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Laurence A Cole

Publications and source records attributed to Laurence A Cole.

At least 19 recordsLinked to original sources
PubMed2006

Hyperglycosylated hCG: a variant with separate biological functions to regular hCG.

Hyperglycosylated hCG (hCG-H) is an over-glycosylated variant of hCG. While regular hCG is produced by differentiated syncytotrophoblast cells, hCG-H is independently secreted by stem cytotrophoblast cells. hCG-H has an independent function to regular hCG. It is the direct promoter of trophoblast invasion and malignancy. Invasion as in implantation of pregnancy and malignancy as in choriocarcinoma. Neither will occur in the absence of hCG-H. hCG-H measurements have multiple functions. Primarily or exclusively hCG-H is produced at the time of implantation of pregnancy and in the 2 weeks that follows. As such, a good pregnancy test should measure regular hCG and hCG-H equally. This is not commonly the case. Most tests poorly detect hCG-H. New pregnancy tests are needed, including those that measure only hCG-H. Considering that hCG-H is critical for implantation, hCG-H is also invaluable for determining pregnancy outcome and detecting failures. It makes a considerable more accurate test for detecting pregnancy failures and ectopic pregnancies than regular hCG. Down syndrome pregnancies are marked by poor trophoblast differentiation. As such, they are very well marked by using a combination of hCG-H measurements and other screening tests. hCG-H is also an absolute tumor marker for malignant or invasive gestational trophoblastic disease, it can discriminate active and inactive (quiescent) disease, and the need for chemotherapy.

Chorionic Gonadotropin↗
PubMed2006

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.

Biomarkers, Tumor↗
PubMed2006

Gestational trophoblastic diseases: 3. Human chorionic gonadotropin-free beta-subunit, a reliable marker of placental site trophoblastic tumors.

OBJECTIVES: Placental site trophoblastic tumor (PSTT) commonly presents with low and variable concentration of hCG immunoreactivity in serum which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease (quiescent GTD). Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low hCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. We investigate the usefulness of hCG-free beta-subunit to make this discrimination. METHODS: Data collected on cases referred to the USA hCG Reference Service for consultation served as a basis for this retrospective analysis. There were 13 cases with histology proven PSTT and 12 with nontrophoblastic malignancy. hCG-free beta-subunit was measured by immunoassay and reported as a proportion of total hCG (hCG-free beta-subunit(%)). hCG-free beta-subunit(%) results were determined for all histologically proven cases of PSTT and for the nontrophoblastic malignancies. Comparisons of hCG-free beta-subunit(%) were made and compared with those of the 82 choriocarcinoma/GTN cases and 69 quiescent GTD cases. The accuracy of hCG-free beta-subunit(%) to discriminate these malignancies was analyzed by investigating the areas under receiver-operating characteristics curve +/- standard error. RESULTS: hCG-free beta-subunit(%) was the predominant hCG form in cases of PSTT (mean +/- standard deviation, 60 +/- 19%) and nontrophoblastic malignancies (91 +/- 11%), thus discriminating these diagnoses from choriocarcinoma/GTN (9.3 +/- 9.2%) and from quiescent GTD (5.4 +/- 7.8%). The cutoff of >35% free beta-subunit is proposed. At this cutoff, 100% detection at 0% false-positive is achieved. The accuracy of hCG-free beta-subunit(%) for this discrimination is 100 +/- 0%. At a proposed cutoff of >80%, the free beta-subunit test will also distinguish PSTT from nontrophoblastic malignancy, with 77% detection at 23% false-positive or an accuracy of 92 +/- 3.2%. CONCLUSION: Measurement of the proportion hCG-free beta-subunit(%) was found to be useful in the diagnosis of PSTT using proposed cutoff values of >35% and >80%. While this finding needs to be confirmed by larger studies, it would be reasonable to measure hCG-free beta-subunit(%) whenever the diagnosis of PSTT is considered.

Choriocarcinoma↗
PubMed2006

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.

Animals↗
PubMed2006

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.

Adult↗
PubMed2006

A single serum test for measuring early pregnancy outcome with high predictive value.

OBJECTIVES: Current testing to determine a failing pregnancy requires two separate clinic visits to measure the hCG doubling rate. Diagnosing a failing pregnancy is often done in emergency departments where simplified and accelerated testing methods are needed. Here, we investigated hyperglycosylated hCG (hCG-H) for predicting pregnancy failure. DESIGN AND METHODS: We studied two independent sets of patient samples collected in the early weeks of gestation. One set was urine samples, and the other was serum samples. In all cases, hCG and hCG-H were measured using automated chemiluminescence immunoassays. Concentrations of hCG and hCG-H were plotted on a scattergram, and levels in failing pregnancies were compared to those in continuing pregnancies. RESULTS: Data indicated that a threshold level of hCG-H (13 microg/L) in both serum and urine samples defined the concentration below where pregnancies were likely to fail. This cut-off corresponded to 73% detection of failures at a 2.9% false positive rate using serum and 75% detection at a 15% false positive rate using urine. Using an hCG cut-off that corresponded to the same false positive rates, hCG detected only 42% of failures using serum and 43% of failures using urine. CONCLUSIONS: Our data indicate that hCG-H provides a much more accurate single test than hCG for assessing pregnancy outcome. Compatible with the use of serum or urine samples, a single hCG-H test might provide simpler, faster, and more accurate results for predicting the progress of a pregnancy than standard hCG testing.

