Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors.

Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.

Sarcoma Spheroids and Organoids-Promising Tools in the Era of Personalized Medicine.

Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes. Their low incidence and high level of histopathological heterogeneity have greatly limited progress in their treatment, and trials of clinical sarcoma are less frequent than trials of other carcinomas. The main advantage of 3D cultures from tumor cells or biopsy is that they provide patient-specific models of solid tumors, and they overcome some limitations of traditional 2D monolayer cultures by reflecting cell heterogeneity, native histologic architectures, and cell-extracellular matrix interactions. Recent advances promise that these models can help bridge the gap between preclinical and clinical research by providing a relevant in vitro model of human cancer useful for drug testing and studying metastatic and dormancy mechanisms. However, additional improvements of 3D models are expected in the future, specifically the inclusion of tumor vasculature and the immune system, to enhance their full ability to capture the biological features of native tumors in high-throughput screening. Here, we summarize recent advances and future perspectives of spheroid and organoid in vitro models of rare sarcomas that can be used to investigate individual molecular biology and predict clinical responses. We also highlight how spheroid and organoid culture models could facilitate the personalization of sarcoma treatment, provide specific clinical scenarios, and discuss the relative strengths and limitations of these models.

Segmental vs non-segmental thoracic pedicle screws constructs in adolescent idiopathic scoliosis: is there any implant alloy effect?

PURPOSE: The aim of this study is to understand how many anchor sites are necessary to obtain maximum posterior correction of idiopathic scoliotic curve and if the alloy of instrumentation, stainless steel or titanium, may have a role in the percent of scoliosis correction. METHODS: We reviewed 143 consecutive patients, affected by AIS (Lenke 1-2), who underwent a posterior spinal fusion with pedicle screw-only instrumentation between 2002 and 2005. According to the implant density and alloy used we divided the cohort in four groups. RESULTS: All 143 patients were reviewed at an average follow-up of 7, 2 years, the overall final main thoracic curve correction averaged 61.4%, whereas the implant density within the major curve averaged 71%. A significant correlation was observed between final% MT correction and preoperative MT flexibility and implant density. CONCLUSIONS: When stainless steel instrumentation is used non-segmental pedicle screw constructs seem to be equally effective as segmental instrumentations in obtaining satisfactory results in patients with main thoracic AIS. When the implant alloy used is titanium one, an implant density of ≥60% should be guaranteed to achieve similar results.

Clinical and microbiological outcomes in haematogenous spondylodiscitis treated conservatively.

INTRODUCTION: Spondylodiscitis refers to infections of the intervertebral disc and the adjacent vertebral body. Although it is still considered a rare condition, its rate is projected to increase. Mortality rate is considered to be low, but an estimated one third of the survivors experience residual disabilities. Literature shows that uncomplicated spondylodiscitis can be adequately treated by early antibiotic therapy and immobilization. The aim of the study is to evaluate the outcome of conservative treatment in patients with haematogenous spondylodiscitis. MATERIALS AND METHODS: All patients with haematogenous spondylodiscitis observed in two orthopaedic centres were retrospectively considered. The medical records, radiologic imaging, bacteriology results, treatment, and complications of all patients were reviewed. RESULTS: Thirty patients (median age 64 years, range 15-77, females 56.7%) were considered in the study, eight (26.7%) showed residual back pain at median follow-up of 117 weeks (range 104-189). A significant difference in SF-36 physical (P < 0.001), SF-36 mental function (P < 0.002), and Oswestry Disability Index (ODI) (P < 0.001) scores was observed among patients with residual local pain compared to the ones who had not. Methicillin-resistant Staphylococcus aureus (MRSA) infection and symptoms duration before the diagnosis were associated with an increased risk of persistent back pain and permanent disability. The most important negative determinants of SF-36 mental function were the age of patients (ρ = 0.36, P < 0.05), the duration of symptoms before the diagnosis (ρ = 0.44, P < 0.05) and MRSA infection (P = 0.006). Spondylodiscitis sustained by MRSA and the duration of symptoms before the diagnosis influenced negatively the physical status (P = 0.002) and ODI (ρ = 0.36, P < 0.05), respectively. CONCLUSIONS: Conservative approaches are safe and effective for patients without complications. A delayed diagnosis and MRSA infections are related to poor clinical outcome among patients treated by conservative treatment; this must be carried out scrupulously with close patient monitoring.

Epigenetic therapies of osteoporosis.

The study of epigenetics reaches its 50th anniversary, however, its clinical application is gradually coming into the clinical setting. Osteoporosis is one of the major and widely diffused bone diseases. Pathogenic mechanisms at the epigenetic level may interfere with bone remodeling occurring during osteoporosis. Preclinical models were used to understand whether such events may interfere with the disease. Besides, observational clinical trials investigated epigenetic-related biomarkers. This effort leads to some epigenetic-related therapies in clinical trials for the treatment of osteoporosis. Bisphosphonates (BPs), target therapy blocking RANK/RANKL pathway, and anti-sclerostin antibody (SOST) are the main therapeutic approaches. However, future large trials will reveal whether epigenetic therapies of osteoporosis will remain a work in progress or data will become more robust in the real-world management of these frailty patients.

Yin Yang I as an Epimodulator of miRNAs in the Metastatic Cascade.

Yin Yang 1 (YY1) belongs to the polycomb group (PcG) of proteins that modify chromatin epigenetically during dynamic regulation of their target genes. The predominant feature of YY1 is the zinc finger, an ancient structural motif that mediates protein-protein interactions and is capable of interacting with both DNA and RNA. Evidence reveals that YY1 acts predominantly as an epigenetic modulator, influencing the activity and/or localization of epigenetic modifiers molecules such as DNA methylation transferases, histone deacetylases, or non-coding RNAs. Deregulation of the epigenome is observed frequently in a variety of cancer types and is often correlated directly with advanced metastatic stages and poor prognosis. In this review, we address the current understanding of YY1 as a recruiter of epi-modifier molecules in the mechanism of aberrant regulation of target genes as a part of the metastatic cascade.

Post-surgery fluids promote transition of cancer stem cell-to-endothelial and AKT/mTOR activity, contributing to relapse of giant cell tumors of bone.

Giant cell tumors of bone (GCTB) are rare sarcomas with a high rate of unpredictable local relapse. Studies suggest that surgical methods affect recurrence, supporting the idea that local disease develops from re-growth of residual cancer cells. To identify early prognostic markers of individual risk of recurrence, we evaluated the effect of post-surgery fluids from a cohort of GCTB patients on growth of primary and established sarcoma cell lines, and mice xenograph. Post-surgery fluids increased cell growth and enhanced expression of CD44++, the principal receptor for the extracellular matrix component hyaluronan and the mesenchymal stem marker CD117+. Cancer cells became highly invasive and tumorigenic, acquiring stemness properties, and activated AKT/mTOR pathway. Prolonged stimulation with post-surgery fluids down-regulated the mesenchymal gene TWIST1 and Vimentin protein, and transdifferentiated cells into tubule-like structures positive to the endothelial markers VE-Cadherin and CD31+. In mice, post-surgery fluids gave rise to larger and more vascularized tumors than control, while in patients AKT/mTOR pathway activation was associated with recurrence by logistic regression (Kaplan-Meier; P<0.001). These findings indicate that post-surgery fluids are an adjuvant in mechanisms of tumor regrowth, increasing stem cell growth and AKT/mTOR activity.