[Current issues in measurement and reporting of urinary albumin excretion]. / Données actuelles sur le dosage de l'excrétion urinaire de l'albumine.

Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the erro-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences has been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no referance materials for either analyte in urine. The recommanded reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethicity) nor the continuous increase in risk related to albumin excretion. Clinical needs have been identified for standardization of (a) urine collection methodes, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative.

AIM: To improve the accuracy and completeness of reporting of studies of diagnostic accuracy in order to allow readers to assess the potential for bias in a study and to evaluate the general isability of its results. METHODS: The standards for reporting of diagnostic accuracy (STARD) steering committee searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies and extracted potential items into an extensive list. Researchers, editors, and members of professional organisations shortened this list during a 2 day consensus meeting with the goal of developing a checklist and a generic flow diagram for studies of diagnostic accuracy. RESULTS: The search for published guidelines about diagnostic research yielded 33 previously published checklists, from which we extracted a list of 75 potential items. At the consensus meeting, participants shortened the list to a 25-item checklist, by using evidence whenever available. A prototype of a flow diagram provides information about the method of recruitment of patients, the order of test execution and the numbers of patients undergoing the test under evaluation, the reference standard, or both. CONCLUSIONS: Evaluation of research depends on complete and accurate reporting. If medical journals adopt the checklist and the flow diagram, the quality of reporting of studies of diagnostic accuracy should improve to the advantage of clinicians, researchers, reviewers, journals, and the public.

[Reporting studies of diagnostic accuracy according to a standard method; the Standards for Reporting of Diagnostic Accuracy (STARD)]. / Verslaglegging van diagnostisch evaluatieonderzoek volgens een standaardmethode; de 'standards for reporting of diagnostic accuracy' (STARD).

The objective of the 'Standards for Reporting of Diagnostic Accuracy' (STARD) initiative is to improve the reporting of studies of diagnostic accuracy, so as to allow readers to assess the potential for bias in a study and to evaluate the generalibility of its results. The group searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies. This was used to draw up a list of potential items. During a consensus meeting, a group of researchers, medical journal editors, and members of professional organisations reduced this list to a usable checklist. Wherever possible, evidence from the literature was used to justify the decisions made. The search for published guidelines about diagnostic research yielded 33 previously published checklists, from which a list of 75 potential items was extracted. At the consensus meeting, participants shortened the list to a 25-item checklist. A generic flow diagram was drawn up to provide guidance on the method for including patients, the order in which tests were to be conducted and the number of patients to undergo the test being evaluated, the reference standard, or both. A scientific publication can only be assessed when the reporting is both correct and complete. Use of the checklist and flow diagram will improve the quality of reports produced, to the advantage of clinicians, researchers, reviewers, journal editors and other interested parties.

Laboratory-related outcomes in healthcare.

Outcomes studies, long common on the therapeutic side of medicine, are appearing in the diagnostic arena. Outcomes can be defined as results of medical interventions (therapies or tests) in terms of health or cost. The studies of outcomes are important because funding for medical interventions increasingly depends on them; a major accrediting agency even defines "quality" entirely in terms of outcomes. The study of laboratory-related outcomes is complex. Multiple steps occur between testing and outcomes, physicians act unpredictably on test results, and outcomes studies have high costs relative to potential profit from the test. Study design often must specify the action that is to follow a test result. The model outcomes study is a randomized controlled trial (RCT). The CONSORT statement, which is used as a guideline for RCTs of therapies, is largely applicable to studies of diagnostic interventions. Recent laboratory-related RCTs have addressed questions such as: "Does routine testing before cataract surgery decrease morbidity or mortality?" and "Does fecal occult bleed testing decrease the incidence of colorectal cancer?" RCTs of tests are sometimes impractical. Other approaches include simulation modeling and the use of intervention and control periods of testing. As for RCTs, these approaches require careful attention to study design, data analysis, and interpretation and reporting of results.

Quality specifications for glucose meters: assessment by simulation modeling of errors in insulin dose.

