Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective treatments. Therefore, there is a need for discovery of novel therapeutic approaches. Patient-derived organoids can accelerate drug discovery and development studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter- as well as intrapatient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-κB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by Neurofibromatosis Type 1 syndrome (NF1). cNFs are fundamentally benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, in NF1 patients, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement with substantial socio-emotional repercussions. To date, surgical removal or laser desiccation are the only treatment options, but can result in scarring and the leave a potential for regrowth. To support drug discovery efforts focused on identifying effective systemic therapies for cNF, we introduce an approach to routinely establish and screen cNF tumor organoids. We optimized conditions to support ex vivo growth of genomically-diverse cNFs. Patient-derived cNF organoids closely recapitulate the molecular and cellular heterogeneity of these tumors as measured by immunohistopathology, DNA methylation, RNA-seq and flow cytometry. Our tractable patient-derived cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.

Background Peer-assisted learning has been shown to be constructive in numerous aspects of undergraduate medical education. The purpose of this study was to evaluate the effectiveness of peer-assisted teaching of medical English skills to nonnative English-speaking medical students. Methods A medical English conversation course was conducted by a group of medical students (i.e. peer-teachers), and targeted participants were intermediate level fellow students from the same program. A longitudinal study was carried out to assess changes in self-assessment of English language skills among course participants. Pre- and post-course appraisal involved a review of previous experience with medical English language, a self-assessment of five English language skills, and an objective measurement of medical English knowledge. In addition, participants were requested to respond to a set of statements related to the importance of medical English skills and the usefulness of peer-assisted teaching of medical English skills. Paired-sample Student t-test was used to compare pre- and post-course appraisal results. Results Forty-two students attended the course and completed pre- and post-course appraisals in full. Data analyses showed a statistically significant increase in participants’ confidence in speaking medical English in public (p < 0.001) and in using English in other medical settings (presenting and discussing cases, writing clinical reports, interviewing patients and reading English medical texts). Objective measurements of medical English knowledge confirmed a significant increase in participants’ knowledge of methods of administration of therapeutics, knowledge of human body parts in English and familiarity with English medical abbreviations. Most course participants agreed that peer-education was effective in teaching medical English skills to non-native English-speaking students and in increasing their confidence when using English in real-life medical scenarios. Conclusions The present study highlights the effectiveness of peer-assisted teaching of medical English skills to nonnative English-speaking medical students. Further validation is required and should compare the effectiveness of traditional versus peer-assisted teaching approaches.

Pheochromocytomas and paragangliomas (PPGL) are rare catecholamine-secreting neuroendocrine tumors known for their genetic diversity. They can be categorized in discrete molecular subgroups, including tumors presenting with pseudohypoxia or kinase signaling activation. Metastatic and recurrent PPGLs have few therapeutic options, in part due to the lack of appropriate study models. Here, we report progress on the establishment of viable organoids from n=10 distinct sporadic or familial PPGLs spanning varios genotypes. We also perform detailed histological, molecular, biochemical, and functional characterization. The ten PPGLs were obtained from patients with distinct clinical history and diverse ethnic and genetic backgrounds. We show how we can generate PPGL organoids from fresh and frozen tissue in a format compatible with histologic characterization and high-throughput drug screening (mini-rings, Phan et al, 2019, Al Shihabi et al, 2022). Our mini ring approach uses fewer cells with no need for expansion in vitro, and is amenable to implement automation for facile high-throughput studies. We can quantify PPGL growth in culture using a machine learning-based pipeline (Al Shihabi et al, 2022). All PPGL organoids for which sufficient number of cells could be obtained grew, regardless of the genotype and molecular subtype. PPGL organoids could be cultured short term (6 days) as well as long term (4 weeks). We investigated cellular composition by staining for the neuroendocrine marker chromogranin A, the sustentacular cell marker S100, and the vascular marker CD34. We also analyzed the expression of catecholamines in the cell culture supernatant by LC/MS/MS. We confirmed that secreted catecholamines matched the primary tumor pattern. Lastly, we present the results of pilot drug screening on both short and long term cultures. Drug sensitivity profiles pinpoint tumor-specific responses. In conclusion, we can establish PPGL organoids that largely recapitulate features of the tumor of origin. These models will provide the ability to investigate tumor initiation and progression for various genetic backgrounds and may reveal novel patterns of drug sensitivity and resistance. Citation Format: Maite Calucho, ZiMing Cheng, Huyen Thi-Lam Nguyen, Ahmad Al Shihabi, Hector Gonzalez-Cantu, Qianjin Guo, Maneesha Thaker, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Patricia Dahia, Alice Soragni. Establishment and validation of pheochromocytoma organoids for high-throughput drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 195.