part of intensified local management with a curative intent.

Dermatofibrosarcoma protuberans: margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients.

INTRODUCTION: Dermatofibrosarcoma protuberans (DFSP) is a potentially malignant dermal mesenchymal tumour with a high risk of local recurrence. DFSP presents a sprawling appearance whose complete excision requires important margins. DFSP was initially resected with a 5cm excision margins, and more recently 3cm then 2cm margins were recommended. Mohs micrographic surgery (MMS) helps reduce these margins thanks to a 3-dimensional excision around the tumour, which is analysed in its entirety. We used the modified MMS called slow-MMS and tried every time it was possible to perform direct closure. METHODS: Thirty-five patients presenting a DFSP between 2004 and 2013 within the Plastic Surgery unit at Claudius Regaud Institute were included in this retrospective study. The patients were treated with slow-MMS using paraffin-embedded sections. RESULTS: One surgery was necessary for 72% of patients. For 17%, we had to perform a second surgery, and for 11% a third one. Our median clinical excision margins was 17mm (range 9.0:30.0). After a median follow-up of 46 months (range 35.2:60.2), we didn't observe any recurrence. Only one case required a local flap; for the others, the loss of substance was resolved with a direct closure. CONCLUSION: Slow-MMS enabled a local control of the margins without recurrence at 46 months in our series. Besides, it helps performing smaller margins than wide excision and thus preserving the tissues. In our opinion, this is the treatment of choice regarding DFSP for which tissue sparing is essential. It seems particularly appropriate near functional areas or on the face.

Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides.

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6ß4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6ß4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.

Role of radiation therapy in the conservative management of sarcoma within an irradiated field.

PURPOSE: To report on clinical outcome and toxicity profile after combined treatment that included radiation therapy (RT) in patients with localized sarcoma within an irradiated field. PATIENTS AND METHODS: Individual clinical data from all consecutive patients diagnosed and treated for a localized SIF between January 2000 and October 2011 at the Institut Claudius Regaud, Toulouse, France, were retrospectively reviewed. Outcomes of patients with SIF who underwent adjuvant or definitive radiotherapy were compared with patients who did not receive further RT. RESULTS: Of the 27 patients eligible for this study: surgery alone (S), surgery followed by RT (S + RT) or definitive RT (RT) was performed in 16, 8 and 2 cases respectively. The rate of unresectable, gross or microscopically positive margin disease among the 10 re-irradiated patients was significantly higher than the non re-irradiated group (90% vs. 12% p < 0.001). After a median follow-up of 3.8 years, there was a trend toward longer survival and better local control in the subgroup of patients who received adjuvant or definitive RT compared to the rest of the cohort with an acceptable toxicity profile. The 4-year relapse free survival rates of patients treated with and without RT were 53% and 27% respectively (p = 0.09). CONCLUSION: SIF complete surgical resection is often difficult to achieve, enhancing the risk of relapse. RT should be discussed in case of unresectable tumor or after suboptimal surgery as part of intensified local management that has a curative intent.

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.

Sonic aerosol therapy to target maxillary sinuses.

AIM: Intranasal aerosol administration of drugs is widely used by ENT specialists. Although clinical evidence is still lacking, intranasal nebulization appears to be an interesting therapeutic option for local drug delivery, targeting anatomic sites beyond the nasal valve. The sonic nebulizer NL11SN associates a 100Hertz (Hz) sound to the aerosolization to improve deposition in the nasal/paranasal sinuses. The aim of the present study was: to evaluate in vivo the influence of associating a 100Hz sound on sinus ventilation and nasal and pulmonary aerosol deposition in normal volunteers, and; to quantify in vitro aerosol deposition in the maxillary sinuses in a plastinated head model. MATERIAL AND METHODS: Scintigraphic analysis of (81m)Kr gas ventilation and of sonic aerosol ((99m)Tc-DTPA) deposition using the NL11SN was performed in vivo in seven healthy volunteers. In parallel, NL11SN gentamicin nebulization was performed, with or without associated 100Hz sound, in a plastinated human head model; the gross amount of gentamicin delivered to the paranasal sinuses was determined by fluorescence polarization immunoassay. RESULTS: Associating the 100Hz sound to (81m)Kr gas ensured paranasal sinus ventilation in healthy volunteers. (99m)Tc-DTPA particles nebulized with the NL11SN were deposited predominantly in the nasal cavities (2/3, vs 1/3 in the lungs). In vitro, the use of NL11SN in sonic mode increased gentamicin deposition threefold in the plastinated model sinuses (P<0.002); the resulting antibiotic deposit would be sufficient to induce a local therapeutic effect. CONCLUSION: The NL11SN nebulizer ensured preferential nasal cavity aerosol deposition and successfully targeted the maxillary sinuses.

[Histological techniques in oncodermatology]. / L'apport des techniques anatomopathologiques en oncodermatologie.

The skin oncology or "oncodermatology" requires a surgical treatment in most cases. For some surgeons, the oncodermatology takes a very important part of their practice. In the course of diagnostic and therapeutic of skin lesions, the pathologist plays now an essential role. He will guide our surgery. The techniques used by this specialist are numerous. Therefore, the objective of this paper is to review the different histological methods used to improve our management of skin tumors.

Diffuse pulmonary uptake on FDG-PET with normal CT diagnosed as intravascular large B-cell lymphoma: a case report and a discussion of the causes of diffuse FDG uptake in the lungs.

A 71-year-old woman was admitted to our hospital with asthenia, weight loss, fever, cognitive impairment and shortness of breath. Physical examination showed hemiparesis and cerebellar ataxia. There was no superficial lymphadenopathy. Blood tests showed raised levels of C-reactive protein and lactate dehydrogenase. Bone marrow aspiration and biopsy were negative. [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed intense uptake within a right apical nodule and intense and diffuse uptake of FDG in the lungs without corresponding structural CT abnormality. Lung biopsy showed intravascular large B-cell lymphoma (IVLBCL). FDG-PET findings in IVLBCL and causes of diffuse FDG lung uptake with and without CT abnormalities are discussed.

Liver resection after downstaging hepatocellular carcinoma with sorafenib.

Background. Sorafenib is a molecular-targeted therapy used in palliative treatment of advanced hepatocellular carcinoma in Child A patients. Aims. To address the question of sorafenib as neoadjuvant treatment. Methods. We describe the cases of 2 patients who had surgery after sorafenib. Results. The patients had a large hepatocellular carcinoma in the right liver with venous neoplastic thrombi (1 in the right portal branch, 1 in the right hepatic vein). After 9 months of sorafenib, reassessment showed that tumours had decreased in size with a necrotic component. A right hepatectomy with thrombectomy was performed, and histopathology showed 35% to 60% necrosis. One patient had a recurrence after 6 months and had another liver resection; they are both recurrence-free since then. Conclusion. Sorafenib can downstage hepatocellular carcinoma and thus could represent a bridge to surgery. It may be possible to select patients in good general condition with partial regression of the tumour with sorafenib for a treatment in a curative intent.