T. Phillip Waalkes

Biological markers in breast carcinoma. I. Incidence of abnormalities of CEA, HCG, three polyamines, and three minor nucleosides

Patients with breast carcinoma were screened for abnormal concentrations of CEA, HCG, putrescine, spermidine, spermine, pseudouridine, N2, N2‐dimethylguanosine, and 1‐methylinosine. Abnormal polyamine levels occurred in less than 15% of the patients. Among the nucleosides, N2, N2‐dimethylguanosine was the most frequently abnormal, occurring in 57% of the patients with metastatic disease. CEA levels were abnormal in 30% of postoperative N+ patients and 74% of patients with metastatic disease, while HCG elevations were found in 45% and 50%, respectively. All the patients with one or more marker abnormalities could be detected by measuring only CEA, N2, N2‐dimethylguanosine, and HCG. Among these three tests, a singular marker abnormality occurred in 35.8% of the patients, and all three tests were abnormal in 21.8% of the patients. The performance of these three tests in each patient revealed one or more abnormalities in 97% of the patients with metastatic disease, and 67% of the postoperative N+ patients.

Biological markers in breast carcinoma: III. Clinical correlations with carcinoembryonic antigen

Plasma CEA levels were evaluated by radioimmunoassay in patients with breast carcinoma in relation to clinical‐pathologic staging, clinical tumor burden, prognosis and organ sites of involvement. Elevated levels were observed in 83/117 (70.9%) patients with metastatic disease, 2/14 preoperative patients and in 3/39 one‐six month postoperative patients. Preoperative levels were elevated in two patients; the levels fell to normal after operation. Changes of elevated CEA levels followed the clinical response to therapy in 22/22 metastatic disease patient‐trials. The levels decreased with a response in 15 trials and rose with progressive disease or relapse in seven trials. The incidence of CEA elevations and quantitative CEA levels both rose with increasing clinical tumor burden from the postoperative state through the preoperative state to two or more organ sites of metastatic involvement. No relationship was demonstrable among limited samples between preoperative or postoperative CEA levels and prognosis; however, in metastatic disease, pretherapy CEA levels >5 ng/ml were associated with low response rates and early therapeutic failure to chemotherapy. The highest frequency of elevated CEA levels was observed in patients with osseous involvement (79%) and the lowest frequency with skin (52%) and breast (50%) metastases. Liver and osseous disease were also associated with higher mean CEA levels than were other sites of metastatic involvement. CEA levels appear to be elevated in the majority of patients with metastatic disease and be of prognostic importance in metastatic disease. The level in patients with metastatic disease appears to reflect the therapy‐associated tumor burden of the host, especially in patients with elevated levels.

Pentamidine: Clinical pharmacologic correlations in man and mice

Patients with malignant disease complicated by diffuse interstitial pneumonia due to proved or suspected Pneumocystis carinii were given pentamidine in the dosage schedule recommended for this infection. By means of a sensitive method of assay, the plasma levels and urinary excretion of pentamidine during therapy were studied in these patients. Following the intramuscular administration of pentamidine, plasma levels were low and urinary excretion prolonged. After a single intraperitoneal injection in mice, the tissue distribution levels and excretion pattern for pentamidine were determined at various time intervals. There was storage of the drug in tissues and excretion was delayed. The highest concentration of pentamidine was found in the kidney. In mice pentamidine is eliminated primarily intact with little, if any, altered. The available data in man also suggested that pentamidine is retained, bound to tissues, and excreted over an extended period. Although renal abnormalities followed pentamidine, it was not possible to implicate the drug in all cases because of the seriousness of the illness and the concomitant use of other drugs. Pentamidine is useful in preventing disease due to Trypanosoma gambiense as well as effective in the treatment of diffuse interstitial pneumonia due to Pneumocystis carinii. The frequency of this type of pneumonia in cancer patients and in patients undergoing organ transplantation suggests the need for studies in animals and man.

Biological markers in breast carcinoma: II. Clinical correlations with human chorionic gonadotrophin

Serum hCG levels were measured in female patients with breast carcinoma and examined with respect to the clinical stage of disease, the clinical tumor burden, prognosis, and the organ sites of involvement. Elevated levels were observed in 65/134 (48.5%) patients with metastatic disease, 5/14 (35.7%) patients pre‐operatively, and in 9/33 (27.2%) N+ patients from one‐six months post‐operatively. The greatest proportion of elevated values (60.5%) was in patients with one metastatic site of involvement. Although no correlations were demonstrated between the preoperative or postoperative samples and subsequent disease recurrence, it was observed that 4/10 patients who did have a recurrence had preceding hCG elevations. In metastatic disease the level in 13 patients starting with values > 5.8 mIU/ml fell with the attainment of a response or rose with therapeutic failure. The hCG level rose from normal to >6.1 mIU/ml in six additional patients that developed progressive disease. A normal hCG level was associated with a 94.5% response rate to combination chemotherapy whereas the response rate with levels >5 mIU/ml was 71.4%. Only hepatic involvement was associated with a disproportionate incidence of elevations, being 63% compared to 42–47% for other sites. Monitoring hCG levels may be of prognostic use in patients being treated with selected chemotherapy programs for metastatic disease. It appears that further studies are warranted to ascertain if these results will extend to additional treatment approaches.

