Most high-grade serous ovarian carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). FT secretory cells become malignant by accumulating genomic aberrations over 6-7 years before seeding the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical surface of STIC lesions and contributed to ovarian colonization by upregulating integrin and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study metastasis to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in L1CAM-dependent manner. words

Most ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical cells of STIC lesions and contributed to ovarian colonization by upregulating integrins and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study dissemination to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in a L1CAM-dependent manner.

Background: Upadacitinib is a selective Janus kinase inhibitor approved by the FDA in March 2022 for the treatment of patients with moderate to severe ulcerative colitis (UC) who have had an inadequate response or intolerance to anti-tumor necrosis factor alpha agents (TNF-a). Methods: This single center retrospective cohort study included adult patients (age .18 years) with moderate to severe UC who were prescribed upadacitinib at the Mayo Clinic, Rochester, Minnesota. After obtaining institutional review board approval, we searched the electronic medical record to identify patients with UC who had previously failed therapy with Anti-TNF-a and were subsequently treated with Upadacitinib. The primary outcome was clinical response as described by patient reported outcomes. Outcomes were assessed at patients' most recent follow-up. We also evaluated for adverse events. Results: A total of 23 UC patients received upadacitinib and were included in this analysis. The median age at diagnosis was 31 years, (range 23-54 years) and 11 patients were males. Prior medications included Azathioprine (n55), Vedolizumab (n515) Ustekinumab (n512) and Tofacitinib (n57). Pre-treatment endoscopic severity was graded as Mayo 2 in 11 and Mayo 3 in 12 cases. The median pretreatment Calprotectin and serum C-reactive protein (CRP) were 920 mcg/g (range 200-3469) and 13 mg/L (range 3-36) respectively. Post treatment information is available for 17 patients (last follow up: September 15, 2022). Median treatment duration was 84 day (16-334 days). Clinical improvement was observed in 12 (70.5%) patients. Amongst the 5 cases that did not respond, 3 cases had primary sclerosing cholangitis, 1 underwent colectomy and colectomy is being considered in 2 cases. There were no adverse effects reported with Upadacitinib use. Conclusion(s):In a single center cohort of 23 patients with UC refractory to anti-TNF-a, upadacitinib use resulted in clinical improvement in 70% of patients with no adverse events. Further longterm data is being collected.