José Genolla

Circulating CA 15-3 levels in the postsurgical follow-up of breast cancer patients and in non-malignant diseases.

SummaryCirculating CA 15-3 antigen levels were evaluated in patients with benign diseases and breast cancer patients with no clinical evidence of disease after surgery (NED). Patients with breast cancer NED were followed for tumor recurrence or death during a median of 12.9 months (range 1 to 25 months). CA 15-3 and carcinoembryonic antigen (CEA) were compared in the same breast cancer NED patient population. Elevated CA 15-3 levels (>40 U/ml) were observed in 38 of 1220 patients with benign diseases (3.1%) and in 25 of 350 breast cancer NED patients (7.1%). Elevations of CEA (>5ng/ml) were observed in 23 patients with breast cancer NED (6.5%). Benign diseases that produced significant elevations of CA 15-3 were chronic hepatitis (42.9%), liver cirrhosis (13.3%), sarcoidosis (16.7%), tuberculosis (9.7%), and systemic lupus erythematosous (6.7%).In breast cancer NED, initial elevations of CA 15-3 were observed in 12 of the 297 patients that remained free of disease during the follow-up, and in 13 of the 40 patients that relapsed (4.0% vs. 32.5%, p<0.001). Initial CEA levels were elevated in 16 patients that remained NED and in 7 patients that relapsed (5.3% vs. 17.5%, p<0.001). Serial determinations of CA 15-3 in patients continuously NED showed persistent elevations in 4 cases. Three of these exhibited concomitant benign diseases. In relapsing patients, serial tumor marker determinations showed that elevations of CA 15-3 before any other clinical evidence of recurrence occurred significantly more frequently than elevations of CEA (45% vs. 25%, p<0.001). Overall, two or more serial elevated values of CA 15-3 were observed in 7 cases, and 6 of them (85%) eventually relapsed. Median survival from study entry was 18.3 months in patients with breast cancer NED that had initial elevated CA 15-3, compared to 25+ months in those with negative CA 15-3 (p<0.0001).We conclude that circulating levels of CA 15-3 antigen can be elevated in some patients with nonmalignant diseases, and that serial determinations of CA 15-3 may be useful in the postsurgical follow-up of patients with breast cancer when specific types of benign diseases that may cause elevations of the antigen are excluded. Additionally, CA 15-3 is more sensitive than CEA in the early diagnosis of breast cancer recurrences, and the simultaneous assay of CEA does not add information to that of CA 15-3 alone.

CA 19-9 in non-neoplastic liver diseases. A clinical and laboratory study.

CA 19-9 is a tumor marker with frequent false-positive results in pancreatic and hepatobiliary diseases. This study was carried out to evaluate the behaviour of CA 19-9 in 159 patients with benign diffuse hepatic disease, 85 cirrhotics and 74 non-cirrhotics, who underwent a thorough clinical and laboratory evaluation. CA 19-9 was correlated with numerous clinical and biochemical features of liver diseases: bilirubin and alkaline phosphatase activity were the most reliable predictors of the CA 19-9 concentrations. There were abnormal concentrations of CA 19-9 in 34.6% of the 159 patients and in 47.1% of the 85 cirrhotics. Because of the large number of abnormal values and the high concentrations attained in some of them, the cut-off used in patients with diffuse hepatic disease needs to be set at more than twice the basal level, thus allows only 10% of false positives. Even higher values are required for cirrhotic or icteric patients. The results indicate that cholestasis plays an important role in causing the raised CA 19-9 in these patients, although there were also abnormal concentrations in normobilirubinemic patients.

Serum CA 15.3 levels in patients with non-tumoral diseases, and establishment of a threshold for tumoral activity. Results in 1219 patients.

