Anti-angiogenic properties of rapamycin on human retinal pericytes in an in vitro model of neovascular AMD via inhibition of the mTOR pathway

Purpose Choroidal neovascularizations (CNV) are partially stabilized through a coverage of pericytes leading to a partial anti-VEGF resistence. Drugs licensed for neovascular AMD (nAMD) do not take this mechanical and growth factor-driven CNV stability into account. The purpose of this work was to see if inhibiting the mammalian target of rapamycin (mTOR) may successfully block angiogenic cellular pathways in primary human retinal pericytes in an in vitro model of nAMD. Methods The mTOR inhibitor rapamycin was used to treat human retinal pericytes (HRP) at doses ranging from 0.005 to 15 g/ml. A modified metabolism-based XTT-Assay was used to assess toxicity and anti-proliferative effects. A scratch wound experiment showed the effects on migration. On Cultrex basement membrane gels, the influence of rapamycin on the development of endothelial cell capillary-like structures by human umbilical vein vascular endothelial cells (HUVEC) in the absence and presence of pericytes was investigated. Results Rapamycin showed no signs of toxicity within its range of solubility. The drug showed dose dependent anti-proliferative activity and inhibited migration into the scratch wound. Endothelial cell tube formation in a HUVEC monoculture was effectively inhibited at 45%. A co-culture of HUVEC with pericytes on Cultrex induced endothelial tube stabilization but was disrupted by the addition of rapamycin leading to degradation of 94% of the tubes. Conclusions Rapamycin allows for an efficient modulation of aspects of angiogenesis in pericytes via mTOR-modulation in vitro. Further studies are needed to elucidate whether rapamycin may have an impact on CNV in nAMD in vivo

The Role of Somatostatin Receptor Scintigraphy on the Diagnosis of Desmoid Tumors

Background. Magnetic resonance imaging is considered as imaging modality of choice in diagnosis of desmoid tumors, though even this technique can lack the ability to distinguish aggressive fibromatosis from other benign or malignant soft tissue tumors. The aim of this study was to investigate if desmoid tumors would show an adequate tracer uptake in somatostatin receptor scintigraphy and moreover to correlate these results with immunohistochemical staining. Patients and Methods. Thirteen patients with desmoid tumors were examined with somatostatin receptor scintigraphy. Additionally, seven of these patients have been tested for the immunohistochemical expression of somatostatin receptor subtype 2A. The results of somatostatin receptor scintigraphy and the results of immunohistochemical staining (somatostatin receptor subtype 2A) were evaluated and correlated. Results. Somatostatin receptor scintigraphy revealed that eight of 13 affected patients (62%) showed an enhanced tracer uptake. On the other hand, the correlation between the results of somatostatin receptor scintigraphy and immunohistochemical investigations was poor (two out of seven cases). Conclusion. The current study demonstrated that desmoid tumors frequently express somatostatin receptor subtype 2, while immunohistochemical investigations did not correlate with these findings. This may likely be due to lack of standardization of this technique and also due to heterogeneous receptor distribution within the tumors

Controversies in the management of patients with soft tissue sarcoma: Recommendations of the Conference on State of Science in Sarcoma 2022.

BACKGROUND Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence. METHODS During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022. RESULTS Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus. CONCLUSIONS In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS

Chordoma Characterization of Significant Changes of the DNA Methylation Pattern

<div><p>Chordomas are rare mesenchymal tumors occurring exclusively in the midline from clivus to sacrum. Early tumor detection is extremely important as these tumors are resistant to chemotherapy and irradiation. Despite continuous research efforts surgical excision remains the main treatment option. Because of the often challenging anatomic location early detection is important to enable complete tumor resection and to reduce the high incidence of local recurrences. The aim of this study was to explore whether DNA methylation, a well known epigenetic marker, may play a role in chordoma development and if hypermethylation of specific CpG islands may serve as potential biomarkers correlated with SNP analyses in chordoma. The study was performed on tumor samples from ten chordoma patients. We found significant genomic instability by Affymetrix 6.0. It was interesting to see that all chordomas showed a loss of 3q26.32 (PIK 3CA) and 3q27.3 (BCL6) thus underlining the potential importance of the PI3K pathway in chordoma development. By using the AITCpG360 methylation assay we elucidated 20 genes which were hyper/hypomethylated compared to normal blood. The most promising candidates were nine hyper/hypomethylated genes C3, XIST, TACSTD2, FMR1, HIC1, RARB, DLEC1, KL, and RASSF1. In summary, we have shown that chordomas are characterized by a significant genomic instability and furthermore we demonstrated a characteristic DNA methylation pattern. These findings add new insights into chordoma development, diagnosis and potential new treatment options.</p> </div

Class comparison results for elucidation of differentially methylated genes in chordoma versus peripheral blood.

<p>Genes significantly (p<0.01) different between classes are depicted, including the parametric p value, false discovery rate (FDR), geometric mean of class-intensities and fold changes are listed.</p

Selected copy number gains/losses of ≥50 frequency. Size is expressed in megabases.

<p>Selected copy number gains/losses of ≥50 frequency. Size is expressed in megabases.</p