The Impact of a Digital Contraceptive Decision Aid on User Outcomes: Results of an Experimental, Clinical Trial.

BACKGROUND: Nearly 40% of unplanned pregnancies in the USA are the result of inconsistent or incorrect contraceptive use. Finding ways to increase women's comfort and satisfaction with contraceptive use is therefore critical to public health. One promising pathway for improving patient outcomes is through the use of digital decision aids that assist women and their physicians in choosing a contraceptive option that women are comfortable with. Testing the ability of these aids to improve patient outcomes is therefore a necessary first step toward incorporating this technology into traditional physician appointments. PURPOSE: To evaluate the effectiveness of a novel contraceptive decision aid at minimizing decisional conflict and increasing comfort with contraception among adult women. METHODS: In total, 310 adult women were assigned to use either the Tuune contraceptive decision aid or a control aid modeled after a leading online contraceptive prescriber's patient intake form. Participants then completed self-report measures of decisional conflict, contraceptive expectations, satisfaction, and contraceptive use intentions. Individual between-subjects analysis of variance (ANOVA) models were used to examine these outcomes. RESULTS: Women using the Tuune decision aid (vs. those using the control aid) reported lower decisional conflict, more positive contraceptive expectations, greater satisfaction with the decision aid and recommendation, and more positive contraceptive use intentions. CONCLUSIONS: Use of Tuune improved each of the predicted patient outcomes relative to a control decision aid. Online decision aids, particularly when used alongside physician consultations, may be an effective tool for increasing comfort with contraceptive use. CLINICAL TRIALS REGISTRATION #: NCT05177783, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT05177783.

Digital decision aids that help women and their physicians choose contraceptive options that women are most comfortable with present one promising way to improve contraceptive use outcomes, such as avoiding unplanned pregnancies. However, current decision aids have been found to struggle in helping improve women's satisfaction with and confidence in their contraceptive choices. The aim of this study was to test the effectiveness of a new digital decision aid, named Tuune, at helping improve women's confidence and comfort with contraception. Three hundred and ten adult women were randomly assigned to use and then receive a contraceptive recommendation from either the Tuune decision aid or a control aid designed after leading traditional health intake forms. Women's confidence and satisfaction with the aids, as well as their contraceptive recommendation, were then compared between groups. We found good evidence to suggest that women using the Tuune contraceptive decision aid were more satisfied and positive about their contraceptive choices and reported greater intentions to use contraception with increased confidence compared to women who used the control decision aid. New online decision aids, like Tuune, may be an effective tool for increasing women's comfort and experiences using contraception.

Recommendations for validation testing of home pregnancy tests (HPTs) in Europe.

Home pregnancy tests (HPTs) available in Europe include accuracy and other performance claims listed on their packaging. Due to the lack of guidance on the standardisation of such products, it is often difficult to replicate these claims when tested on a clinical sample, whether in a laboratory setting or by lay users. The In Vitro Diagnostic Regulation is a set of requirements that mandate comprehensive validation data on human pregnancy tests and other in vitro devices. It is due to replace the current European Directive (98/79/EC) and fully implemented in Europe by 2022. In June 2019, a panel of seven experts convened to discuss the validation studies required to provide the information needed to meet the new regulation for HPTs in Europe and proposed 15 recommendations for best practice. Defining best practice at all stages of validation of these important tests may ensure that tests marketed in Europe are fit for purpose, enabling lay users to be confident of the high quality of the HPT results they obtain. The panelists believe that the recommendations proposed here for the validation of HPTs may constructively contribute to improved standardisation of validation procedures in Europe.

Comparative study of outcomes for elderly hip fractures presenting directly to a referral hospital versus those transferred from peripheral centres.

