Abstract Many reproductive age women with cancer who receive chemotherapy are exposed to gonadotoxic agents and risk diminished ovarian reserve, sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid (HFF), when added to our stem cell differentiation system, enhances the steroidogenic potential of differentiating stem cells and increases the subpopulation of cells that express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormone synthesis and produces functional stem cell-derived oocytes. Additionally, these cells also ameliorate subfertility in nude mice, as demonstrated by the delivery of multiple litters of healthy pups from stem cell-derived oocytes. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat the endocrinologic and reproductive sequelae of premature ovarian insufficiency. One Sentence Summary We show that orthotopic injection of sorted, differentiated iPSCs in ovaries of subfertile mice restores reproductive hormone synthesis and fertility.
Women with recurrent endometrial cancer who fail carboplatin and paclitaxel have a poor prognosis with few effective options. The recent GARNET Trial showed promising results for dostarlimab in these patients. We developed a decision model to compare the cost-effectiveness of dostarlimab to other treatment options in patients with progressive/recurrent deficient mismatch repair (dMMR) endometrial cancer who have failed first-line chemotherapy.
Methods
A Markov model was created to simulate the clinical trajectory of women with progressive/recurrent dMMR endometrial cancer who failed carboplatin and paclitaxel (figure 1). The initial decision point in the model was treatment with either dostarlimab, pembrolizumab or pegylated liposomal doxorubicin (PLD). Model probabilities, cost and utility values were derived with assumptions drawn from published literature. The effectiveness was measured in terms of quality adjusted life years (QALYs) gained. The primary outcome was incremental cost-effectiveness ratios (ICERs), expressed in 2018 US dollars/QALYs. One-way sensitivity analyses were performed to vary the assumptions across a range of plausible values.
Results
PLD was the least costly strategy at $54,307, followed by pembrolizumab ($160,780) and dostarlimab ($251,132). PLD was cost-effective compared with dostarlimab with an ICER of $199,621, while pembrolizumab was subjected to extended dominance (table 1). Multiple one-way sensitivity analyses did not substantially impact the cost-effectiveness.
Conclusions
Dostarlimab is associated with greater survival compared with other treatments for women with recurrent dMMR endometrial cancer. However, the agent is substantially more costly.
