Screening with tumor markers: critical issues.

Reviewing the literature it would appear that tumor markers have often flattered to deceive. Early promise does not often seem to be borne out in extended trials. Despite apparently high specificity, very few markers are capable of assisting in a screening process. This brief review attempts to put the roles of tumor markers in perspective and explain how their misapplication has led to misunderstanding of their potential value in a clinical context. It also considers the theoretical basis for their use and highlights how misunderstanding of these can lead to flawed studies and application.

Markers of tumor burden : an overview.

Since ancient times, cancer has been known to humankind. The ancient Greeks and Romans have left us with writings in which various treatment options are discussed (1). Disease processes and causes were not well understood, however; the humoral pathology established by the ancient Greeks of the school of Galen in the second century ad was to survive virtually intact until the mid-nineteenth century. It is perhaps all the more remarkable then, that the first tumor marker-Bence Jones' protein in multiple myeloma-should come to light in what was still by and large the prescientific medical culture prevailing in 1845.

Serum amylase isoenzymes in patients undergoing operation for ruptured and non-ruptured abdominal aortic aneurysm.

OBJECTIVE: Previous work has suggested that hyperamylasemia in patients who undergo operation for ruptured abdominal aortic aneurysm (AAA) is associated with poor outcome. The aims of this study were to determine, for the first time, the source of serum amylase in such patients and to examine the prognostic significance of amylase isoenzyme expression. METHODS: This study was designed as a prospective clinical and laboratory study. The study consisted of 40 patients who underwent operation for ruptured AAA and 10 patients who underwent operation for non-ruptured AAA. The main outcome measures were serum total and pancreatic and salivary amylase activities determined with enzymatic colorimetric assay before operation and 6 hours after aortic clamp release. RESULTS: Five of 40 patients (12.5%) with rupture and one of 10 patients (10%) with non-rupture had elevated total amylase levels before operation, and seven of 31 patients (23%) with rupture and five of 10 patients (50%) with non-rupture had elevated total amylase levels after operation. The preoperative salivary amylase (P =.05) and postoperative pancreatic amylase (P <.02) levels were significantly lower in ruptured AAA as compared with non-ruptured AAA. The preoperative salivary amylase level was significantly lower in non-survivors of rupture, such that a level equal to or less than 45 U/L was associated with death in 11 of 13 patients (85%). CONCLUSION: These data do not support previous works that suggest that hyperamylasemia is associated with poor outcome in ruptured AAA. By contrast, a low preoperative salivary amylase level was associated with increased mortality in ruptured AAA and may be a marker of the severity of shock.

Performance improvement: the organization's quest.

In today's health care marketplace, quality has become an expectation. Stakeholders are demanding quality clinical outcomes, and accrediting bodies are requiring clinical performance data. The Roosevelt Institute's quest was to define and quantify quality outcomes, develop an organizational culture of performance improvement, and ensure customer satisfaction. Several of the organization's leaders volunteered to work as a team to develop a specific performance improvement approach tailored to the organization. To date, over 200 employees have received an orientation to the model and its philosophy and nine problem action and process improvement teams have been formed.

Community photoscreening of six to nine month old infants for amblyopiogenic risk factors.

Photorefraction (PR) is gaining acceptance as potentially the most effective objective screening technique for amblyopia risk factors in the preverbal child. This study determined the validity and feasibility of using the Auckland eccentric photorefractor in the detection of amblyopiogenic factors in six to nine month old infants in an established community-based vision screening program. Photographs were analysed and compared to results of clinical examination including cycloplegic refraction. Amblyopia risk factors were present in 7.2% of the infants clinically examined. Analysis only of readable photographs in children who were also clinically examined, gave sensitivities ranging from 71% to 79%, and specificities ranging from 81% to 86%. Inclusion in the analysis of photo-failures lowered sensitivity figures to 56% to 61%, and specificity to 63% to 70%. Photofailures were predominantly due to poor operator technique. Calculation of kappa scores indicated fair observer reliability. In conclusion, PR could provide a feasible and sufficiently reliable screening technique in the infant, but requires adequate training and auditing of screening personnel performance for optimum effectiveness.

Serological markers for metastatic breast cancer.

