Non-gestational choriocarcinoma with hyperprogression on pembrolizumab: A case report and review of the literature.

Non-gestational choriocarcinoma is a rare and aggressive germ cell tumor. Here we present the case of a post-menopausal 49-year-old woman who presented with metastatic disease and initially achieved a complete radiographic and biomarker response with seven cycles of EMA-CO chemotherapy. Upon recurrence, she received two separate courses of chemotherapy, initially with paclitaxel/cisplatin/etoposide and later FOLFOX. Tumor analysis revealed 22% PD-L1 positivity (tumor proportion score) and she was treated with pembrolizumab. However, ßhCG levels rose abruptly and uncharacteristically through all three cycles of anti-PD1 therapy. The patient developed dyspnea on exertion, cough, and right flank pain. CT imaging demonstrated marked progression of liver metastases and innumerable new pulmonary metastases and the patient died 10 weeks after starting pembrolizumab. Here we describe the clinical presentation and management of this patient, along with analysis of molecular aberrations which could potentially explain hyperprogression in response to pembrolizumab.

The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer.

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.

Increased cell-free fetal DNA release after apoptosis and sterile inflammation in human trophoblast cells.

PROBLEM: Cell-free fetal DNA (cffDNA) shed from the placenta can be detected in maternal blood and increases incrementally during gestation. Concentrations are further elevated with pregnancy complications. Specific activators of cffDNA release in such complications have not been identified. Here, we use trophoblast cells from early and term placenta to examine cffDNA release following apoptosis, infection, and sterile inflammatory stress. METHOD OF STUDY: HTR8/SVneo cells were used to model first-trimester trophoblasts, and term cytotrophoblasts (CTBs) were isolated from placentae collected after uncomplicated deliveries. Trophoblasts were treated with varying concentrations of doxorubicin (DOX), lipopolysaccharide (LPS), or high-mobility group box protein 1 (HMGB1) for 18 h. Cells or supernatants were quantified for caspase-3/7 cleavage, pro-inflammatory cytokine secretion, and cffDNA release. RESULTS: Both HTR8/SVneo and CTBs underwent caspase-3/7 cleavage following DOX treatment, with HTR8/SVneo cells more sensitive to apoptosis than term CTBs. Apoptotic cells released more cffDNA in a dose-dependent manner. Treatment with LPS resulted in an increase in pro-inflammatory IL-6 release, particularly in term CTBs compared to early trophoblasts; however, LPS did not affect cffDNA release. Lastly, while neither cell released more TNF-α following stimulation with HMGB1, both HTR8/SVneo and CTBs released significantly more cffDNA in the presence of HMGB1. CONCLUSIONS: These data show that apoptosis and sterile inflammation induced by DOX and HMGB1, respectively, cause an increase in cffDNA concentrations in both first-trimester and term trophoblasts. Understanding physiologic release of cffDNA during healthy and complicated pregnancy can identify new targets for the diagnosis and treatment of gestational complications.

Heart Block Caused by Cardiac Metastasis From Merkel Cell Carcinoma: A Case Report.

Merkel cell carcinoma (MCC) is a rare, rapidly proliferating skin cancer that commonly metastasizes to regional lymph nodes. We present the case of a 73-year-old woman with a history of MCC and non-Hodgkin B-cell lymphoma who presented with second-degree heart block (Mobitz type II) caused by an interatrial mass. Temporary pacing was required before biopsy, which revealed metastatic MCC. Treatment included permanent pacing, anti-programmed cell death ligand 1 immunotherapy, and radiation to the heart resulting in notable decrease in tumor size and normalized cardiac rhythm.

Whole-Genome Analysis of Individual Meiotic Events in Drosophila melanogaster Reveals That Noncrossover Gene Conversions Are Insensitive to Interference and the Centromere Effect.

A century of genetic analysis has revealed that multiple mechanisms control the distribution of meiotic crossover events. In Drosophila melanogaster, two significant positional controls are interference and the strongly polar centromere effect. Here, we assess the factors controlling the distribution of crossovers (COs) and noncrossover gene conversions (NCOs) along all five major chromosome arms in 196 single meiotic divisions to generate a more detailed understanding of these controls on a genome-wide scale. Analyzing the outcomes of single meiotic events allows us to distinguish among different classes of meiotic recombination. In so doing, we identified 291 NCOs spread uniformly among the five major chromosome arms and 541 COs (including 52 double crossovers and one triple crossover). We find that unlike COs, NCOs are insensitive to the centromere effect and do not demonstrate interference. Although the positions of COs appear to be determined predominately by the long-range influences of interference and the centromere effect, each chromosome may display a different pattern of sensitivity to interference, suggesting that interference may not be a uniform global property. In addition, unbiased sequencing of a large number of individuals allows us to describe the formation of de novo copy number variants, the majority of which appear to be mediated by unequal crossing over between transposable elements. This work has multiple implications for our understanding of how meiotic recombination is regulated to ensure proper chromosome segregation and maintain genome stability.