BACKGROUND: The geography of rural Australia poses a myriad of logistical dilemmas, including the provision of timely access to emergency orthopaedic hip fracture surgery. Current guidelines support surgery within 48 h, and delays to transfer to a referral hospital may result in worse outcomes and increase mortality rates. The aim of this study was to examine the effect of transfer delays on the clinical outcomes of hip fractures in a rural setting. METHODS: We retrospectively reviewed 265 hip fracture patients who underwent surgical management between 2013 and 2015 at a rural referral hospital. Factors such as age, time to surgery, delay to surgery, preoperative clinical deterioration, preoperative transthoracic echocardiogram, American Society of Anesthesiologists class and 30-day and 1-year mortality rates were examined. Unadjusted odds ratios were calculated for statistically significant primary and secondary outcomes. RESULTS: The mean delay to transfer was 19.9 h. Patients were 6.76 times more likely to undergo surgery within 48 h if they presented to the referral hospital first. Surgery within 48 h was more likely in those who presented to the referral hospital first, had no preoperative transthoracic echocardiogram and did not experience a preoperative clinical deterioration. The 30-day mortality rates were significantly higher in those who had surgery after 48 h or underwent a preoperative clinical deterioration. CONCLUSION: Increased time to hip fracture surgery was associated with increased mortality rates. Transfer delays from a peripheral hospital had a significant bearing on time to surgery. Early transfer to a referral hospital is recommended.

Secretome profile selection of optimal IVF embryos by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

PURPOSE: Selecting an embryo at the transfer stage with the best chance of a successful pregnancy is still largely dependent on preceding subjective evaluation of morphokinetics. Expensive prenatal genomic profiling has been so far proved ineffective. Proteomics and metabolomics are promising new approaches to assess embryo viability, but methodologies are often complex and do not lend themselves to rapid analysis in the critical time between blastocyst formation and embryo transfer. Here, we used matrix-assisted laser desorption ionization time-of-flight (MALDI ToF) mass spectrometry to assess the secretome of blastocysts in the minutes prior to embryo transfer and correlated spectral features with pregnancy outcome. METHODS: Four hundred one samples of spent blastocyst culture media were collected from embryo cultures at the time of embryo transfer, of which 136 were used to construct the predictive model. The media samples were frozen at - 20 °C and stored for analysis. Sample analysis was conducted in batches using 1 µl of spent embryo in direct MALDI ToF mass spectral analysis. Quantitative characteristics within this mass range (2000-17,000 m/z) were used to generate a score for selected mass regions (bins) in order to predict pregnancy outcome for each sample. RESULTS: With a simple algorithm based on nine mass bins within the 2000-10,000 m/z region, it was possible to identify samples with the best chance of becoming an ongoing pregnancy (positive predictive value of 82.9%, p = 0.0018). CONCLUSION: A simple, direct and rapid analysis of spent culture fluid from blastocysts at the point of embryo transfer can quickly identify optimal embryos with the best chance of achieving ongoing pregnancy. Methods like this, which take less than 20 min to perform, could dramatically improve the approach to embryo selection and live births.

Evidence for, and Associated Risks with, the Human Chorionic Gonadotropin Supplemented Diet.

Trend diets can be commonplace amongst those who are trying to lose weight but in most cases there is some shred of evidence to suggest they might be of some benefit. Seldom is there a diet which is such a fad that it is not only completely unfounded but also potential harmful. The human chorionic gonadotropin or "hCG diet" is such a diet, which after half a century still has no evidence to support its efficacy; in fact all scientific publications subsequent to the original article counter these claims. In this short communication, we review the literature and present data on exactly what some of the hCG diet preparations actually contain and highlight that, based on current data, these may do more harm than good. It is worrying that more consideration is not given to the possible danger of administration of hCG preparations to individuals without an evidence-based rational.

Direct and rapid mass spectral fingerprinting of maternal urine for the detection of Down syndrome pregnancy.