Abortion, Spontaneous↗
PubMed2006

The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing cancers.

This report was conceived at the 13th World Congress of Gestational Trophoblastic Disease after multiple presentations indicated widespread discrepancies in human chorionic gonadotropin (hCG) use and results. There appears to be a need for a discussion to describe the advantages and limitations of commonly used hCG tests in the management of gestational trophoblastic disease, and to monitor testicular, germ cell and other hCG-producing malignancies. In most countries hCG tests are certified only for pregnancy testing. Use in managing gestational trophoblastic diseases and other malignancies is considered an "off-label" use. Tests are not optimized or calibrated for these applications, and their use and the results therefore have to be considered experimental. Widespread variations in results occur and may lead to needless or inappropriate therapy. It therefore seems important for laboratory directors and treating physicians to familiarize themselves with which hCG test their laboratory is using and, if necessary, to contract an external laboratory for measuring hCG in the management of gestational trophoblastic disease and cancer.

Biological Assay↗
PubMed2006

Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin.

Recent publications show that the measurements of particular human chorionic gonadotropin (hCG) variants are extremely beneficial in the diagnosis, monitoring and treatment of gestational trophoblastic disease (GTD). Here we review the possible sources of hCG and the use of commercial tests in the optimal management of GTD, quiescent GTD,false positive hCG results, placental site trophoblastic tumor (PSTT) detection, nontrophoblastic neoplasms and pituitary hCG. Hyperglycosylated hCG (hCG-H) measurements are ideal for discriminating active (invasive) from inactive (quiescent or benign) disease. hCG-H testing is also more sensitive than regular hCG in detecting recurrent or persistent disease. After excluding false positive hCG results, and in the absence of any radiographic evidence of tumor, hCG-H should be measured before starting chemotherapy or surgery in women presenting with low hCG (<1,000 mIU/mL) with or without a history of GTD. The hCG free beta assay is an invaluable test in discriminating PSTT from other GTDs, thereby aiding the determination of appropriate treatment options.

Biological Assay↗
PubMed2006

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.

Animals↗
PubMed2005

Choriocarcinoma and gestational trophoblastic disease.

Gestational trophoblastic disease (GTD) encompasses a unique group of uncommon but interrelated conditions derived from placental trophoblasts. For the purposes of discussion GTD is the appropriate collective name for hydatidiform mole, whereas the term gestational trophoblastic neoplasia (GTN) is reserved for cases with persistent human chorionic gonadotropin (hCG) titer elevation after evacuation of hydatidiform mole, metastatic disease, or choriocarcinoma. Although the pathology and clinical behavior of CM and PM are different, the initial management of both conditions is surgical evacuation by suction curettage, determination of the baseline, and follow-up with (hCG) titers. There are guidelines for risk-factor scoring and a staging system that classifies untreated patients into distinct prognostic categories so that treatment outcomes can be objectively compared. The rates of GTN and choriocarcinoma are decreasing and survival has dramatically improved.

Chorionic Gonadotropin↗
PubMed2005

Gestation trophoblastic diseases: management of cases with persistent low human chorionic gonadotropin results.

The finding of persistent low levels of human chorionic gonadotropin (hCG) raises concern, regardless of the antecedent history, and often provokes the evaluating physician to embark on further work-up. The USA hCG Reference Service was started in 1998 to aid physicians with these persistent low hCG cases. This article reviews the observations of the USA hCG Reference Service for 134 cases with persistent low hCG results. Examination of these cases provides clear insight for the appropriate management of those presenting with persistent low levels of hCG. Three distinct sources are discussed for persistent low hCG results: quiescence gestational trophoblastic disease, false-positive hCG results, and pituitary hCG.

Chorionic Gonadotropin↗
PubMed2005

Positive pregnancy tests in a nongravid, premenopausal woman due to hCG beta-chain production by multiple myeloma.

Positive pregnancy test results occurred in a nongravid, premenopausal woman while she was receiving chemotherapy for multiple myeloma. We tested 2 hypotheses to account for this finding: (1) Heterophil antibodies caused positive interference in the immunoassays. (2) Genuine human chorionic gonadotropin (hCG) originated from a nonsyncytiotrophoblastic source. Paraprotein was eliminated as a source of positive interference because 3 different instruments with unique capture and signal antibodies gave similar results (83, 90, and 97 mIU/mL [83, 90, and 97 IU/L]). Human antimouse antibodies (HAMAs) were unlikely to cause positive interference because immunoreactivity was maintained after serum was treated to neutralize heterophil antibodies. Immunoassays performed after gel filtration of serum indicated that immunoreactivity was due to genuine hCG. The high-molecular-weight fraction (heterophil antibody) had 6 mIU/mL (6 IU/L) of hCG. The low-molecular-weight fraction (hCG) had 86 mIU/mL (86 IU/L) of hCG. Immunohistochemical stains revealed that myeloma cells expressed immunoreactive hCG. Hence, multiple myeloma caused positive pregnancy test results in a nongravid woman.