Three serum markers, TPS, CA 15.3 and CEA, were used to monitor the response to treatment of 20 patients with metastatic breast cancer. At the time of the first evidence of metastases or at the time of progression of known metastatic disease, 84% of TPS values were above the reference limit, as compared to 74% for CA 15.3 and 84% for CEA. If the treatment instituted was effective, 60% of TPS values showed an early (within 2 or 3 weeks after commencement or change of therapy) reduction in level against only 27% of CA 15.3 and 27% of CEA levels. This suggests that TPS provides a more sensitive and earlier predictor of therapeutic response. In patients with clinical evidence of further progression of disease while on therapy, 86% of TPS values showed persistent elevation or increase, as compared to 71% of CA 15.3 levels and only 36% of CEA levels. It was also noted in these patients that TPS values rose earlier than either CA 15.3 or CEA. This indicates that TPS is a more reliable predictor of response to treatment than the other two markers. In addition, we found that, at the time of presentation, in women who had visceral metastases (liver, lung, or brain alone or in combination), 87% of TPS values were raised, as compared to 80% of CA 15.3 and 73% of CEA values. In women who had bone and soft tissue metastases at presentation, 75% of TPS values were elevated, against 50% of CA 15.3 and 75% of CEA values.(ABSTRACT TRUNCATED AT 250 WORDS)

The prognostic value of serum CA 125 in patients with advanced ovarian carcinoma: an analysis of 573 patients by the Medical Research Council Working Party on Gynaecological Cancer.

A number of studies have suggested that serum CA 125 levels may be an important prognostic factor for survival of patients with ovarian carcinoma. We investigated, in a large group of patients from 11 UK centers, which combination of CA 125 measurements provided the best prognostic index, and whether the predictive power could be improved by the addition of other factors. Analysis of the data from 248 patients showed that the absolute value of the third CA 125 sample was the single most important factor for predicting progression at 12 months, with the addition of residual bulk only slightly improving the predictive power. Seventy-four patients had CA 125> 70, and of these 57% were correctly predicted to progress or die within 12 months, but 43% remained alive and progression free. The best predictor for progression produced a false positive rate of 19%. We therefore conclude that prognostic information based upon CA 125 measurements up to the start of the third course of initial chemotherapy is not accurate enough to be used to manage individual patients.

The prognostic value of early CA125 serum assay in epithelial ovarian carcinoma.

We examined the prognostic value of early serum CA125 assay in 58 patients with advanced epithelial ovarian cancer together with residual disease, age, tumour grade, performance status, and the presence of ascites or adhesions at primary surgery. CA125 was a highly significant predictor of both progression free and overall survival after the first cycle and throughout primary chemotherapy. After the first cycle, CA125 was by far the most significant predictor of progression free survival (P < 0.0005). At this time, CA125 was a highly significant predictor of survival (P < 0.005), but did not add to performance status (P < 0.001) in multivariate analysis. We were able to identify three statistically-distinct prognostic groups. Patients in the upper quartile, with CA125 levels greater than 450 U ml-1, had a very poor median survival of 7 months. Patients in the lower quartile, with CA125 levels less than 55 U ml-1 had a good median survival of 23 months. Those in the two interquartile groups, who had CA125 levels ranging from 58-221 U ml-1 and 228-434 U ml-1, had relatively intermediate median survival times of 16 months and 15 months respectively. Although CA125 levels provided significant prognostic information, in the majority of patients CA125 merely confirmed overall clinical impression.

The value of the human milk fat globule membrane antigen HMFG2 in epithelial ovarian cancer monitoring: comparison with CA125.

We assayed serum HMFG2 in serial samples from 215 primary epithelial ovarian cancer patients using an 'in-house' single determinant ELISA, 45% of patients with stage I, 54% with stage II, 61% with stage III and 75% with stage IV disease had elevated serum HMFG2. Post-operative levels were significantly related with residual tumour volume (P < 0.005), and fell in the majority of responders, although the association with response to first-line chemotherapy was not significant. HMFG2 had a sensitivity of 50% specificity of 83%, accuracy of 61%, PVP of 86% and PVN of 45% for disease at second-look laparotomy. Serial levels gave a lead time to clinical relapse in 47% of patients who responded to therapy, including one patient with negative CA125 levels. HMFG, paralleled CA125 in many respects, although it was elevated in fewer patients. In a stepwise discriminant analysis, HMFG2 added to the discrimination of CA125 (r = 0.183, P < 0.005), although additional accurate information was only given in patients with advanced poorly differentiated serous cystadenocarcinoma. Given that HMFG2 is expressed in few patients who are CA125 negative it is unlikely that it will have a significant clinical impact upon patient management.

Measurement of placental alkaline phosphatase activity in benign and malignant pleural effusions.

The usefulness of placental alkaline phosphatase (PLAP) as a diagnostic marker of malignancy was assessed in pleural fluid from 60 patients with effusions. Pleural fluid PLAP activities were measured by an enzyme linked immunoassay (ELISA) using the two monoclonal antibodies H17E2 and H317. Similar values were found in groups of patients with primary bronchial tumours (n = 12), secondary malignancies (n = 23), and "benign" conditions (n = 25). The highest values were found in a small subgroup of patients with metastatic ovarian carcinoma. However, the production of this enzyme by normal lung makes the measurement of PLAP in pleural fluid unhelpful as a diagnostic aid to distinguish "benign" from malignant effusions.