BACKGROUND: The established methods of antenatal screening for Down syndrome are based on immunoassay for a panel of maternal serum biomarkers together with ultrasound measures. Recently, genetic analysis of maternal plasma cell free (cf) DNA has begun to be used but has a number of limitations including excessive turn-around time and cost. We aimed to develop an alternative method based on urinalysis that is simple, affordable and accurate. METHOD: 101 maternal urine samples sampled at 12-17 weeks gestation were taken from an archival collection of 2567 spot urines collected from women attending a prenatal screening clinic. 18 pregnancies in this set subsequently proved to be Down pregnancies. Samples were either neat urine or diluted between 10 to 1000 fold in dH2O and subjected to matrix assisted laser desorption ionization (MALDI), time of flight (ToF) mass spectrometry (MS). Data profiles were examined in the region 6,000 to 14,000 m/z. Spectral data was normalised and quantitative characteristics of the profile were compared between Down and controls. RESULTS: In Down cases there were additional spectral profile peaks at 11,000-12,000 m/z and a corresponding reduction in intensity at 6,000-8,000 m/z. The ratio of the normalised values at these two ranges completely separated the 8 Down syndrome from the 39 controls at 12-14 weeks. Discrimination was poorer at 15-17 weeks where 3 of the 10 Down syndrome cases had values within the normal range. CONCLUSIONS: Direct MALDI ToF mass spectral profiling of maternal urinary has the potential for an affordable, simple, accurate and rapid alternative to current Down syndrome screening protocols.

B152 anti-hyperglycosylated human chorionic gonadotropin free ß-Subunit. A new, possible treatment for cancer.

OBJECTIVE: To investigate the ability of B152 to block cancer growth in cell lines in vivo and in nude mice in vitro. STUDY DESIGN: We examined JAR, JEG-3, and NTERA trophoblastic cancer cell lines and KLE, Hec-1A, SCaBER, and T24 nontrophoblastic cancer cell lines. JEG-3 cells were transplanted into 8 nude mice. Four nude mice were administered B152 antibody, and 4 were administered control non-specific IgG. Two studies were completed: first with antibody treatment started 2 weeks after cancer transplantation, and second with antibody treatment started at the time of transplantation. RESULTS: In 3 trophoblastic cancer lines and 4 non-trophoblastic cancer cell lines, B152 suppressed the growth of cancer cells, forcing cells into a state of regression. When B152 was administered to nude mice with tumor xenographs, the antibody blocked cancer cell growth and invoked oncostasis. When B152 was administered to nude mice starting at time of xenograph transplantation, the antibody prevented tumor growth completely. CONCLUSION: B152 suppresses tumor growth by seemingly blocking hyperglycosylated human chorionic gonadotropin (hCG) free ß-subunit effects. Thus, highly specific antibodies against hCG such as B152 may form part of a novel adjuvant treatment regimen against hCG-producing tumors in humans. This may form a new treatment for humans.

Direct analysis of hCGßcf glycosylation in normal and aberrant pregnancy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The analysis of human chorionic gonadotropin (hCG) in clinical chemistry laboratories by specific immunoassay is well established. However, changes in glycosylation are not as easily assayed and yet alterations in hCG glycosylation is associated with abnormal pregnancy. hCGß-core fragment (hCGßcf) was isolated from the urine of women, pregnant with normal, molar and hyperemesis gravidarum pregnancies. Each sample was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis following dithiothreitol (DTT) reduction and fingerprint spectra of peptide hCGß 6-40 were analyzed. Samples were variably glycosylated, where most structures were small, core and largely mono-antennary. Larger single bi-antennary and mixtures of larger mono-antennary and bi-antennary moieties were also observed in some samples. Larger glycoforms were more abundant in the abnormal pregnancies and tri-antennary carbohydrate moieties were only observed in the samples from molar and hyperemesis gravidarum pregnancies. Given that such spectral profiling differences may be characteristic, development of small sample preparation for mass spectral analysis of hCG may lead to a simpler and faster approach to glycostructural analysis and potentially a novel clinical diagnostic test.

Novel insights into the expression of CGB1 & 2 genes by epithelial cancer cell lines secreting ectopic free hCGß.

