A 44-year-old woman presented with lower abdominal pain and bilateral ovarian masses on ultrasound. Exploratory laparotomy revealed extensive peritoneal and intra-abdominal disease and an abnormal appendix. Bilateral salpingo-oophorectomy, infracolic omentectomy, ileocolic resection and primary anastomosis were performed. Final pathology revealed a primary appendiceal adenocarcinoma, poorly differentiated, of signet ring cell type. CT scan postoperatively revealed gross residual disease. The patient was treated with FOLFOX chemotherapy combined with bevacizumab. Repeat CT scan showed a decrease in residual disease and the patient clinically improved. After her treatment has been continued for 13 months, she remains clinically well and her CT scan shows sustained disease stability. Disseminated appendiceal carcinoma is generally considered to be refractory to 5-FU-based chemotherapy and, to our knowledge, this is the first reported case of a patient with appendiceal adenocarcinoma demonstrating clinical benefit and sustained stability of disease with combination chemotherapy plus bevacizumab.
Methods: A novel patient-derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by H&E, IHC, and next-generation sequencing (T200.1 panel). Drug efficacy studies of 5-fluorouracil with and without radiotherapy are being performed.Results: Mechanical abrasion of mouse GEJ prior to surgical implantation of patient-derived tumor in situ promotes tumor engraftment (100%, n¼6). Complete PDOX engraftment was observed with rapid intra and extraluminal tumor growth as evidenced by Magnetic Resonance Imaging. Patient-derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Next-generation sequencing with the T200.1 revealed that the loss of heterozygosity of NOTCH3, TGFb1, EZH2, and MLL3 are maintained with similar allelic frequency between the patient tumor and the two xenografts. Additional somatic SNVs such as ARID1A, NSD1 (CDS157-158), NSD1 (CDS158-159), KDM6A, XPO1, MAPK1 and EGFR were found to be acquired in xenograft tumor tissues that were not observed in patient tumor. Targeted radiation resulted in (60%) partial response as assessed by RECIST and tumor volume measurements. Drug and radiation efficacy studies are currently ongoing. It will be important to note if the PDOX model reproduces the results observed in clinical trials for these patients. Conclusion:A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating to clinics. This model can be applied to address the importance of tumor microenvironment in metastatic and immunological studies and to develop novel therapeutic approaches for the treatment of GEJ cancer.Legal entity responsible for the study: The author.
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