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.

Sleep-disordered breathing in pregnancy: a review of the physiology and potential role for positional therapy.

BACKGROUND: Sleep disordered breathing (SDB) has been shown to be associated with negative clinical sequelae such as systemic hypertension and cardiovascular disease. It has been reported in the literature that approximately 53-56 % of patients with obstructive sleep apnea (OSA) have positional OSA, known as POSA. POTENTIAL TREATMENT FOR SDB IN PREGNANCY: These findings have led to a resurgence of positional therapy as an effective treatment for select patients with SDB. Pregnant patients can also be diagnosed with SDB, the negative consequences of which not only pertain to the patient but to the unborn fetus as well. Despite this, however, SDB is under-diagnosed in pregnant patients and research looking at SDB in pregnant patients and potential therapies are scarce. CONCLUSIONS: This article reviews the literature regarding the physiologic respiratory changes that occur during pregnancy, SDB in pregnancy, supine hypotensive syndrome (SHS), complications and current treatments for these events and potential roles for positional therapy in pregnant women whose problems may be specifically position dependent.

Humoral immune responses to MUC1 in women with a BRCA1 or BRCA2 mutation.

INTRODUCTION: Breast cancer patients with early disease and a natural humoral response to MUC1 have a favourable prognosis, suggesting a possible role of MUC1 antibodies (ab) in controlling haematogenous tumour dissemination and outgrowth. The aim of the study was to evaluate humoral immune responses to MUC1 in women at hereditary high risk of breast cancer to investigate whether this immune response could play a role in the prevention of disease. MATERIALS AND METHODS: CA15.3 (U/mL), and IgG and IgM ab to MUC1 (arbitrary units per mL, Arb-U/mL) were measured in serum samples obtained from 422 women at hereditary high risk of breast/ovarian cancer, of whom 127 BRCA1/2 carriers, attending the Familial Cancer Clinic of the VU University Medical Centre, and from 370 age-matched healthy controls. Serum samples obtained from women who developed breast cancer (N=12) or breast cancer recurrence (N=17), and from women who underwent prophylactic mastectomy (N=12) and had no breast lesions were also tested. RESULTS: CA15.3 ranked significantly higher in mutation carriers than in controls (P=0.03). MUC1 IgG ab levels ranked significantly lower in BRCA1/2 mutation carriers than in controls (P=0.003). MUC1 IgG levels were not significantly different (P=0.53) between women who developed primary breast cancer (median 0.72Arb-U/ml, range 0.52-2.44Arb-U/ml) and women who underwent prophylactic mastectomy and had no breast lesions (median 1.04Arb-U/ml, range 0.43-2.88Arb-U/ml). CONCLUSION: Serum levels of natural IgG ab to MUC1 are lower in BRCA1/2 mutation carriers than in healthy controls. Furthermore, in contrast to previous results in women with sporadic breast cancer, no elevated MUC1 IgG ab were seen in women at hereditary high risk who developed breast cancer. Prophylactic immunotherapy with MUC1 substrates may be a strategy to reduce the risk of breast cancer in BRCA1/2 mutation carriers, strengthening tumour immune surveillance.

Physostigmine, galanthamine and codeine act as 'noncompetitive nicotinic receptor agonists' on clonal rat pheochromocytoma cells.