Adult↗
PubMed2004

Between-method variation in human chorionic gonadotropin test results.

BACKGROUND: Results on sera and calibrators vary 1.4- to 2.3-fold among commercial human chorionic gonadotropin (hCG) assays. The relative contributions of calibrators, standards, hCG charge isoforms, and major structural variants to this variation have not been quantified. METHODS: Purified hCG was separated by isoelectric focusing into four fractions with pI ranges of 3-4, 4-5, 5-6, and 6-7. These four fractions together with pure hCG, hyperglycosylated hCG, hCG beta-subunit (hCGb), nicked hCG, and hCGb core fragment (hCGbcf) were tested in nine commonly used commercial serum assays for hCG. The compositions of pure hCG preparations, standards, and commercial hCG preparations were determined by immunoassay. RESULTS: The three pure hCG preparations and the four hCG charge isoforms each showed parallel responses in the nine commercial hCG assays. Although wide variations were found in the detection of hCG structural variants by the nine assays (range for hyperglycosylated hCG, 468-1544 IU/L; for hCGb, 3187-5535 IU/L; for nicked hCG, 2736-4240 IU/L; and for hCGbcf, <2-130 IU/L), this did not correlate with the between-method variation observed in results for the three pure hCG preparations. Commercial preparations of hCG and calibrators showed great variation in their content of hCG structural variants (from 34% to 100% intact hCG). CONCLUSIONS: Intermethod differences in hCG results were not explained by changes in responses attributable to hCG charge isoforms or to hCG structural variants, but wide variation was observed in concentrations of hCG structural variants in calibrators and in detection of these structural variants. Differences in assay specificity and in composition of the calibrators are the most likely sources of between-method variation.

Calibration↗
PubMed2004

Sialic acid-deficient invasive trophoblast antigen (sd-ITA): a new urinary variant for gestational Down syndrome screening.

BACKGROUND: Invasive trophoblast antigen (ITA), also known as hyperglycosylated hCG, is a glycosylation variant of hCG produced by invasive cytotrophoblast cells. Publications show that ITA is potentially a sensitive test for Down syndrome screening, reportedly detecting 38 and 80% of cases at a 5% false-positive rate in the first and second trimesters of pregnancy respectively. ITA has six oligosaccharides varying greatly in terminal sialic acid content (0-19 residues), leading to wide-charge heterogeneity. With the objective of developing an improved Down syndrome screening test, we examined the charge, or sialic acid variants, of ITA. METHODS: Twenty urine samples were collected from the 16th to 18th week of gestation from 10 patients with trisomy 21 fetuses, demonstrated by karyotype analysis, and from 10 patients with normal karyotype pregnancies. Proteins in each sample were separated by preparative isoelectric focusing. Fractions were collected, pooled into the pl ranges of 3.0 to 4.0, 4.1 to 5.0, 5.1 to 6.0 and 6.1 to 7.0 and assayed for ITA. RESULTS: A difference in the distribution of ITA charge variants was demonstrated between cases and controls, most apparent in the less acidic (pl 5.1-7.0) range. The controls and Down syndrome samples contained 26.7 +/- 14% versus 45.6 +/- 20%, respectively, of the less acidic form of ITA (P = 0.02). CONCLUSIONS: The ITA in Down syndrome cases is composed of a much higher proportion of less acidic ITA. This could be the major source of elevated levels of ITA in Down syndrome pregnancies. It is postulated that the development of a new assay specifically measuring ITA that is deficient in sialic acid might enhance the utility of the already highly sensitive screening tests for Down syndrome.

Biomarkers↗
PubMed2004

Accuracy of home pregnancy tests at the time of missed menses.

OBJECTIVE: The purpose of this study was to investigate the validity of home pregnancy tests (HPTs) around the time of the missed menses. STUDY DESIGN: Levels of human chorionic gonadotropin (hCG) were determined in urine around the time of the missed menses, and 5th and 95th centiles were calculated. In a blind study evaluating 18 brands of HPTs, each was tested six times with five concentrations of hCG, 0 to 100 mIU/mL. Sensitivity was defined as the concentration at which six of six brands gave positive results, at the suggested reading time or at an extended time. RESULTS: It was estimated that a sensitivity of 12.5 mIU/mL was needed to detect 95% of pregnancies at the time of missing menses. Only 1 of 18 HPTs had this sensitivity. If faintly discernible results considered, 2 of 18 brands gave false-positive or invalid results. Clear positive results were given by only 44% of the brands at 100 mIU/mL hCG. If one accepted faintly discernible and extended reading times, all brands responded at 100 mIU/mL. A test with 100 mIU/mL sensitivity would detect approximately 16% of pregnancies at the time of missed menses. CONCLUSION: The utility of HPTs is questioned. Clinicians need to be aware of the limitations of current HPT brands.

Chorionic Gonadotropin↗