BACKGROUND: Proposed quality specifications for glucose meters allow results to be in error by 5-10% or more of the "true" concentration. Because meters are used as aids in the adjustment of insulin doses, we aimed to characterize the quantitative effect of meter error on the ability to identify the insulin dose appropriate for the true glucose concentration. METHODS: Using Monte Carlo simulation, we generated random "true" glucose values within defined intervals. These values were converted to "measured" glucose values using mathematical models of glucose meters having defined imprecision (CV) and bias. For each combination of bias and imprecision, 10,000-20,000 true and measured glucose concentrations were matched with the corresponding insulin doses specified by selected insulin-dosing regimens. Discrepancies in prescribed doses were counted and their frequencies plotted in relation to bias and imprecision. RESULTS: For meters with a total analytical error of 5%, dosage errors occurred in approximately 8-23% of insulin doses. At 10% total error, 16-45% of doses were in error. Large errors of insulin dose (two-step or greater) occurred >5% of the time when the CV and/or bias exceeded 10-15%. Total dosage error rates were affected only slightly by choices of sliding scale among insulin dosage rules or by the range of blood glucose. To provide the intended insulin dosage 95% of the time required that both the bias and the CV of the glucose meter be <1% or <2%, depending on mean glucose concentrations and the rules for insulin dosing. CONCLUSIONS: Glucose meters that meet current quality specifications allow a large fraction of administered insulin doses to differ from the intended doses. The effects of such dosage errors on blood glucose and on patient outcomes require study.

Parathyroid hormone-related protein and its receptor in human glial tumors.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP) and its mRNA have been found to be expressed in a variety of human tumors including breast, prostate, colon, lung, renal and ovarian cancers. The purpose of this study is to evaluate the expression of PTH/PTHrP receptor and ligand in human glial tumors. METHODS: We examined the coexpression of PTH/PTHrP receptor and ligand in 73 glial tumors of different histological grades and 4 nonneoplastic human brain specimens and three glioblastoma cell lines, by using Western Blot analysis and immunohistochemical analysis. RESULTS: PTHrP and PTH/PTHrP receptors were shown in the neurons, reactive astrocytes and the endothelial cells of normal brain tissue as well as tumor cells, reactive astrocytes and vasculature of nonneoplastic tissue. They were expressed at higher levels in pure astrocytic tumors as compared to tumors with oligodendroglial components. CONCLUSION: PTH/PTHrP receptor and PTHrP ligand are co-expressed in human glial tumors. There increased expression suggests an autocrine and/or paracrine loop may exist.

Toward a checklist for reporting of studies of diagnostic accuracy of medical tests.

BACKGROUND: : "Diagnostic accuracy" refers to the ability of medical tests to provide accurate information about diagnosis, prognosis, risk of disease, and other clinical issues. Published reports on diagnostic accuracy of medical tests frequently fail to adhere to minimal clinical epidemiological standards, and such failures lead to overly optimistic assessments of evaluated tests. Our aim was to enumerate key items for inclusion in published reports on diagnostic accuracy, with a related aim of making the reports more useful for systematic reviews. METHODS: : We examined published reports on shortcomings of studies of diagnostic accuracy. We prepared an initial draft of a checklist to address common errors and presented it at a meeting of editors. After incorporation of comments from editors, we published a revised version in Clinical Chemistry in 1997 for comment from readers. One of us (E.M.) additionally circulated copies of the draft to methodologists and others interested in Evidence-Based Medicine. We updated the checklist with input from these sources. RESULTS: : The updated document lists items for inclusion in the title, abstract, methods, results, and discussion sections of published papers. Depending on the nature of the study, the total number of items for a single paper is approximately 40. We invite comments on this document, which is freely available at Clinical Chemistry Online, where it can accessed readily from the Table of Contents for the July 2000 issue at www. clinchem.org/content/vol46/issue7/. Comments (eLetters) can be posted there for general reading. CONCLUSIONS: : The suggested revisions incorporated in this report appear useful to ensure inclusion of additional information that can allow assessment of the validity of the conclusions and the applicability of the study in other settings. The list can be useful in formulating guidelines and a checklist, which will require testing by authors and study of their effect on published studies of diagnostic accuracy.

