Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma.

AIMS: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment. METHODS AND RESULTS: Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2]). CONCLUSIONS: The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.

TP53 as a Diagnostic Aid in the Distinction of Ovarian Mucinous Borderline Tumors From Mucinous Carcinoma.

Ovarian mucinous borderline tumors (MBTs) are clinically managed as benign neoplasms while the management of ovarian mucinous carcinomas (MC) is dependent on tumor stage. Despite the standardization of sampling of ovarian mucinous neoplasms, limited interobserver reproducibility between MBT and MC persists. Based on our recent finding that abnormal TP53 expression is associated with unfavorable outcome in MBT, we hypothesized that TP53 status might improve the reproducible distinction of MBT from MC. A virtual slide set of 85 consecutive ovarian mucinous neoplasms received at a single institution, with each case represented by 3 full sections, were reviewed by 3 pathologists in 2 iterations. The initial assessment was based solely on morphologic review, while the second iteration was performed with knowledge of TP53 status. The reproducibility of a trinary categorization (MBT, MBT with intraepithelial carcinoma [IEC], MC) significantly improved from a κ of 0.60 based on the initial morphologic assessment to a κ of 0.76 (t-test, P =0.0042) after consideration of TP53 immunohistochemistry (IHC) results. Six out of 85 patients died of disease, and in 2 of them, at least 1 pathologist assessed MBT with IEC and not MC even after integration of TP53 IHC. With the integration of TP53 IHC, substantial interobserver agreement for MBT and MC can be reached, particularly in cases with an uncertain degree of confluent growth. TP53 IHC can also be used to highlight and support the presence of IEC in MBT, however, discordances remained in 2 cases with adverse outcome.

Effects of an Early Pregnancy Assessment Clinic (EPAC) on the Management of Spontaneous Abortions.

OBJECTIVE: Patients who experience spontaneous abortion often present to the emergency department (ED), which may restrict the physician's recommendations for and the patient's choice of therapy. With support provided by an early pregnancy assessment clinic (EPAC), expectant and medical management may become more feasible options for spontaneous abortion. This study aimed to compare the therapeutic choices before and after the establishment of an EPAC and hypothesized that the proportion of miscarriages treated expectantly or medically would increase. METHODS: We conducted a retrospective cohort study that compared patients presenting to the ED and the EPAC with spontaneous abortion. We excluded patients with hemodynamic instability, complete abortions, ectopic pregnancies, and molar pregnancies. The primary outcome was the initial chosen treatment. The retrospective chart review included demographics, type of spontaneous abortion and management, procedural dictations, ED notes, and EPAC clinic documentation. Secondary end points included wait times, repeat visits, and success rates for the initial treatment option. RESULTS: We reviewed 103 ED and 92 EPAC patient records. Patients in the ED were 1.52 times more likely to choose surgery over expectant or medical management (P = 0.004). Patients in the ED were 1.41 times more likely to have surgery as their final treatment compared with patients in the EPAC (P = 0.006). There were no significant differences in length of stay, number of visits required, or adverse outcomes. CONCLUSION: Our study demonstrates that an EPAC results in more patients choosing and successfully being treated by expectant or medical management for spontaneous abortion.

Occult Leiomyosarcomas in a Canadian Province: A Retrospective Cohort Study.

OBJECTIVE: The risk of unexpected uterine leiomyosarcoma (LMS) following surgery for presumed benign leiomyoma is quoted to be between 1 in 498 and 1 in 5000. The objectives of the present study were to determine the prevalence of uterine LMS in a specific patient population and the rate of diagnosis of occult uterine LMS and to evaluate the risk of unintended morcellation of LMS in Saskatchewan. METHODS: This study was a Canadian Task Force Classification II-2 multicentre retrospective cohort study in academic-affiliated tertiary care centres. All women with the histopathologic diagnosis of uterine LMS in Saskatchewan between January 2000 and December 2014 were included. Women with metastatic LMS at diagnosis or other types of uterine sarcomas were excluded. Data including patients' characteristics, clinical presentation, physical examination findings, imaging, pathology reports, surgical interventions, and survival outcomes were reviewed. RESULTS: A total of 28 patients had a confirmed histopathologic diagnosis of LMS over the 15-year study period. Approximately 26 212 hysterectomies were performed in Saskatchewan over the same time frame. The prevalence of uterine LMS in this patient population over the study time frame is estimated to be one in 853. Mean age at diagnosis was 53.8 ± 10.0. Medical records of 25 patients could be retrieved, and 15 cases (60%) had an occult diagnosis. There were five cases of unintended morcellation (one power, four mechanical). Survival outcomes were comparable in women with unintended morcellation of occult disease and in those without morcellation. CONCLUSION: This study contributes to the existing body of literature on morcellation of occult LMS, and it ascertains the rate of LMS in a patient population. The results of this study provide valuable information to health care professionals, policy makers, and women in Saskatchewan so that they may make more informed decisions concerning uterine masses.

