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Among women who are undergoing in vitro fertilization (IVF), the transfer of frozen embryos has been shown to result in a higher rate of live birth than the transfer of fresh embryos in those with infertility associated with the polycystic ovary syndrome. It is not known whether frozen-embryo transfer results in similar benefit in women with infertility that is not associated with the polycystic ovary syndrome.We randomly assigned 782 infertile women without the polycystic ovary syndrome who were undergoing a first or second IVF cycle to receive either a frozen embryo or a fresh embryo on day 3. In the frozen-embryo group, all grade 1 and 2 embryos had been cryopreserved, and a maximum of two embryos were thawed on the day of transfer in the following cycle. In the fresh-embryo group, a maximum of two fresh embryos were transferred in the stimulated cycle. The primary outcome was ongoing pregnancy after the first embryo transfer.After the first completed cycle, ongoing pregnancy occurred in 142 of 391 women (36.3%) in the frozen-embryo group and in 135 of 391 (34.5%) in the fresh-embryo group (risk ratio in the frozen-embryo group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.65). Rates of live birth after the first transfer were 33.8% and 31.5%, respectively (risk ratio, 1.07; 95% CI, 0.88 to 1.31).Among infertile women without the polycystic ovary syndrome who were undergoing IVF, the transfer of frozen embryos did not result in significantly higher rates of ongoing pregnancy or live birth than the transfer of fresh embryos. (Funded by My Duc Hospital; ClinicalTrials.gov number, NCT02471573 .).

Background Colorectal cancer (CRC) is the second leading cause of cancer related mortality. Over 80% of CRC develop from adenomatous polyps. Hence, early treatment and prevention of adenomas would lead to a significant decrease of disease burden for CRC. MYB is a transcription factor that is over-expressed in both adenomatous polyp precursors and colorectal cancer and hence an ideal immunotherapeutic target. We have developed a cancer vaccine, TetMYB, that targets MYB and aim to evaluate its efficacy in the prophylactic and therapeutic management of adenomatous polyps. Material and Methods Six to eight-week-old Apcmin/+ (Familial Adenomatous Polyposis model) and Apc580S (sporadic model) C57BL/6 mice were used. The Apcmin/+ mice are carried a germline mutation of one Apc allele whereas the Apc580S model has an inducible silencing of one Apc allele, when exposed to Tamoxifen, via the Cre-Lox recombination enzyme system. In the prophylactic treatment group, Apcmin/+ and Apc580S C57BL/6 mice were vaccinated and then surveyed for clinical signs of distress according to animal ethical endpoints. Number of adenoma and survival were measured. In the therapeutic cohort, Apc580S C57BL/6 mice were given Tamoxifen-laced food to activate Cre-Lox recombinase mediated silencing of one Apc allele and thus inducing adenoma development. Following adenoma detection using mouse colonoscopy, mice were vaccinated with TetMYB and treated with anti-PD-1 antibody and were analyzed for adenoma growth rate. Results In both the prophylactic and therapeutic setting, mice vaccinated with TetMYB had a significantly improved outcome. In the prophylactic treatment group, the vaccinated Apcmin/+ mice had a median survival benefit of 70 days (p = 0.008) and the vaccinated Apc580S mice having a mean survival benefit of 134 days (p = 0.01) over the unvaccinated mice. In the prophylactic cohort, immunofluorescence confirmed a stronger cytotoxic CD8+ T-cell infiltrate in the vaccinated group, implying an anti-tumor immune response. In the therapeutic cohort, vaccinated Apc580S mice showed significantly reduced adenoma growth rate compared to the unvaccinated mice (p = 0.0005). Conclusion TetMYB vaccine has shown benefit in a prophylactic and therapeutic setting in the management of colonic adenoma in a murine model. This will form the basis for a future clinical trial to prevent and treat colonic adenomatous polyps, and perhaps colorectal cancer prevention. Citation Format: Toan D. Pham, Sandra Carpinteri, Shienny Sampurno, Lloyd Pereira, Sara Roth, Vignesh Narasimhan, Kasmira Wilson, Phillip Darcy, Jayesh Desai, Alexander G. Heriot, Robert G. Ramsay. Novel vaccine targeting colonic adenoma: A pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1472.

Although many patients with localised anal squamous cell carcinoma (ASCC) initially achieve a complete response with standard chemoradiotherapy, those with persistent, relapsed or metastatic disease (35% of all patients) have limited treatment options and poor outcomes. Recent genomic profiling studies have identified PIK3CA as the most frequently mutated gene in anal cancers. Amplification of the PIK3CA gene and mutations in other PI3K pathway genes, have also been detected providing a strong rationale for targeting the PI3K pathway in these tumours. Similarly, the finding that many ASCC tumours express immune checkpoint receptors including PD-L1, has focussed attention on the potential use of checkpoint blockade in anal cancer. However, the use of targeted and/or immune therapies in the management of ASCC has been hampered by a lack of representative preclinical models for in vitro and in vivo testing of potential new therapeutic approaches. We have used mice with a Cre recombinase (Cre)-conditional knock-in of the Pik3caH1047R mutation and deletion of PTEN, crossed with mice expressing a tamoxifen-inducible Cre under the control of the ubiquitin C promoter, to generate a novel model of ASCC. By applying 4-hydroxy-tamoxifen topically to the anal canal we simultaneously induce expression of Pik3caH1047R and deletion of PTEN specifically in the anal epithelium. This results in anal tumors within 3 weeks with 100% penetrance. As all mice are on a C57Bl/6 background we are able to transplant the tumors subcutaneously into wild type C57Bl/6 mice as a syngeneic graft. To improve the utility of the model, we used tumors from these mice to establish a syngeneic mouse ASCC cell line. This line was then transduced with a human papilloma virus 16 E6/7 lentivirus to recapitulate the human virally-driven form of the disease. The cell line expresses both the Pik3ca mutation and E6/7 oncogenes and is positive for the squamous markers p63 and CK5/6. It had a similar response to 5-fluorouracil, Mitomycin C and radiotherapy, as a panel of human ASCC cell lines (also derived in our laboratory) and was sensitive to a PI3K inhibitor (BYL719). It was tumorigenic in both immunocompetent C57Bl/6 and immunodeficient NSG mice, additionally developing lung metastases in the NSG mice. The syngeneic C57Bl/6 tumors induce a peri-tumoral infiltrate, consisting of a heavy myeloid population, with high PDL1 expression, and a T-cell population expressing PD1; similar to human patients with treatment resistant disease. A major barrier to identifying new treatment options and improving overall survival in anal cancer has been the lack of preclinical models. We have now generated and characterised a novel, relevant Pik3ca-driven mouse model and syngeneic cancer cell line that will facilitate the in vitro and in vivo preclinical testing of targeted and immune therapies for ASCC. Citation Format: Glen R. Guerra, Sara Roth, Joseph C. Kong, Rosemary M. Millen, David S. Liu, Shienny Sampurno, Vignesh Narasimhan, Toan D. Pham, Karen G. Montgomery, Alexander G. Heriot, Robert G. Ramsay, Wayne A. Phillips. A novel Pik3ca-driven mouse model and syngeneic cancer cell line for the preclinical testing of targeted and immune therapies for anal squamous cell carcinoma (ASCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4618.