Expression of parathyroid hormone-related peptide (PTH-rp) and its receptorin the porcine ovary: regulation by transforming growth factor-beta and possible paracrine effects of granulosa cell PTH-rp secretion on theca cells.

Parathyroid hormone-related peptide (PTH-rp) and the PTH-rp receptor are expressed in certain cancers as well as in many normal tissues. To evaluate the expression of this Ca(2+)-regulating hormone and its receptor in porcine ovary, we isolated partial cDNAs encoding homologous PTH-rp and PTH-rp receptor using reverse transcription-polymerase chain reaction (RT-PCR). The cDNA encoding PTH-rp (419 base pairs [bp]) was 92% and 87% homologous to human and rat sequences, respectively, while the PTH-rp receptor clone (167 bp) was 94% and 91% identical to the human and rat genes. Qualitative estimates of PTH-rp mRNA by RT-PCR indicated that the PTH-rp gene is expressed at high levels in the corpus luteum but is undetectable in granulosa and theca cells isolated from small (1-5 mm) and medium-sized (5-8 mm) antral follicles. In contrast, PTH-rp receptor transcripts were most abundant in corpora lutea and theca cells, and least abundant (albeit detectable) in granulosa cells. Regulation of PTH-rp protein production was assessed in serum-free monolayer cultures of porcine granulosa cells. Transforming growth factor (TGF)-beta1 (100 ng/ml) increased PTH-rp concentrations (assayed by two-site immunoradiometric assay of culture media) as well as corresponding PTH-rp mRNA accumulation (assessed by RT-PCR) in a time-dependent manner, with maximal responses of 3- to 5-fold at 96 h. TGF-beta1 dose-response studies revealed an ED(50) of 0. 24-0.38 ng/ml with a maximal effect at 30 ng/ml. Other growth factors and hormones, including insulin, insulin-like growth factor (type I), epidermal growth factor, FSH, estradiol, and interleukin-1, failed to alter PTH-rp secretion. Biological effects of PTH-rp were evident in purified porcine theca cells. Using the Ca(2+)-sensitive fluorescent indicator dye, fura-2, and digital imaging videomicroscopy, we found that PTH-rp (1 microM) stimulated intracellular free calcium ion concentrations ([Ca(2+)](i)) in single porcine theca cells. The [Ca(2+)](i) elevation was characterized by a slow and prolonged rise. After PTH-rp stimulation, theca cells maintained responsiveness to hormone stimulation by LH, which elicited a typical theca cell [Ca(2+)](i) response. Our results allow a hypothesis of a paracrine intrafollicular signaling system involving interaction between theca cell-derived TGF-beta and granulosa cell-derived PTH-rp, with feedback by PTH-rp on theca cells. Alternatively, expression of mRNAs encoding PTH-rp and its receptor in corpora lutea suggests that this peptide may play a role in luteal cell function. The precise role of this intraovarian PTH-rp system will require further study.

Anatomy of a meta-analysis: a critical review of "exercise echocardiography or exercise SPECT imaging? A meta-analysis of diagnostic test performance".

BACKGROUND: Accurate diagnosis of coronary heart disease has the potential to contribute substantially to cost-effective delivery of health services. Recent work by Fleischmann et al (JAMA 1998;280:913-20) represents an effort to summarize the accuracy of exercise echocardiography and exercise single photon emission computed tomography (SPECT). METHODS AND RESULTS: A critique of the previous work was constructed, obtaining the 44 articles used. These articles were reviewed and summarized with established techniques for meta-analysis. The studies summarized by Fleischmann et al were found to be significantly heterogeneous (echocardiography and SPECT, both P<.001). In the SPECT cohort, combination of different radioisotopes and reading techniques, and inclusion of reports using experimental techniques, were sources of heterogeneity. In the echocardiography cohort, experimental techniques and an individual series were identified. When the sample was stratified for sources of heterogeneity, it was found that there was no significant difference in diagnostic accuracy between the echocardiography and SPECT techniques used in current clinical practice. Meta-regression with summary receiver operating characteristic curve techniques, after adjustment of the model for multicolinearity and outliers, revealed that there were no significant differences between SPECT as used in current clinical practice and echocardiography. CONCLUSION: The report by Fleischmann et al contains serious flaws that limit its validity and generalizability.