Ferric derisomaltose and Outcomes in the Recovery of Gynecologic oncology: ERAS (Enhanced Recovery After Surgery) (FORGE) - a protocol for a pilot randomised double-blinded parallel-group placebo-controlled study of the feasibility and efficacy of intravenous ferric derisomaltose to correct preoperative iron-deficiency anaemia in patients undergoing gynaecological oncology surgery.

INTRODUCTION: Iron-deficiency anaemia is common in gynaecological oncology patients. Blood transfusions are immunosuppressive and carry immediate and long-term risks. Oral iron replacement remains the standard of care but requires prolonged treatment courses associated with gastrointestinal side effects, poor compliance and variable absorption in cancer patients. Intravenous iron has been shown to decrease the need for allogeneic blood transfusion in gynaecological oncology patients undergoing chemotherapy, but the efficacy of this treatment in the preoperative period is unknown. The goal of this pilot study is to determine the effect of intravenous ferric derisomaltose on preoperative haemoglobin in patients undergoing surgery for gynaecological malignancy. METHODS AND ANALYSIS: We will conduct a pilot single-centre, parallel-arm randomised controlled trial of intravenous ferric derisomaltose versus placebo among consenting patients with iron-deficiency anaemia having elective major surgery on the gynaecological oncology service. Patients, clinicians and outcome assessors will be blinded. The intervention consists of a single infusion of 500-1000 mg of intravenous ferric derisomaltose administered a minimum of 21 days prior to the planned operation. The primary outcome is mean preoperative haemoglobin concentration measured 0-3 days prior to surgery in patients receiving intravenous ferric derisomaltose compared with those receiving placebo. Secondary outcomes include the following: change in haemoglobin concentration, postoperative haemoglobin concentration, perioperative blood transfusion rates, patient-reported quality of life scores (Quality of Recovery 15, Modified Short Form 36 v1, EuroQol 5-dimension 5-level and Functional Assessment of Cancer Therapy - Anaemia), surgical site infection, complication rates, length of hospital stay and readmission rate. Analyses will follow intention-to-treat principles for all randomised participants. All patients will be followed up to 60 days following surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Health Research Ethics Board of Alberta (Project ID: HREBA.CC-22-0187) and Health Canada (HC6-024-c264013). Results will be disseminated through presentation at scientific conferences, peer-reviewed publication and social and traditional media. TRIAL REGISTRATION NUMBER: NCT05407987.

Determination of the absolute configuration of aromatase and dual aromatase-sulfatase inhibitors by vibrational and electronic circular dichroism spectra analysis.

The absolute configuration of a newly designed, letrozole-based chiral aromatase inhibitor that could not be defined by crystallographic techniques has been determined by means of vibrational and electronic circular dichroism and by optical rotation measurements combined with density functional theory calculations on possible conformers. The same absolute configurational assignment can be applied to the individual enantiomeric sulfamate esters, which are derived from the corresponding enantiomers of the chirally separated parent phenols, based on the similarity of the ECD spectrum of the sulfamate derivative to that of its phenolic precursor. The two enantiomeric sulfamate esters studied here are the first examples of nonsteroidal dual aromatase-sulfatase inhibitor whose activities have been evaluated on optically resolved enantiomers.

In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy.

PURPOSE: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

Development of a sensitive high-performance liquid chromatography method for the detection of 667 COUMATE in vivo.

Steroid sulphatase inhibitors which decrease or prevent the biosynthesis of oestrogens, potentially have an important role in the treatment of breast cancer in postmenopausal women. The non-steroidal sulphatase inhibitor 667 COUMATE has been shown to be active both in vitro and in vivo. The pharmacokinetics of this drug have not been investigated. In preparation for the clinical evaluation of this agent, a sensitive and robust reversed phase high-performance liquid chromatography (HPLC) method was developed for the detection of 667 COUMATE in biological fluids. The sulphatase inhibitor was extracted from plasma with diethyl ether and separated from putative metabolites and endogenous plasma components with a C3-phenyl column. Using this method an extraction efficiency of 76+/-5% and a limit of detection of less than 0.1 ng/ml was achieved. The stability of this agent was investigated under different pH conditions and during storage in plasma at room temperature or -20 degrees C. 667 COUMATE was found to be stable when stored in acidified plasma (pH 4.5) at -20 degrees C. In conclusion, the HPLC method developed is a reproducible and sensitive assay that will enable quantitation of the potent non-steroidal sulphatase inhibitor 667 COUMATE in biological fluids in the forthcoming Phase I clinical trial.

Docking studies of sulphamate inhibitors of estrone sulphatase in human carbonic anhydrase II.

We describe the docking of selected steroidal and non-steroidal estrone sulphatase inhibitors, including the Phase I clinical trial candidate 667COUMATE (6), into the active site of human carbonic anhydrase II (hCA II). The docking scores are compared with the inhibition of hCA II and show good correlation with biological activity.