Development and Internal Validation of Nomograms for Survival of Advanced Epithelial Ovarian Cancer Based on Established Prognostic Factors and Hematologic Parameters.

Objective: To assess the association between pretreatment thrombocytosis, anemia, and leukocytosis and overall survival (OS) of advanced-stage EOC. Furthermore, to develop nomograms using established prognostic factors and pretreatment hematologic parameters to predict the OS of advanced EOC patients. Methods: Advanced-stage EOC patients treated between January 1996 and January 2010 in eastern Netherlands were included. Survival outcomes were compared between patients with and without pretreatment thrombocytosis (≥450,000 platelets/µL), anemia (hemoglobin level of <7.5 mmol/L), or leukocytosis (≥11.0 × 109 leukocytes/L). Three nomograms (for ≤3-, ≥5-, and ≥10-year OS) were developed. Candidate predictors were fitted into multivariable logistic regression models. Multiple imputation was conducted. Model performance was assessed on calibration, discrimination, and Brier scores. Bootstrap validation was used to correct for model optimism. Results: A total of 773 advanced-stage (i.e., FIGO stages IIB-IV) EOC patients were included. The median [interquartile range, IQR] OS was 2.3 [1.3-4.2] and 3.0 [1.4-7.0] years for patients with and without pretreatment thrombocytosis (p < 0.01). The median OS was not notably different for patients with and without pretreatment leukocytosis (p = 0.58) or patients with and without pretreatment anemia (p = 0.07). The final nomograms comprised established predictors with either pretreatment leukocyte or platelet count. The ≥5- and ≥10-year OS models demonstrated good calibration and adequate discrimination with optimism-corrected c-indices [95%-CI] of 0.76 [0.72-0.80] and 0.78 [0.73-0.83], respectively. The ≤3-year OS model demonstrated suboptimal performance with an optimism-corrected c-index of 0.71 [0.66-0.75]. Conclusions: Pretreatment thrombocytosis is associated with poorer EOC survival. Two well-performing models predictive of ≥5-year and ≥10-year OS in advanced-stage EOC were developed and internally validated.

Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1.

The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression.

Chemotherapy sensitivity testing on ovarian cancer cells isolated from malignant ascites.

BACKGROUND: In epithelial ovarian cancer (EOC), 15-20% of the tumors do not respond to first-line chemotherapy (paclitaxel with platinum-based therapy), and in recurrences this number increases. Our aim is to determine the feasibility of cell proliferation assays of tumor cells isolated from malignant ascites to predict in vitro chemotherapy sensitivity, and to correlate these results with clinical outcome. MATERIALS AND METHODS: Ascites was collected from twenty women with advanced EOC. Cell samples were enriched for tumor cells and EOC origin was confirmed by intracellular staining of CK7, surface staining of CA125 and EpCAM, and HE4 gene expression. In vitro sensitivity to chemotherapy was determined in cell proliferation assays using intracellular ATP content as an indirect measure of cell number. In vitro drug response was quantified by calculation of the drug concentration at which cell growth was inhibited with 50%. Clinical outcome was determined using post-treatment CA125 level. RESULTS: Cell samples of twenty patients were collected, of which three samples that failed to proliferate were excluded in the analysis (15%). Three other samples were excluded, because clinical outcome could not be determined correctly. In twelve of the fourteen remaining cases (86%) in vitro drug sensitivity and clinical outcome corresponded, while in two samples (14%) there was no correspondence. CONCLUSIONS: Our study demonstrates the feasibility of drug sensitivity tests using tumor cells isolated from ascites of advanced EOC patients. Larger observational studies are required to confirm the correlation between the in vitro sensitivity and clinical outcome.

Development of a decision aid for primary treatment of patients with advanced-stage ovarian cancer.

INTRODUCTION: Despite renewed treatment options for advanced epithelial ovarian cancer, survival remains poor. The Patient Association and the Gynecological Oncology Working Party in the Netherlands have identified a need for a tool to improve shared decision-making. The aim of this study was to develop an evidence-based online decision aid for patients with advanced epithelial ovarian cancer and their medical team. METHODS: First, we identified the patients' and clinicians' needs using surveys and in-depth interviews. Second, we conducted multidisciplinary face-to-face meetings with representatives from all stakeholders (clinicians and patient representatives) to determine the content of the decision aid. Third, we developed the decision aid using standardized criteria and national guidelines. Finally, we tested the usability of the tool with patients and clinicians who participated in the needs assessment. RESULTS: Patients and clinicians indicated the need for more sources of reliable information that include all treatment options available in the Netherlands. Although most interviewees were satisfied with the level of information available at the time of their own treatment, the majority (90%) of the patients stated that no choice of treatment was offered. We developed a consultation sheet and an online decision aid based on patient interviews and team discussions. The sheet contains a summary of all treatment options and login codes for the decision aid; it will be offered to patients at their first consultation. The decision aid can be used at home and includes information about epithelial ovarian cancer and all available treatment options and questions about quality of life and treatment preferences, delivering a personalized summary for discussion during the following consultation about the primary treatment choices. DISCUSSION: In cooperation with patients and clinicians, we developed a decision aid for advanced-stage epithelial ovarian cancer patients and their medical team to support shared decision-making, based on a confirmed need for more extensive information sources. The decision aid is currently under assessment in a multicenter implementation trial.

Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0.

Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.

Preoperative CT-Angiography Predicts Ex Vivo Vein Length for Right Kidneys After Laparoscopic Donor Nephrectomy.

BACKGROUND Implantation of a kidney with a short renal vein is technically more challenging and therefore prone for technique-related complications. It remains unclear whether pre-operative computed tomography angiography (CTA), to assess vascular anatomy of the donor kidney, can be used to predict renal vein length. MATERIAL AND METHODS Right and left renal vein lengths of 100 consecutive kidney donors were measured in an oblique-coronal plane multiplanar reconstruction image of 100 consecutive kidney donors in whom ex vivo vein length was measured after recovery. In a second retrospective cohort of 100 consecutive kidney donors donating a right kidney, preoperative CTA vein length measurements were correlated to anastomosis time and early graft outcome. RESULTS Left and right renal vein lengths, measured on CTA, were 43.2 mm and 30.0 mm, respectively. No correlation was found between CTA and ex vivo measurements for the left renal vein (p=.610), whereas a significant correlation was found for the right renal vein (p=.021). In the retrospective cohort, right renal vein length was significantly correlated with the anastomosis time but not with early graft outcome. CONCLUSIONS The length of the right, but not the left, renal vein can be predicted by preoperative CTA, but this does not hold true for the left renal vein.