Focus on the Tumour Periphery in MRI Evaluation of Soft Tissue Sarcoma: Infiltrative Growth Signifies Poor Prognosis

Purpose. Infiltrative microscopical peripheral growth of soft tissue sarcomas (STS) has been shown to be of prognostic importance and preoperative risk stratification could individualize neoadjuvant treatment. Patients and methods. We assessed peripheral tumour growth pattern on preoperative MRI from 78 STS. The findings were correlated to histopathology and to outcome. Results. The MRI-based peripheral tumour growth pattern was classified as pushing in 34 tumours, focally infiltrative in 25, and diffusely infiltrative in 19. All tumours with diffuse infiltration on MRI also showed microscopical infiltration, whereas MRI failed to identify infiltration in two-thirds of the microscopically infiltrative tumours. Diffusely infiltrative growth on MRI gave a 2.5 times increased risk of metastases (P = .01) and a 3.7 times higher risk of local recurrence (P = .02). Discussion. Based on this observation we suggest that MRI evaluation of STS should focus on the peripheral tumour growth pattern since it adds prognostic information of value for decisions on neoadjuvant therapies

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer

Objectives Maintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe, a Delphi study was conducted among European experts to understand the heterogeneity of clinical practice and identify key factors driving maintenance treatment decisions for advanced ovarian cancer.Methods A pragmatic literature review was conducted to identify key questions regarding maintenance treatment strategies in patients with advanced ovarian cancer. Utilizing a Delphi methodology, consensus was assessed among a panel of 16 experts using a questionnaire based on results of the pragmatic literature review.Results Panelists agreed that BRCA mutation and homologous recombination status should be assessed in parallel at diagnosis, and that first-line platinum chemotherapy may be initiated concurrently. There was a consensus that alternative homologous recombination deficiency tests are acceptable provided they are clinically validated. Panelists agreed that Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 elimination rate constant K (KELIM) scores can help assess tumor chemosensitivity and guide treatment-related decisions. Panelists defined high-risk disease as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III with residual disease after initial/interval cytoreduction. Risk of disease progression was a key determinant of choice between PARP inhibitor, bevacizumab, or both in combination, as maintenance therapy in advanced ovarian cancer.Conclusions Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression

Soft Tissue Sarcoma Patterns multiplicity, heterogeneity and growth characteristics

Soft tissue sarcomas (STS) represent a group of rare and heterogenous tumors that optimally should be diagnosed and treated within multidisciplinary teams. This thesis has studied various aspects ? pathological, genetical, and clinical ? of STS. In study I, we demonstrated that 20% of the patients in a population-based series of 818 STS developed second primary malignancies. An increased risk of developing a second malignancy was identified (SMR 1.3; 95% CI=1.0-1.5), with a particularly high risk of developing a second STS (SMR 17.6; 95% CI=8.1-33.5). Study II included 13 patients who had developed at least two primary STS and we applied array-based comparative genomic hybridization to study the genetic profiles of these tumors. Cluster anaysis and comparison between the genetic profiles suggested that 8 cases represented second primary STS, whereas 5 cases likely represented soft tissue metastases. In study III cDNA microarray was applied to 26 synovial sarcomas and identified differentially expressed genes in relation to gene fusion type. Among the discriminators were several genes that have previously been found to be up-regulated in SS, including AXL, ZIC2, SPAG7, AGRN, FOXC1, NCAM1. In study IV we assessed the impact of targeting peripheral versus central tumor areas using tissue microarray-based staining for Ki-67 in leiomyosarcomas and demonstrated that the Ki-67 expression was higher in the tumor periphery in 18/25 tumors. These observations suggest that Ki-67 evaluation for prognostic purposes should be standardized regarding the part of the tumor investigated. In study V, peripheral tumor growth pattern was evaluated on preoperative MRI with correlations to microscopical growth pattern and prognosis. All tumors with diffuse infiltration on MRI also showed microscopical infiltration, whereas MRI failed to identify infiltration in one-third of the microscopically infiltrative tumors. Diffusely infiltrative growth on MRI correlated with prognosis with a 2.5 times increased risk of metastases (p=0.01) and a 3.7 times higher risk of local recurrence (p=0.02). In summary, we have demonstrated that patients with STS are at increased risk of developing second primary tumors, including STS, with genetic profiles supporting independent tumor origin. We have also demonstrated that the underlying gene fusion type in synovial sarcoma influence the gene expression profile. Finally, the tumor periphery seems to provide the best information; our studies suggest that evaluation of Ki-67 staining should be standardized, perhaps to the periphery, and that MRI-based classification of the peripheral tumor growth pattern may provide prognostic informatio

Genetic Profiling Differentiates Second Primary Tumors from Metastases in Adult Metachronous Soft Tissue Sarcoma

Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult. Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype. Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS. Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications

Mesothelin Expression in Patients with High-Grade Serous Ovarian Cancer Does Not Predict Clinical Outcome But Correlates with CD11c+ Expression in Tumor.

INTRODUCTION: Mesothelin (MSLN) is overexpressed in several tumors including ovarian cancer and is the target of current trials. There is limited and conflicting data on MSLN prognostic impact in ovarian cancer. METHODS: We performed a retrospective study on patients with high-grade serous ovarian cancer, analyzing MSLN expression by immunohistochemistry and examining the correlation of its expression to overall and progression-free survival. Correlations of expression of MSLN, CD8, and macrophage markers in different tumor compartments were also investigated. RESULTS: Positive MSLN expression was detected in 55.1% of primary tumors and 51.5% of the metastases. MSLN expression was not correlated with survival. We observed a significant positive correlation (r = 0.34, p = 0.01) between MSLN expression in the metastatic site and CD11c expression in total tumor area and perivascular area in the primary tumor. CONCLUSION: Our results show that MSLN expression does not correlate with clinical outcome. The impact of the correlation between MSLN and CD11c+ cells on immunotherapy outcome should be further explored

Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential

Background Soft tissue sarcoma (STS) diagnosis is challenging because of a multitude of histopathological subtypes, different genetic characteristics, and frequent intratumoral pleomorphism. One-third of STS metastasize and current risk-stratification is suboptimal, therefore, novel diagnostic and prognostic markers would be clinically valuable. We assessed the diagnostic and prognostic value of array-based gene expression profiles using 27 k cDNA microarrays in 177, mainly high-grade, STS of 13 histopathological subtypes. Results Unsupervised analysis resulted in two major clusters - one mainly containing STS characterized by type-specific genetic alterations and the other with a predominance of genetically complex and pleomorphic STS. Synovial sarcomas, myxoid/round-cell liposarcomas, and gastrointestinal stromal tumors clustered tightly within the former cluster and discriminatory signatures for these were characterized by developmental genes from the EGFR, FGFR, Wnt, Notch, Hedgehog, RAR and KIT signaling pathways. The more pleomorphic STS subtypes, e.g. leiomyosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma, were part of the latter cluster and were characterized by relatively heterogeneous profiles, although subclusters herein were identified. A prognostic signature partly characterized by hypoxia-related genes was identified among 89 genetically complex pleomorphic primary STS and could, in a multivariate analysis including established prognostic markers, independently predict the risk of metastasis with a hazard ratio of 2.2 (P = 0.04). Conclusion Diagnostic gene expression profiles linking signaling pathways to the different STS subtypes were demonstrated and a hypoxia-induced metastatic profile was identified in the pleomorphic, high-grade STS. These findings verify diagnostic utility and application of expression data for improved selection of high-risk STS patients