Multiplex serum immune profiling reveals circulating LAG-3 is associated with improved patient survival in high grade serous ovarian cancer.

OBJECTIVE: High grade serous ovarian cancer (HGSOC) exhibits low response rates to clinically available immunotherapies. Nevertheless, emerging research has demonstrated that certain immune factors are predictive for HGSOC patient clinical outcomes, with our own groups previous work demonstrating that intratumoral levels of the immune checkpoint receptor LAG-3 is associated with improved patient survival. In this current study we sought to uncover non-invasive circulating immune prognostic and predictive signatures in HGSOC. METHODS: A multiplex approach was employed that examined circulating levels of immune checkpoint receptors LAG-3 and PD-1 along with 48 common cytokine and chemokines in a cohort of 75 HGSOC treatment naïve patient serum samples. RESULTS: Elevated serum LAG-3 was significantly associated with improved progression-free survival (PFS) and overall survival (OS) in HGSOC, while circulating PD-1 levels were largely unrelated with patient clinical outcomes. Cytokine and chemokine analysis revealed lower IL-15 expression correlated with improved PFS and OS, while increased IL-1α, IL-1Ra, IL-6, IL8 and VEGF were significantly associated with preoperative CA-125 levels. ROC analysis demonstrated that serum LAG-3 levels exhibited consistent reasonable predictability as a single agent. CONCLUSIONS: Serum-derived LAG-3 was identified out of a diverse array of chemokine and cytokines as the immune-based factor most significantly associated with improved HGSOC survival. These findings suggest that LAG-3 could be implemented as a non-invasive patient predictive marker for improved HGSOC clinical outcomes.

Adaptive transcriptomic and immune infiltrate responses in the tumor immune microenvironment following neoadjuvant chemotherapy in high grade serous ovarian cancer reveal novel prognostic associations and activation of pro-tumorigenic pathways.

The high rate of ovarian cancer recurrence and chemoresistance necessitates further research into how chemotherapy affects the tumor immune microenvironment (TIME). While studies have shown that immune infiltrate increases following neoadjuvant (NACT) chemotherapy, there lacks a comprehensive understanding of chemotherapy-induced effects on immunotranscriptomics and cancer-related pathways and their relationship with immune infiltrate and patient responses. In this study, we performed NanoString nCounter® PanCancer IO360 analysis of 31 high grade serous ovarian cancer (HGSOC) patients with matched pre-treatment biopsy and post-NACT tumor. We observed increases in pro-tumorigenic and immunoregulatory pathways and immune infiltrate following NACT, with striking increases in a cohort of genes centered on the transcription factors ATF3 and EGR1. Using quantitative PCR, we analyzed several of the top upregulated genes in HGSOC cell lines, noting that two of them, ATF3 and AREG, were consistently upregulated with chemotherapy exposure and significantly increased in platinum resistant cells compared to their sensitive counterparts. Furthermore, we observed that pre-NACT immune infiltrate and pathway scores were not strikingly related to platinum free interval (PFI), but post-NACT immune infiltrate, pathway scores, and gene expression were. Finally, we found that higher levels of a cohort of proliferative and DNA damage-related genes was related to shorter PFI. This study underscores the complex alterations in the ovarian TIME following chemotherapy exposure and begins to untangle how immunologic factors are involved in mediating chemotherapy response, which will allow for the future development of novel immunologic therapies to combat chemoresistance.

The feasibility of screening for malnutrition in the outpatient setting and the prevalence of malnutrition in patients with newly-diagnosed ovarian carcinoma.