CA 15.3 is a circulating antigen expressed by human breast carcinoma cells and defined by two monoclonal antibodies (115D8 and DF3). Some clinical studies have indicated that its main clinical application lies in the monitoring of breast cancer patients undergoing treatment (1, 2), especially in detecting early relapses, a situation in which CA 15.3 was more sensitive than carcinoembryonic antigen (CEA) (Colomer and Ruibal, manuscript in preparation). However, there are few published reports dealing with the behavior of CA 15.3 in patients with non-tumoral diseases. This is of great interest in relation to the use of circulating levels of the antigen as a follow-up parameter in breast cancer patients. In preliminary studies (3, 4), we established that 40 UI ml could be used as a threshold for tumoral activity (1.5% of positive determinations in patients with benign diseases). Likewise, this level was useful to distinguish stage II-III breast cancer patients with no evidence of disease (NED) from stage IV breast cancer patients in complete clinical remission (2). We present here the final results obtained in a group of 1219 patients with non-tumoral diseases. CA 15.3 serum levels were determined by IRMA (Centocor. USA). The lower limit of sensitivity was 2 U/ml. Serum samples were frozen until assay. Each sample was assayed in duplicate or triplicate. Other technical aspects are detailed elsewhere (3). The control group consisted of 255 blood donors HBsAg-(117 male and 138 female; mean age 38 years, range 18-66) and the study group of 1219 patients with non-tumoral diseases (Tab. I). In the control group, serum CA 15.3 levels ranged from 2 to 57 U/ml, with a mean of 16.5 and a standard deviation of 9.5 U/ml (males 17.3 ± 10.8; range 2-57; females 15.7 ± 8.8; range 2-44). 35 U/ml was taken as the upper normal level. The distribution of serum CA 15.3 levels in the study group is depicted in Table I. As can be seen, only 67 (5.5%) patients presented CA 15.3 levels

Evaluation of the behavior of carcinoembryonic antigen in cirrhotic patients.

Benign liver diseases are a cause of increased serum levels of CEA. We studied the behavior of CEA in 86 patients with liver cirrhosis who underwent extensive clinical and laboratory evaluation. We found abnormal CEA levels in 38.4% of the patients (28.6% Childs grade A, 40.6% Childs B, and 42.4% Childs C) with a mean of 4.75 ng/ml. Significant differences were found between patients and controls. There was a trend towards higher levels of CEA in more severe cirrhosis according to Childs classification, although this was not significant. We found significant correlations between CEA and some liver tests, including glycocholic acid (r = 0.264., p = 0.012), a marker of severity in liver diseases. The increase of CEA in these patients is probably due to alterations in its metabolic processing caused by hepatocellular dysfunction. Moderate elevations of serum CEA can be expected in cirrhotic patients independently of malignancy.

Serum laminin levels offer only a little additional information in liver disease

We have measured serum laminin, a marker of portal hypertension, in 151 patients with nonmalignant liver diseases, to evaluate its utility in cirrhosis and portal hypertension. There were abnormal serum levels in 43.1% of the patients as a whole and in 62.7% of the cirrhotics. Laminin showed a correlation with many laboratory tests, especially those that reflect liver insufficiency and alcohol intake. Cirrhotics had higher laminin levels than noncirrhotics (p < 0.0001); an association was also found with portal hypertension (p < 0.0001), but laminin was also increased in patients without portal hypertension. Our results suggest that liver dysfunction can also lead to abnormal laminin concentrations, probably through slower metabolization rate. Laminin serum concentrations reflect the severity of the liver disease, and are also a marker of alcohol consumption. Determination of laminin serum levels could play an adjunctive role with respect to other liver tests in the evaluation of these patients although the measure does not really provide more useful information.

Whole‐remnant and maximum‐voxel SPECT/CT dosimetry in 131I‐NaI treatments of differentiated thyroid cancer

PURPOSE To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). METHODS Eighteen DTC patients were administered 1.11 GBq of 131 I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. RESULTS The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in theS-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. CONCLUSIONS Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.

Levels of CA-19.9, CA-125, and CA-195 in seminal plasma and in vitro fertilization rates

OBJECTIVE To assess the relationship between carbohydrate tumor markers in seminal plasma and fertilization rates in IVF cycles. DESIGN Prospective study. SETTING Academic tertiary hospital. PATIENTS Forty-six consecutive couples subjected to IVF in which at least one oocyte was obtained. MAIN OUTCOME MEASURES Determination of CA-19.9, CA-125, and CA-195 in seminal plasma 1 week before IVF. RESULTS CA-125 was higher in the group without fertilization (321 +/- 198 U/mL, mean +/- SD) than in the group in which at least one oocyte was fertilized (155 +/- 165 U/mL), whereas CA-19.9 and CA-195 were similar in both groups. However, at the cutoff 66%, lower values of CA-19.9 were found in the fertilization group rate < 66% (707 +/- 1,217 versus 1,069 +/- 1,084) and of CA-195 (67 +/- 44 versus 218 +/- 274). No correlation was found between tumor marker levels and fertilization rates. CONCLUSION CA-125 seems to be an indicator of sperm fertilization capacity, whereas the importance of CA-195 and CA-19.9 will require further studies.