BACKGROUND: Ectopic secretion of human chorionic gonadotrophin free beta (hCGß) by epithelial cancer is associated with aggressive tumors which more readily metastasize, possibly by acting as an autocrine anti-apoptotic agent. hCGß is encoded by six homologous CGB genes, with poorly-understood variable transcriptionally active expression profiles; CGB1 and CGB2 have always been considered pseudogenes. However, transcripts from CGB1 and -2 can be detected in placental, testicular and pituitary tissues. The expression and function of these genes in cancer is less well-known. MATERIALS AND METHODS: Expression profiles of CGB genes in epithelial cancer cells by quantitative polymerase chain reaction (qPCR) were explored, along with the consequence of specific siRNA silencing of CGB1 and 2. Immunohistochemical and immunoassay techniques were used to detect the translation and secretion of hCGß in these cells. RESULTS: CGB1 and -2 gene transcripts were only detected in cells which secreted hCGß. siRNA-mediated silencing of CGB1 and -2 transcripts significantly reduced secreted protein in concordance with a reduction in cell survival to a greater degree than that of other CGB genes. CONCLUSION: CGB genes 1 and 2, previously considered as pseudogenes, are notably expressed by epithelial cancer cell lines. The transcription of these genes, but not other CGB genes, correlates with a functionally expressed protein and propensity for cancer growth.

Stable knockdown of hCGß mRNA expression in bladder cancer cells results in significant growth inhibition.

BACKGROUND: Expression of human chorionic gonadotropin beta subunit (hCGß) by epithelial carcinomas is associated with a poor prognosis and has a proposed autocrine growth effect on cancer cells by inhibition of apoptosis. MATERIAL AND METHODS: We transduced the hCGß-expressing bladder cancer cell line SCaBER with short hairpin (sh) RNA lentiviral gene-specific (CGB) constructs and determined its impact on the synthesis of hCGß and the resultant effect on cancer cell growth. RESULTS: Stable CGB gene-silenced clones exhibited a 60%-80% reduction in the level of hCGß expressed and a reduced growth rate of more than 40% compared to wild-type SCaBER cells. CONCLUSIONS: shRNA Lentiviral particles achieve stable knockdown of hCGß translation in the bladder cancer cell line SCaBER. This transforms the phenotype by reducing hCGß expression and cell growth rate. This is consistent with the proposed autocrine/paracrine function of ectopic hCGß expression during oncogenesis.

Single point biochemical measurement algorithm for early diagnosis of ectopic pregnancy.

OBJECTIVES: Tubal rupture as a result of an ectopic pregnancy is the leading cause of first trimester maternal mortality. Currently, the diagnosis of ectopic pregnancy depends on transvaginal ultrasound and serial serum measurements of human chorionic gonadotrophin (hCG), which requires follow up. The objective of this study was to examine whether single point measurements at presentation could distinguish between women with ectopic pregnancy, viable pregnancy, and spontaneous miscarriage. DESIGN AND METHODS: Serum total hCG (hCGt), hyperglycosylated hCG (hCGh), free beta subunit of hCG (hCGß), progesterone (P), and CA-125 were measured by chemiluminescence immunoassay over a 3 month period in 441 women presenting at the emergency room with abdominal pain and a positive pregnancy test. Patient outcomes were followed and confirmed by histology. 65 samples were excluded due to poor sample storage, or lost to follow up. RESULTS: The pregnancy outcomes were 175 viable pregnancies, 175 spontaneous miscarriages, and 26 ectopic pregnancies. A serum hCGt <3736 mIU/mL cut off was 100% sensitive, with 76% specificity, for distinguishing ectopic pregnancy from viable pregnancy; but did not differentiate spontaneous miscarriage. Serum CA125 <41.98 U/mL produced 100% sensitivity and 43% specificity in distinguishing ectopic pregnancy from spontaneous miscarriage. Sequential application of hCGt and CA-125 cut off followed by ultrasound could detect 100% of ectopic pregnancies with 87% specificity for all intrauterine pregnancies. CONCLUSION: The combination of serum hCGt <3736 mIU/mL, followed by CA125 <41.98 U/mL is a promising algorithm for detecting all ectopic pregnancy at initial presentation.