Differing susceptibility of echocardiographic contrast agents to adverse effects of biologic factors: multicenter, videodensitometric comparison of octafluoropropane-filled microspheres with air-filled microspheres for left ventricular opacification.

BACKGROUND: Echocardiographic contrast enhancement of the left ventricle has diagnostic value in the assessment of regional and global left ventricular (LV) function. The efficacy of both octafluoropropane-filled human albumin microbubbles (OCTA) and of air-filled human albumin microbubbles (AIR) for LV endocardial delineation and qualitative LV opacification has previously been reported. However, pulmonary disease, obesity, impaired LV function, and decreased echogenicity may diminish the efficacy of contrast agents for LV opacification. The purpose of this study was to compare the susceptibility of 2 contrast agents currently approved by the Food and Drug Administration to these biologic factors. METHODS: To compare quantitative LV opacification with OCTA (0.2, 0. 5, 3.0, 5.0 mL) versus AIR (0.08 mL/kg, 0.22 mL/kg), we performed videodensitometry in 199 patients (average age 59.2 +/- 13.3 years, 79% men) studied in 2 identical, prospective, multicenter, blinded trials, of whom 74 had impaired LV function, pulmonary disease, or both, 70 were obese (body mass index >30 kg/m(2)), and 45 were nonechogenic (>/=4 of 6 endocardial segments were not seen in the apical 4-chamber view). Changes in videodensity from noncontrast to contrast agent with the same gain settings were determined at end diastole and end systole (gray scale 0 to 255 U) for 2 regions of interest: left ventricle apex-to-mid-cavity and mid-cavity-to-base. The relative influence of clinically evident pulmonary disease, impaired LV function on echocardiography, and echogenicity on LV opacification produced by both contrast agents was determined by multivariate analysis. RESULTS: Significant videodensity increases ranging from 67% to 143% were observed with both agents. At the recommended initial doses (0.5 mL for OCTA, 0.22 mL/kg for AIR), OCTA produced greater opacification than AIR in both regions of interest and at both phases of the cardiac cycle. Poor LV function was associated with decreased LV opacification for AIR but not for OCTA. Diminished echogenicity was more strongly associated with impaired opacification for AIR than for OCTA. Obesity and clinically evident pulmonary disease were associated with diminished chamber opacification with both OCTA and AIR. CONCLUSIONS: In addition to the superiority of octafluoropropane-filled microspheres to air-filled microspheres for LV opacification, the efficacy of OCTA is relatively unaffected by impaired LV function and is less susceptible to the effects of poor echogenicity than AIR.

Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension.

The ability of the dopamine-1 (D1)-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D1-like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D1-like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (n=6) and HT (n=4). However, the D1-like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum response=67+/-1%) than in HT (maximum response=17+/-5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32+/-3%) than in HT (14+/-3%). The fenoldopam-mediated increase in cAMP production was blocked by SCH23390 (a D1-like receptor antagonist) and by antisense D1 oligonucleotides in both HT and NT, indicating action at the D1 receptor. The stimulatory effects of forskolin and parathyroid hormone-related protein of cAMP accumulation were not statistically different in NT and HT, indicating receptor specificity and an intact G-protein/AC pathway. The fenoldopam-stimulated PLC activity was not impaired in HT, and the primary sequence and expression of the D1 receptor were the same in NT and HT. However, D1 receptor serine phosphorylation in the basal state was greater in HT than in NT and was not responsive to fenoldopam stimulation in HT. These studies demonstrate the expression of D1 receptors in human RPT cells in culture. The uncoupling of the D1 receptor in both rats (previously described) and humans (described here) suggests that this mechanism may be involved in the pathogenesis of hypertension; the uncoupling may be due to ligand-independent phosphorylation of the D1 receptor in hypertension.

Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial.

OBJECTIVES: The echocardiographic contrast-enhancing effects and safety profile of ALBUNEX (a suspension of air-filled albumin microspheres) were compared with the new contrast agent OPTISON (formerly FS069: a suspension of albumin microspheres containing the gas perfluoropropane) in 203 patients with inadequate noncontrast echocardiograms. BACKGROUND: The efficacy of ALBUNEX has been limited by its short duration of action. By using perfluoropropane instead of air within the microsphere, its duration of action is increased. METHODS: Each patient received ALBUNEX (0.8 and 0.22 mL/kg) and OPTISON (0.2, 0.5, 3.0, and 5.0 mL) on separate days a minimum of 48 hours apart. Echocardiograms were evaluated for increase in left ventricular (LV) endocardial border length, degree of LV opacification, number of LV endocardial border segments visualized, conversion from a nondiagnostic to a diagnostic echocardiogram, and duration of contrast enhancement. A thorough safety evaluation was conducted. RESULTS: Compared with ALBUNEX, OPTISON more significantly improved every measure of contrast enhancement. OPTISON increased well-visualized LV endocardial border length by 6.0+/-5.1, 6.9+/-5.4, 7.5+/-4.7, and 7.6+/-4.8 cm, respectively, for each of the four doses, compared with only 2.2+/-4.5 and 3.4+/-4.6 cm, respectively, for the two ALBUNEX doses (p < 0.001). 100% LV opacification was achieved in 61%, 73%, 87%, and 87% of the patients with the four doses of OPTISON, but in only 16% and 36% of the patients with the two ALBUNEX doses (p < 0.001). Conversion of nondiagnostic to diagnostic echocardiograms with contrast occurred in 74% of patients with the optimal dose of OPTISON (3.0 mL) compared with only 26% with the optimal dose of ALBUNEX (0.22 mL/kg) (p < 0.001). The duration of contrast effect was also significantly greater with OPTISON than with ALBUNEX. In a subset of patients with potentially poor transpulmonary transit of contrast (patients with chronic lung disease or dilated cardiomyopathy), OPTISON more significantly improved the same measures of contrast enhancement compared with ALBUNEX and did so to the same extent as in the overall population. Side effects were similar and transient with the two agents. CONCLUSION: OPTISON appears to be a safe, well-tolerated echocardiographic contrast agent that is superior to ALBUNEX.

Expression and specific immunolocalization of the human parathyroid hormone/parathyroid hormone-related protein receptor in the uteroplacental unit.

OBJECTIVE: Our purpose in these studies was to determine the expression and cellular localization of the parathyroid hormone/parathyroid hormone-related protein receptor in the human uteroplacental unit. STUDY DESIGN: Human uteroplacental tissues were obtained and ribonucleic acid was extracted. Reverse transcriptase-polymerase chain reaction was performed with use of primers for both the parathyroid hormone/parathyroid hormone-related protein receptor and human phosphoglyceraldehyde dehydrogenase. Ethidium bromide-stained gels and Southern blots were evaluated, and polymerase chain reaction fragments were sequenced. For immunohistochemistry, slides were incubated with a newly developed antibody (3D1.1) specific for the parathyroid hormone/parathyroid hormone-related protein receptor, and bound monoclonal antibody was detected by use of the avidin-biotin technique. RESULTS: Reverse transcriptase polymerase chain reaction gels and blots showed that receptor messenger ribonucleic acid was present in choriodecidua, placenta, and myometrium. Sequence analysis revealed complete identity of the receptor product and the known nucleotide sequence in the receptor. There was intense receptor staining of the myometrial smooth muscle as well as staining of the endothelium and smooth muscle of the associated vasculature. In umbilical cord immunoreactive receptor was found in the vascular endothelium and vascular smooth muscle cells and in stromal cells. In choriodecidua receptor was found in chorionic trophoblasts and decidualized endometrial stromal cells. In all tissues immunostaining was specific, as evidenced by the blocking of staining after addition of receptor peptide to the antibody (absorbed controls). CONCLUSION: The parathyroid hormone/parathyroid hormone-related protein receptor is widely expressed in the human uteroplacental unit. The cellular localizations of the receptor in smooth muscle reflect the ability of parathyroid hormone-related protein to relax both uterine and vascular smooth muscle. The presence of novel autocrine and paracrine systems in the human uteroplacental unit is suggested by the finding that the same cells or adjacent cells produce both parathyroid hormone-related protein and its receptor.

