Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

A case of loss of heterozygosity in the BRCA2 gene of a borderline ovarian tumor: case report and review of literature.

Germline BRCA1 and BRCA2 mutations highly increase the risk of breast and female adnexal cancer. The role of these genes in the tumorigenesis of other malignancies is still under debate. Borderline ovarian tumors (BOT) are occasionally found in families with a strong history of breast and/or female adnexal cancer with or without proven germline mutations. We investigated whether a BOT arising in a germline BRCA2 mutation carrier could be attributed to this mutation, in which case BOT should be added to the BRCA2 related tumor spectrum. Tumor DNA of a serous borderline ovarian tumor (sBOT) of a 55-year-old female carrier of a pathogenic BRCA2 mutation (6085G>T) was analyzed for loss of heterozygosity (LOH) of BRCA2. The sBOT cells, unexpectedly, revealed loss of the mutant allele of BRCA2, while ovarian stroma cells and peripheral blood lymphocytes contained both wild-type and mutant allele of BRCA2. The finding that no loss of the wild-type BRCA2 allele was found in the tumor tissue but loss of the mutant allele was seen suggests that sBOT are not part of the BRCA2 related tumor spectrum. In the literature BOT's in germline BRCA1 and BRCA2 mutation carriers are described incidentally, while in patients with a BOT a germline BRCA1 or BRCA2 mutation is rarely found. Therefore, we conclude that borderline ovarian tumors are neither part of the BRCA1- nor the BRCA2- related tumor spectrum.

Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma.

BACKGROUND: Nitric oxide (NO) may exert protective properties within the airways of asthmatic patients. It was postulated that airways obstruction in asthma may be associated with endogenous NO deficiency caused by limited availability of NO synthase substrate. METHODS: In a double blind, crossover study 14 asthmatic patients received pretreatment with oral L-arginine (50 mg/kg body weight) or placebo prior to histamine challenge. Histamine challenge was performed until a 50% fall in forced expiratory volume in one second (FEV(1)) occurred and the response was expressed as the provocative concentration causing a 20% fall in FEV(1) (PC(20)) and as the dose-response slope (maximal % fall in FEV(1)/cumulative dose (micromol)). RESULTS: Pretreatment with L-arginine did not affect PC(20) histamine (mean change in doubling dose 0.18 (95% confidence interval (CI) -0.36 to 0.71), p = 0.5) but the dose-response slope to histamine was slightly reduced (mean change: 0.7 (95% CI 0.6 to 0. 9), p = 0.016). CONCLUSIONS: Oral L-arginine does not influence airway hyperresponsiveness to histamine as reflected by PC(20), although the dose-response slope is slightly reduced in patients with asthma. This indicates only marginal, clinically unimportant limitation of NO synthase substrate in asthma.