Descriptive analysis of MRI functional changes occurring during reduced dose radiotherapy for myxoid liposarcomas

Objectives: Myxoid liposarcomas (MLS) show enhanced response to radiotherapy due to their distinctive vascular pattern and therefore could be effectively treated with lower radiation doses. This is a descriptive study to explore the use of functional MRI to identify response in a uniform cohort of MLS patients treated with reduced dose radiotherapy Methods: 10 patients with MLS were imaged pre-, during, and post-radiotherapy receiving reduced dose radiotherapy and the response to treatment was histopathologically assessed post-radiotherapy. Apparent diffusion coefficient (ADC), T2* relaxation time, volume transfer constant (Ktrans), initial area under the gadolinium curve over 60 s (IAUGC60) and (Gd) were estimated for a central tumour volume. Results: All parameters showed large inter- and intrasubject variabilities. Pre-treatment (Gd), IAUGC60 and Ktrans were significantly different between responders and non-responders. Post-radiotherapy reductions from baseline were demonstrated for T2*, (Gd), IAUGC60 and Ktrans for responders. No statistically significant ADC differences were demonstrated between the two response groups. Significantly greater early tumour volume reductions were observed for responders. Conclusions: MLS are heterogenous lesions, characterised by a slow gradual contrast-agent uptake. Pre-treatment vascular parameters, early changes to tumour volume, vascular parameters and T2* have potential in identifying response to treatment. The delayed (Gd) is a suitable descriptive parameter, relying simply on T1 measurements. Volume changes precede changes in MLS functionality and could be used to identify early response. Advances in knowledge: MLS are are characterised by slow gradual contrast-agent uptake. Measurement of the delayed contrast-agent uptake (Gd) is simple to implement and able to discriminate response.

Human leukocyte antigen I is significantly downregulated in patients with myxoid liposarcomas

The characteristics of the tumor immune microenvironment remains unclear in liposarcomas, and here we aimed to determine the prognostic impact of the tumor immune microenvironment across separate liposarcomas subtypes. A total of 70 liposarcoma patients with three subtypes: myxoid liposarcoma (n = 45), dedifferentiated liposarcoma (n = 17), and pleomorphic liposarcoma (n = 8) were enrolled. The presence of tumor infiltrating lymphocytes (CD4+ , CD8+ , FOXP3+ lymphocytes) and CD163+ macrophages and expression of HLA class I and PD-L1 were assessed by immunohistochemistry in the diagnostic samples; overall survival and progression-free survival were estimated from outcome data. For infiltrating lymphocytes and macrophages, dedifferentiated liposarcoma and pleomorphic liposarcoma patients had a significantly higher number than myxoid liposarcoma patients. While myxoid liposarcoma patients with a high number of macrophages were associated with worse overall and progression-free survival, dedifferentiated liposarcoma patients with high macrophage numbers showed a trend toward favorable prognosis. Expression of HLA class I was negative in 35 of 45 (77.8%) myxoid liposarcoma tumors, whereas all dedifferentiated liposarcoma and pleomorphic liposarcoma tumors expressed HLA class I. The subset of myxoid liposarcoma patients with high HLA class I expression had significantly poor overall and progression-free survival, while dedifferentiated liposarcoma patients with high HLA class I expression tended to have favorable outcomes. Only four of 17 (23.5%) dedifferentiated liposarcomas, two of eight (25%) pleomorphic liposarcomas, and no myxoid liposarcoma tumors expressed PD-L1. Our results demonstrate the unique immune microenvironment of myxoid liposarcomas compared to other subtypes of liposarcomas, suggesting that the approach for immunotherapy in liposarcomas should be based on subtype.

Immunohistochemical Detection of Cancer-Testis Antigen PRAME

Cancer-testis (CT) antigens were identified by their ability to elicit T- or B-cell immune responses in the autologous host. They are typically expressed in a wide variety of neoplasms and in normal adult tissues are restricted to testicular germ cells. PReferentially expressed Antigen of Melanoma (PRAME) is a member of the family of nonclassical CT antigens being expressed in a few other normal tissues besides testis. Interestingly, knowledge about the protein expression of many CT antigens is still incomplete due to the limited availability of reagents for their immunohistochemical detection. Here, we tested several commercially available serological reagents and identified a monoclonal antibody suitable for the immunohistochemical detection of PRAME in formalin-fixed paraffin-embedded specimens. We also tested a wide array of normal and neoplastic tissues. PRAME protein expression in normal tissues is congruent with original molecular data being present in the testis, and at low levels in the endometrium, adrenal cortex, and adult as well as fetal ovary. In tumors, there is diffuse PRAME immunoreactivity in most metastatic melanomas, myxoid liposarcomas, and synovial sarcomas. Other neoplasms such as seminomas and carcinomas of various origins including endometrial, serous ovarian, mammary ductal, lung, and renal showed an intermediate proportion of cases and variable extent of tumor cells positive for PRAME protein expression. As seen with other CT antigens, hepatocellular and colorectal carcinoma, Leydig cell tumors, mesothelioma, and leiomyosarcoma are poor expressers of PRAME.

Prevalence of tumor pathology of dogs in the metropolis

A statistical analysis of the prevalence of tumor pathology of dogs in the city of Dnipro. 418 cases of registered oncological diseases of dogs were analyzed. It was found that malignant neoplasms are 1.5 times more common than benign. The most common tumors in dogs are tumors of the breast (35,9%), skin (22,0%), genitals (15,3%) and lymphoma(8,4%). Malignant neoplasms of the breast are registered 3.6 times more often than benign and surpass them in morphological varieties. Fibroadenomas and infiltrating and non-infiltrating carcinomas were mainly registered. Approximately the same number of cases of infiltrating and non-infiltrating cancers were noted. Benign skin tumors are more common than malignant. Mastocytosis, melanoma, and squamous and basal cell carcinomas of the skin and sebaceomas were the most commonly reported. In terms of morphological varieties, benign skin neoplasms are superior to malignant ones. Lipomas and papillomas are very common. Genital neoplasms of females and males are also common. Almost half of male genital tumors were malignant seminomas. Among benign neoplasms, serteliomas and leydigomas were more common. In females, the most common are uterine leiomyoma, vaginal fibroma and ovarian carcinoma. Lymphomas (8.4%) are also widespread in dogs in the metropolis. The average age of registration of these neoplasms was 7.5 years. Benign tumors in the oral cavity of dogs were twice as common as malignant, of which fibrosarcomas, squamous keratinized and non-keratinized carcinomas, and salivary gland adenocarcinomas were reported. In females, oral neoplasia occurred 3.2 times more often than in males. Only malignant venereal sarcomas and carcinomas were found in the nasal cavity of dogs. Sexual and pedigree predisposition was not observed here. Among neoplasms of muscles and bones there was only a malignant oncological pathology. Rhabdomyosarcomas, fibrosarcomas, myxoid liposarcomas and other soft tissue sarcomas were diagnosed in different parts of the dog’s body. Bone neoplasms are represented by osteosarcomas. Dogs of large breeds were most often affected and in most cases the hind limbs were affected. The predominant histological subtype was osteoblastic osteosarcoma.

Prevalence of the Hippo Effectors YAP1/TAZ in Tumors of Soft Tissue and Bone

Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement of YAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining of YAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization of YAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression of YAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence of YAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit from YAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.

PD-L1 expression in 522 selected sarcomas with subset analysis of recurrent or metastatic matched samples and association with tumour-infiltrating lymphocytes

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher’s exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.