Human chorionic gonadotropin (hCG) in the secretome of cultured embryos: hyperglycosylated hCG and hCG-free beta subunit are potential markers for infertility management and treatment.

Human chorionic gonadotropin (hCG) is produced by trophoblast cells throughout pregnancy, and gene expression studies have indicated that hCG-beta subunit (hCGß) expression is active at the 2 blastomere stage. Here, we investigated the qualitative hCG output of developing embryos in culture and hCG isoforms expressed in the secretome as a novel sensitive method for detecting hCG. Culture media was collected from the culture plates of 118 embryos in culture (including controls and embryos at different stages of culture) from 16 patients undergoing routine fertility treatment. The hCGß was detectable in media from 2 pronuclear (2PN) stage embryos through to the blastocyst stage. The hCGß was absent in 1PN and arrested embryos as well as all media controls. Prior to hatching, hyperglycosylated hCG (hCGh) was observed selectively in 3PN embryos, but after hatching, along with hCG, became the dominant hCG molecule observed. We have reported at the 2PN stage the earliest evidence of hCGß expression in embryos. There is a suggestion this may be indicative of quality in early embryos, and hCGh seen at the pronuclear stage may suggest triploid abnormality. The dominance of hCG, and hCGh expression, seen after blastocyst hatching may be indicative of potential implantation success. Thus, hCG isoforms have potential roles as biomarkers of embryo viability for embryo/blastocyst transfer.

Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients.

PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN: Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-ß) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307 induced consistent humoral and T-cell responses to hCG-ß when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-ß. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy.

Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters.

Human chorionic gonadotropin (hCG) is a heterogeneous glycoprotein hormone comprising an alpha-subunit and beta-subunit that can vary in peptide and carbohydrate structure. After conception, hCG produced by early trophoblast cells acts on luteinizing hormone (LH)/hCG receptor corpus luteum cells to promote progesterone production and establish maternal recognition of pregnancy. hCG is not simply 1 molecule, and 2 variants of hCG appear to have independent activities in promoting tumor cell growth, invasion and malignancy. Hyperglycosylated hCG (H-hCG), produced by cytotrophoblast cells, is a marker for cytotrophoblast cells and tumor marker for gestational trophoblastic diseases. H-hCG promotes growth and invasion in these cells during pregnancy implantation, and growth in varying degrees by many nontrophoblastic neoplasms. beta-hCG is a marker of poor prognosis shown to promote growth and invasion in vitro, suggesting autocrine growth factor properties. Vaccines to beta-hCG have been successfully demonstrated, suggesting a potential adjuvant therapy in cancer treatment. Although sufficiently distinct in both structure and occurrence, similarities have been observed between H-hCG and beta-hCG as promoters of cell growth, invasion and malignancy. It is somewhat irregular for 2 structural variants of a molecule to have independent actions, actions very different to the gonadotropic function of the established hormone hCG.

Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis.

OBJECTIVE: Hyperglycosylated human chorionic gonadotropin (hCG-H) is a carbohydrate variant of hCG with double-sized oligosaccharide side chains. While hCG-H is produced exclusively by stem cytotrophoblast cells in gestational choriocarcinoma, by pregnancy cytotrophoblast at implantation and by the cytotrophoblast produced in testicular malignancies, regular hCG is produced only by differentiated syncytiotrophoblast cells. STUDY DESIGN: hCG-H was measured using the Nichols Advantage hCG-H assay (Nichols Institute Diagnostics, San Clemente, California). RESULTS: hCG-H has a function separate from regular hCG. hCG-H, but not regular hCG, acts in vivo and in vitro to promote invasion, whether invasion through membranes or tumor formation. Invasion or tumorigenesis is completely blocked by administration of specific antibody to hCG-H. The same hCG-H-modulated invasion mechanisms are observed in early pregnancy, gestational choriocarcinoma and testicular cancers. CONCLUSION: hCG-H is a cytokinelike molecule, produced by cells different from those that make regular hCG and having a completely separate function. It appears to be the modulator of invasion as in implantation of pregnancy, gestational choriocarcinoma and testicular cancer malignancy.

Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize.

OBJECTIVE: To investigate the biochemical relationship between follicular/oocyte maturity and follicular inhibins and activin levels. DESIGN: Prospective study. SETTING: Research laboratory in university hospital. PATIENT(S): Thirty-five women undertook IVF/ICSI program. INTERVENTION(S): Individual follicular fluid aspirations, oocyte isolation, follicular fluid storage. MAIN OUTCOME MEASURE(S): Inhibin A, inhibin B, and activin A concentrations, oocyte retrieval, and fertility outcome. RESULT(S): Inhibin A, inhibin B, and activin A concentrations varied from 7.9 to 436 ng/mL, 9.7 to 786 ng/mL, and 1.7 to 267.9 ng/mL, respectively. There was no change of inhibin A concentrations, whereas inhibin B and activin A concentrations dropped dramatically as the follicles enlarged. Total follicular content of inhibin A and activin A increased, and inhibin B remained constant. Both inhibin A and inhibin B levels were significantly higher in those follicles from which an oocyte could be recovered, but they did not differ with respect to subsequent oocyte fertilization. CONCLUSION(S): Inhibin A is actively produced throughout follicular growth to retain a set concentration. In contrast, inhibin B appears not to be actively produced, and the concentration drops as follicles enlarge. Activin A concentrations also decrease, but there is some extra synthesis. Higher levels of inhibin A and B are associated with oocyte presence but not with fertilization rates.

Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG.

OBJECTIVE: Hyperglycosylated hCG (hCG-H) is a glycosylation variant of hCG produced by cytotrophoblast cells at implantation of pregnancy and in choriocarcinoma. We investigated the biological function of hCG-H in invasion in vitro and in vivo and the use of hCG-H antibodies in blocking tumorigenesis and cancer growth in vivo. METHODS AND RESULTS: hCG-H accounts for 43% to 100% of total hCG immunoreactivity in the culture fluid of choriocarcinoma cell lines and 100% in primary cultures of pregnancy cytotrophoblast cells. We investigated the action of hCG and hCG-H on isolated cytotrophoblast cell primary cultures and on 3 different lines of choriocarcinoma cells cultured on Matrigel basement membrane inserts (culture models for assessing tumor invasion). The addition of hCG-H to medium significantly promoted invasion of membranes with both pregnancy and cancer cell line sources, while regular hCG had no significant effect. JEG-3 human choriocarcinoma cells were transplanted subcutaneously into athymic nude mice. Tumors rapidly formed. B152, mouse monoclonal antibody against hCG-H, and non-specific mouse IgG (control) were administered twice weekly once tumors were clearly visible. While a correlation between time and growth was observed with the control group (r(2)=0.97), no correlation was observed with the B152-treated mice (r(2)=0.15). B152 blocked tumor growth (t test, IgG vs. B152, P=0.003). In a second experiment, antibody B152 or IgG was administered to mice at the time of choriocarcinoma transplantation. B152 significantly inhibited tumorigenesis (t test P=0.0071). CONCLUSIONS: hCG-H is a critical promoter in human cytotrophoblast and human choriocarcinoma cell invasion in vivo and in vitro, promoting tumor growth and invasion through an autocrine mechanism. hCG-H is a signal for choriocarcinoma cell invasion, making it a biological tumor marker. Antibodies against hCG-H block tumor formation and growth. Human or humanized antibodies against hCG-H may be useful in treating and managing choriocarcinoma and other gestational trophoblastic malignancies.

Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia.

OBJECTIVES: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia. METHODS: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)). RESULTS: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor. DISCUSSION AND CONCLUSION: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.

Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results.

OBJECTIVES: A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future. METHODS: The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test. RESULTS: Among these 170 patients, the average persistent hCG result was 102 +/- 152 mIU/ml, with a range of 6.1-900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma (n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present. CONCLUSION: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.