Mechanical stretch increases secretion of parathyroid hormone-related protein by cultured bladder smooth muscle cells.

Parathyroid hormone-related protein (PTHrP) immunoreactivity has been detected in the bladder and increases in response to dilatation secondary to obstruction. The hypothesis that PTHrP could be increased solely by stretch rather than other possible in vivo variables was tested by stretching cultured bladder smooth muscle cells and analyzing the culture medium for this protein. In response to mechanical stretch, PTHrP was increased in smooth muscle cell cultures. Immunoradiometric assay revealed maximal rates of secretion for the first eight hours. Comparison of percent change in PTHrP secretion of flexed cells for the various flex parameters revealed a difference (p = .006) when the degree of stretch (i.e. percent elongation) was altered. The protein synthesis inhibitor cycloheximide inhibited basal and stretch-induced PTHrP secretion. PTHrP (1-100 nM) relaxed carbachol-contracted bladder body and base by 15% and 45% respectively. PTHrP did not affect bladder contractions induced by potassium (124 mM) or alpha-beta MeATP (10 microM). Increased PTHrP secretion in response to stretch of smooth muscle raises the possibility of an autocrine action to relax the bladder during filling. PTHrP may also exert a paracrine action on vessels regulating blood flow during bladder filling or it may modulate neural activity.

Coexpression of parathyroid hormone-related protein and its receptor in breast carcinoma: a potential autocrine effector system.

Parathyroid hormone-related protein (PTHrP), the pathogenic factor in most cases of humoral hypercalcemia of malignancy, is also expressed by many normal tissues. Its diverse biologic activities in these tissues are mediated by the PTH/PTHrP receptor through autocrine and paracrine mechanisms. Recent data suggest that PTHrP and its receptor might also influence the growth and metastatic spread of some cancers through similar local actions. Accordingly, immunohistochemical studies using murine monoclonal antibodies to detect coexpression of PTHrP and the PTH/PTHrP receptor were performed on 52 invasive breast carcinomas to assess the existence of this potential autocrine effector system. All of the 52 invasive breast carcinomas expressed reactivity for PTHrP, and 50 (96%) of these tumors also expressed reactivity for the receptor. Although additional investigations are necessary for evaluation of the role of PTHrP and PTH/PTHrP receptor in tumor pathogenesis, our current study demonstrates the presence of this potential autocrine effector system in the great majority of invasive breast carcinomas.

Molecular and immunological detection of circulating tumor cells and micrometastases from solid tumors.

Histological, immunological, and molecular methods have been used for detecting micrometastases from nonhematopoietic malignancies. Early studies utilizing cytological methods to identify circulating tumor cells demonstrated the uncertain significance of micrometastasis detection for predicting eventual recurrent disease. Recently, reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of circulating tumor cells has been suggested as a potential technique for staging of cancer. Studies using RT-PCR thus far indicate that test results may be negative in some patients with known metastatic disease, thereby raising doubts about the utility of the method for staging of disease. In this review, we survey the relevant literature and discuss the range of current applications of histological, immunological, and molecular methods for detecting micrometastases from solid tumors in blood, bone marrow, and lymph nodes and the progress toward determining the significance of micrometastasis detection.