Investigation of the c-neu proto-oncogene related protein, p185, in the serum of primary epithelial ovarian cancer patients.

The relatively high incidence of amplification and overexpression of the neu (c-erb B2/HER-2) oncogene in breast cancer, and its association with poor prognosis, particularly in node negative patients, may allow identification of patients who require aggressive therapy to prevent an early relapse. It's association with ovarian cancer, however, is less well defined than in breast cancer. An ELISA for the c-neu proto-oncogene related protein, p185, has been developed recently using the monoclonal antibodies NB3 and TA1. In the first study of it's kind, we assayed serum samples from patients with primary epithelial ovarian cancer for circulating c-neu p185. Elevated levels were found in 21/178 (11.8%) patients. No correlation was found between serum levels and either the presence or volume of tumor, when assessed either after primary or at second-look surgery. A change in c-neu p185 levels did not correlate with response to chemotherapy. When subjected to univariate and multivariate analyses together with other known prognostic factors, serum c-neu p185 was not a significant predictor of progression-free survival or overall survival. Although c-neu p185 may be involved in the pathogenesis of ovarian cancer, it's assay in serum has no value in prognosis or monitoring.

Serological monitoring of epithelial ovarian cancer.

Serum CA125 measurement has an established role in monitoring epithelial ovarian cancer patients, assisting in determining response to chemotherapy and providing a lead time to clinical relapse. Over the past few years there has been a decrease in the use of second-look laparotomy to determine response; however, this is largely due to the lack of impact that this procedure has on survival rather than the growing use of less invasive scanning techniques or CA 125 assay to determine disease status. The value of a marker lead time depends ultimately on a patient's remaining therapeutic options; the influence on survival of therapeutic intervention at pre-clinical diagnosis of relapse remains to be tested in a randomized controlled trial. The third area where CA 125 may help patient management is in predicting progression-free survival and overall survival. Treating patients with aggressive chemotherapy regimes would not be justified (given the deterioration in the quality of life for a period of months that may result from such therapy) if a poor outcome could be predicted. Deciding when to stop ineffective treatment is extremely difficult for the clinician given patients' desire for active therapy. The prognostic value of CA 125 needs to be further clarified before it can influence such treatment decisions. The aim of this study was to help clarify the role of CA 125 in patient management and to assess several other putative EOC markers, including determinants found on the polymorphic epithelial mucin (PEM)--the most promising alternative marker protein to date.

Vasopressin secretion in diabetic subjects with and without autonomic neuropathy: responses to osmotic and postural stimulation.

1. The release of arginine vasopressin (AVP) after an osmotic stimulus and head-up tilt was assessed in diabetic subjects with and without autonomic neuropathy. 2. Six diabetic subjects with (DAN +ve) and five without (DAN -ve) evidence of autonomic neuropathy and five normal subjects were infused with 5% (w/v) NaCl at a rate of 0.05 ml min-1 kg-1 body weight for 120 min. Blood pressure, heart rate and plasma AVP were measured over this period. 3. Seven DAN +ve, six DAN -ve and six normal subjects were tilted head-up to 45 degrees for 120 min. Blood pressure, heart rate and plasma AVP were measured during the study. 4. Infusion of 5% (w/v) NaCl produced appropriate rises in plasma osmolality and plasma AVP levels which did not differ between the three groups, confirming the normal osmotic release of AVP in the diabetic subjects. 5. During head-up tilt, there were no differences in AVP responses between the three groups, despite a major hypotensive stimulus in the DAN +ve group. 6. We conclude that osmotic release of AVP is normal in diabetes, but that cardiovascular release of AVP is impaired in diabetic subjects with cardiovascular reflex evidence of autonomic neuropathy, reflecting an afferent defect.

Immunoassay of CA125 in ovarian cancer: a comparison of three assays for use in diagnosis and monitoring.

There is increasing evidence to support the use of CA125 in the follow-up and management of patients with ovarian cancer and several commercial kits are now available for its measurement. This study investigated and compared the performance of three of them: an enzyme immunoassay (EIA) and an immunoradiometric assay (IRMA) from Abbott Diagnostics, and an IRMA from CIS, U.K. One hundred and thirty-two serum samples from 42 patients with advanced epithelial ovarian cancer were thawed once and assayed for CA125 using each kit. Both IRMAs performed better than the EIA in terms of CV, sensitivity, specificity, and accuracy. The results confirm the usefulness of CA125 as a marker for ovarian cancer. However, discrepancies between results using different kits suggest the need for improved standardization.