The role of platelets and the release of serotonin and histamine during anaphylaxis in the rabbit

Abstract During anaphylaxis in the rabbit, whole blood serotonin and histamine decrease, plasma serotonin and histamine increase, and the lung content for these amines is transiently elevated. The drop in whole blood serotonin and histamine is due to the disappearance of the platelets which are caught in the lung. Injection of the antigen into the systemic circulation produced the same results, indicating the phenomenon to be specific mainly for the lung. The in vitro results with normal blood and the in vivo effects in normal rabbits caused by the antigen-antibody complex were the same as those seen when a sensitized rabbit and the specific antigen were used. Speculation as to the role of platelet serotonin in human hypersensitivity reaction is made. The presence of histamine and the lack of serotonin in human lung as well as the relationship to human allergic pulmonary manifestations, are discussed. The pulmonary aspects of platelet thrombi in fatal anaphylaxis in rabbits are considered.

Determination of polyamines in human urine by an automated ion-exchange method

Abstract A sensitive and reliable automated cation-exchange method for the determination of polyamines in human urine has been developed and applied to samples from both normal subjects and patients bearing various types of cancer. A relatively large number of cancer patients urine samples are currently being analyzed, and these data will be the subject of a later paper.

Further Studies on Release of Serotonin and Histamine During Anaphylaxis in the Rabbit

Summary 1. Reserpine injected intravenously into rabbits in the amount of 0.1 mg/kg causes a marked lowering of platelet serotonin and histamine without reducing serotonin or histamine in the intestinal tract below the normal range. 2. Sensitized rabbits, pretreated with 0.1 mg/kg of reserpine, had an elevated plasma level of histamine but not of serotonin during anaphylaxis. These findings suggest that the major portion of the rise in plasma serotonin during anaphylaxis is secondary to a release from platelets, whereas the histamine found in the plasma is probably released both from platelets and tissues. In rabbits that had been pretreated with 5 mg/kg of reserpine, histamine levels in the plasma during anaphylaxis were still elevated. 3. The significance of levels attained in the plasma as an index of release from tissues during anaphylaxis is discussed.

High-resolution liquid chromatographic analysis of methylated purine and pyrimidine bases in transfer RNA

Methylated and major purine and pyrimidine bases were separated and quantified by high-resolution liquid chromatography after hydrolyzing transfer ribonucleic acids (tRNAs). Separation was accomplished by eluting the hydrolyzed samples from an anion-exchange column with a concentration gradient of ammonium acetate at pH 9.2. Isolated sample of tRNA were hydrolyzed to the free bases with a trifluoroacetic acid-formic acid mixture of 200 degrees. Detection limits of 100-200 ng/ml were measured for the methylated bases; analytical data are reported for ten methylated bases plus the four major bases of calf liver and rat liver tRNA.

The role of histamine and serotonin during anaphylaxis in the mouse

Abstract Anaphylaxis was produced in female white mice and was associated with a high mortality. Death appeared to be due to respiratory failure. Histamine and serotonin analyses were done on tissues and blood after anaphylactic shock. No significant changes in serotonin content were found in in vitro or in vivo studies. Histamine, on the other hand, was found to rise in the lung of the sensitized animals during anaphylaxis. This finding suggests that histamine is released from some other site in the body and bound in the lung following antigen-antibody reaction. Thus, histamine appears to be of distinct importance in mouse anaphylaxis, while the role of serotonin is questionable. However, the entire phenomenon of anaphylaxis in the mouse is undoubtedly a very complex process, with many details still obscure. Changes in tissue histamine and serotonin were also studied after injection of these amines into mice which had received pertussis vaccine. The possible mechanism by which pertussis vaccine alters the response to histamine and serotonin was discussed.

In vivo Release of Histamine from Rabbit Blood by Reserpine

Summary Intravenous reserpine in rabbits has been demonstrated by chemical means to release histamine from whole blood. 1. The minimal histamine levels were reached in one to 2 days with complete recovery to control values in 5 to 7 days. 2. Simultaneous serotonin determinations, revealed that the rate and degree of liberation, and the recovery of both histamine and serotonin were very similar. 3. Platelets, isolated 24 hours after reserpine, showed a marked reduction in both histamine and serotonin compared to control platelets.