Introduction: Malnutrition is an independent risk factor for poor surgical outcomes, early chemotherapy discontinuation, and increased mortality. We evaluated the feasibility of outpatient malnutrition screening in patients with suspected gynecologic malignancy. We estimated the prevalence of malnutrition using Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (AND-ASPEN) criteria in patients undergoing surgery for newly-diagnosed ovarian carcinoma (OC). Methods: Patients scheduling a new clinic appointment for suspected gynecologic malignancy from 2/2018-2/2019 completed the Malnutrition Screening Tool via phone. Patients with positive screening test were recommended expedited Nutrition consultation. To estimate the prevalence of malnutrition in patients with newly-diagnosed OC, formal malnutrition evaluation by a Registered Dietician was ordered during hospitalization for all patients undergoing surgery (primary cytoreduction and interval cytoreduction) for newly-diagnosed OC. Results: Of 187 outpatients screened, 29 (16%) had a positive malnutrition screen. Eleven of 29 (38%) were willing to schedule outpatient Nutrition appointment; four were evaluated. Two (1% of all outpatients screened) were diagnosed with malnutrition. 107 patients underwent surgery for primary OC; 70 received Nutrition consult. Only 3 of 70 (4%) were formally diagnosed with malnutrition using AND-ASPEN criteria. Conclusion: Outpatient screening of patients with suspected gynecologic malignancy for malnutrition is feasible. However, the prevalence of malnutrition detected through outpatient screening and in the newly-diagnosed OC population is surprisingly low, suggesting that outpatient screening at time of initial consultation may not be ideal timing. Improving access to dietitians during chemotherapy and later in the cancer course when malnutrition is likely more prevalent may be beneficial.

A case of metastatic dysgerminoma treated with two cycles neoadjuvant chemotherapy followed by fertility-sparing minimally invasive surgery.

•Neoadjuvant chemotherapy (NACT) followed by fertility-sparing surgery is a feasible treatment of metastatic dysgerminoma•As few as two cycles of NACT may result in enough of a tumor response for fertility-sparing surgery to be possible.•Tumor lysis syndrome is a possibility when administering chemotherapy to patients with metastatic dysgerminoma.

Two cases of extragonadal malignant transformation of endometriosis after TAH/BSO for benign indications.

•Extragonadal malignant transformation of endometriosis can occur after oophorectomy.•Endometriosis-associated malignancy can occur in the absence of hormone replacement.•Estrogen and progesterone receptor status can influence treatment strategies.•The role of chemotherapy for malignant transformation of endometriosis is not clear.

Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells.

Host-microbial interactions play a key role during the development of colitis. We have previously shown that chinase 3-like 1 (CHI3L1) is an inducible molecule overexpressed in colonic epithelial cells (CECs) under inflammatory conditions. In this study, we found that chitin-binding motif (CBM) of CHI3L1 is specifically associated with the CHI3L1-mediated activation of the Akt-signaling in CEC by transfecting the CBM-mutant CHI3L1 vectors in SW480 CECs. Downstream, CHI3L1 enhanced the secretion of IL-8 and TNFα in a dose-dependent manner. We previously show that 325 through 339 amino-acids in CBM are crucial for the biological function of CHI3L1. Here we demonstrated that 325th-339th residues of CBM in CHI3L1 is a critical region for the activation of Akt, IL-8 production, and for a specific cellular localization of CHI3L1. In conclusion, CBM region of CHI3L1 is critical in activating Akt signaling in CECs, and the activation may be associated with the development of chronic colitis.

Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells.

The family of mammalian chitinases includes members both with and without glycohydrolase enzymatic activity against chitin, a polymer of N-acetylglucosamine. Chitin is the structural component of fungi, crustaceans, insects and parasitic nematodes, but is completely absent in mammals. Exposure to antigens containing chitin- or chitin-like structures sometimes induces strong T helper type-I responses in mammals, which may be associated with the induction of mammalian chitinases. Chitinase 3-like-1 (CHI3L1), a member of the mammalian chitinase family, is induced specifically during the course of inflammation in such disorders as inflammatory bowel disease, hepatitis and asthma. In addition, CHI3L1 is expressed and secreted by several types of solid tumors including glioblastoma, colon cancer, breast cancer and malignant melanoma. Although the exact function of CHI3L1 in inflammation and cancer is still largely unknown, CHI3L1 plays a pivotal role in exacerbating the inflammatory processes and in promoting angiogenesis and remodeling of the extracellular matrix. CHI3L1 may be highly involved in the chronic engagement of inflammation which potentiates development of epithelial tumorigenesis presumably by activating the mitogen-activated protein kinase and the protein kinase B signaling pathways. Anti-CHI3L1 antibodies or pan-chitinase inhibitors may have the potential to suppress CHI3L1-mediated chronic inflammation and the subsequent carcinogenic change in epithelial cells.