Preliminary study of alpha-fetoprotein in nonmalignant liver diseases. A clinico-biochemical evaluation

This preliminary study was carried out to evaluate the behavior of AFP in 155 patients with benign diffuse liver diseases who underwent thorough clinical and laboratory evaluation. We found correlations between AFP and some clinical and biochemical parameters characteristic of liver diseases; serum glutamic oxalacetic transaminase (GOT) proved the most relevant (r = 0.27 p = 0.0004) and most reliable marker to predict AFP levels. 22.6% of the patients as a whole, 25.6% of the 86 cirrhotics and 18.8% of the 69 non-cirrhotics, had increased levels of AFP. Patients with active liver disease as measured by increased GOT, had higher AFP levels than patients with quiescent liver diseases (p = 0.0048), suggesting that cytolysis and/or regeneration plays a role in the increase in AFP. Elevation of the cutoff level was necessary to improve the specificity of AFP as a tumor marker. In our series, the cutoff of 9 ng/ml was exceeded by only 10% of the patients.

CA 15.3 in Nonmalignant Liver Diseases

CA 15.3 is a recent tumor marker for a wide range of cancers that is usually used for monitoring breast carcinoma patients. This study was performed to evaluate CA 15.3 behaviour in 161 patients with benign diffuse hepatic diseases who underwent thorough clinical and biochemical evaluation. Abnormal serum levels of this antigen were found in 8.7% of the 161 patients, 11.6% of the 86 cirrhotics, and 5.3% of the 75 noncirrhotic patients. The correlation between CA 15.3 and certain parameters characteristic of liver diseases was checked. IgA showed the most relevant correlation (r = 0.39, p < 0.00001) and in our series a normal level of IgA was practically determinant of normal CA 15.3 levels. Our results also support the role played by hepatocellular dysfunction in increasing levels of this antigen in spite of the low number of false-positive results. CA 15.3 can be used as a tumor marker in these patients at levels used for healthy subjects.

Dosimetric results in treatments of neuroblastoma and neuroendocrine tumors with (131)I-metaiodobenzylguanidine with implications for the activity to administer.

PURPOSE The aim was to investigate whole-body and red marrow absorbed doses in treatments of neuroblastoma (NB) and adult neuroendocrine tumors (NETs) with (131)I-metaiodobenzylguanidine and to propose a simple method for determining the activity to administer when dosimetric data for the individual patient are not available. METHODS Nine NB patients and six NET patients were included, giving in total 19 treatments as four patients were treated twice. Whole-body absorbed doses were determined from dose-rate measurements and planar gamma-camera imaging. For six NB and five NET treatments, red marrow absorbed doses were also determined using the blood-based method. RESULTS Dosimetric data from repeated administrations in the same patient were consistent. In groups of NB and NET patients, similar whole-body residence times were obtained, implying that whole-body absorbed dose per unit of administered activity could be reasonably well described as a power function of the patient mass. For NB, this functional form was found to be consistent with dosimetric data from previously published studies. The whole-body to red marrow absorbed dose ratio was similar among patients, with values of 1.4 ± 0.6-1.7 ± 0.7 (1 standard deviation) in NB treatments and between 1.5 ± 0.6 and 1.7 ± 0.7 (1 standard deviation) in NET treatments. CONCLUSIONS The consistency of dosimetric results between administrations for the same patient supports prescription of the activity based on dosimetry performed in pretreatment studies, or during the first administration in a fractionated schedule. The expressions obtained for whole-body absorbed doses per unit of administered activity as a function of patient mass for NB and NET treatments are believed to be a useful tool to estimate the activity to administer at the stage when the individual patient biokinetics has not yet been measured.