The acetylcholine esterase inhibitor (-)-physostigmine has been shown to act as agonist on nicotinic acetylcholine receptors from muscle and brain, by binding to sites on the alpha-polypeptide that are distinct from those for the natural transmitter acetylcholine (Schröder et al., 1994). In the present report we show that (-)-physostigmine, galanthamine, and the morphine derivative codeine activate single-channel currents in outside-out patches excised from clonal rat pheochromocytoma (PC12) cells. Although several lines of evidence demonstrate that the three alkaloids act on the same channels as acetylcholine, the competitive nicotinic antagonist methyllycaconitine only inhibited channel activation by acetylcholine but not by (-)-physostigmine, galanthamine or codeine. In contrast, the monoclonal antibody FK1, which competitively inhibits (-)-physostigmine binding to nicotinic acetylcholine receptors, did not affect channel activation by acetylcholine but inhibited activation by (-)-physostigmine, galanthamine and codeine. The three alkaloids therefore act via binding sites distinct from those for acetylcholine, in a 'noncompetitive' fashion. The potency of (-)-physostigmine and related compounds to act as a noncompetitive agonist is unrelated to the level of acetylcholine esterase inhibition induced by these drugs. (-)-Physostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response. In contrast, they sensitize PC12 cell nicotinic receptors in their submaximal response to acetylcholine. While the abundance of nicotinic acetylcholine receptor isoforms expressed in PC12 cells excludes identification of specific nicotinic acetylcholine receptor subtypes that interact with noncompetitive agonists, the identical patterns of single-channel current amplitudes observed with acetylcholine and with noncompetitive agonists suggested that all PC12 cell nicotinic acetylcholine receptor subtypes that respond to acetylcholine also respond to noncompetitive agonist. The action of noncompetitive agonists therefore seems to be highly conserved between nicotinic acetylcholine receptor subtypes, in agreement with the high level of structural conservation in the sequence region harboring major elements of this site.

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study.

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. II. The rundown and inward rectification of agonist-elicited whole-cell currents and identification of receptor subunits by in situ hybridization.

Our previous study demonstrated for the first time that nicotinic currents evoked in rat hippocampal neurons could be grouped into four categories (types IA, IB, II and III) according to their functional and pharmacological characteristics. In the second part of our continuing studies, the structural and functional diversity of nicotinic receptors expressed in hippocampal neurons was further explored. Type IA, the predominant and alpha-bungarotoxin-sensitive current, but not type II, the alpha-bungarotoxin-insensitive current, showed rundown in the peak amplitude during the whole-cell recording. The rundown of type IA currents could be prevented when the ATP-regenerating compound phosphocreatine, alone or in combination with ATP and creatine phosphokinase, was added to the internal recording solution. The addition to the internal solution of either the microfilament-stabilizing agent phalloidin (5 microM) or the microtubule-stabilizing agent taxol (50 microM) did not alter or prevent rundown in type IA currents. Type IA and type II currents showed inward rectification. The inward rectification of type IA currents was dependent on the presence of intracellular Mg++, whereas that of type II currents was independent of Mg++. When Mg++ was present in the internal pipette solution, the inward rectification of type IA currents was sustained throughout the recording time. However, when nominally Mg(++)-free internal solution was used, the inward rectification decreased with recording time in type IA currents, but not in type II currents, as a consequence of removal of intracellular Mg++. In situ hybridization demonstrated the presence of alpha 7-, alpha 4- and beta 2-nicotinic acetylcholine receptor subunit mRNAs in cultured hippocampal neurons. The distribution among the neurons of the mRNAs for alpha 7- and alpha 4-nicotinic acetylcholine receptor subunits, correlated with the frequency with which type IA and type II currents, respectively, could be evoked in these neurons. The present results provide evidence for 1) the presence of intracellular high-energy phosphate-dependent processes linked with the nicotinic acetylcholine receptor subserving type IA currents, 2) a requirement of intracellular Mg++ for the inward rectification of type IA currents and 3) a correlation between the distribution of nAChR subunits and the different probabilities of eliciting distinct types of nicotinic currents in hippocampal neurons.

Neuronal nicotinic receptors in the locust Locusta migratoria. Cloning and expression.

We have identified five cDNA clones that encode nicotinic acetylcholine receptor (nAChR) subunits expressed in the nervous system of the locust Locusta migratoria. Four of the subunits are ligand-binding alpha subunits, and the other is a structural beta subunit. The existence of at least one more nAChR gene, probably encoding a beta subunit, is indicated. Based on Northern analysis and in situ hybridization, the five subunit genes are expressed. localpha1, localpha3, and locbeta1 are the most abundant subunits and are expressed in similar areas of the head ganglia and retina of the adult locust. Because Loc