John A. Kellen

Carcinoembryonic antigen in breast cancer.

Carcinoembryonic antigen (CEA) levels were determined in 742 postoperative patients with breast cancer. Within this group the percentage of elevated (≥ 4.0 ng/ml) assays increased with UICC clinical stage and was 14.8% (12/81), 23.7% (27/114), 73.1% (190/260) and 20.0% (49/245) for stages I, 11, 111, IV and X (unstagable due to insufficient data) patients. We have now followed the above 482 stages I, II, III and X patients in whom CEA was performed ≤3 months after initial surgery at a time when there was no evidence of residual disease, for an average interval of 255 days from date of diagnosis. At present 16.2% (17/105) of patients with elevated CEA values compared to only 4.8% (18/377) of patients with normal values have developed recurrent disease (p < .0005). There is an association of elevation of CEA postoperatively with different clinical stages of breast cancer. Elevated CEA levels postoperatively are associated with an increased risk of development of recurrent disease in breast cancer patients.

Carcinoembryonic antigen (CEA) and other tumor markers in ovarian and cervical cancer.

Combinations of carcinoembryonic antigen (CEA), gamma glutamyl transpeptidase (GGT), pregnancy‐associated macroglobulin (PAM) and placenta‐like alkaline phosphatase (PLAP) were studied in groups of patients with ovarian and cervical cancer. In ovarian cancer, only CEA and PLAP levels appeared to reflect tumor burden and were complementary in detecting active disease. In cervical cancer, CEA and GGT reflected tumor burden, while PLAP showed just the reverse—the highest degree of positivity being present in minimal disease. PLAP positivity was even more pronounced in patients with cervical dysplasia and carcinoma in situ while CEA and GGT were negative. The data indicate that the use of marker combinations can improve our capacity to detect minimal disease and provide information regarding tumor biology that may not be available by studying individual markers or by other means. It remains to be determined whether the use of tumor markers can influence existing therapy sufficiently to alter the outcome in cancers which are notoriously difficult to treat.

Link between Carcinogenicity and Hepatic Metabolism of 7,12-Dimethylbenz(α)anthracene

Inhibition of hepatic drug metabolism in the Sprague-Dawley rat by coumarin pretreatment or pregnancy reduced significantly the incidence of mammary tumors induced by 7,12-dimethylbenz(α)anthracene (D

A proposal for a more uniform output in laboratory data

Abstract A simple mathematical conversion is proposed, which gives one single set of numbers for all laboratory tests with fixed values for upper and lower “normal limits”. This “clinical unit” system if adopted, would eliminate the multiple “normal values” between hospitals and laboratories, and might allow cliniciand to compare laboratory results more effectively.

Effects of antibodies to choriogonadotropin in malignant growth: I. Rat 3230 AC mammary adenocarcinoma

To determine whether the in vivo production of antibodies against choriogonadotropin (CG) could modify the relationship between host and malignant growth, the effects of preimmunization with a conjugate of the β‐subunit of CG and tetanus toxoid (CGβ‐tt) on the development and growth of lung metastasis following I.V. injection of R 3230 rat mammary adenocarcinoma cells into Fischer 344 female rats have been investigated. This neoplasm has been previously demonstrated to synthesize CG‐like material. A test group of 70 animals and two matched control groups of 15 animals each were used. One of the control groups was untreated and the other received tetanus toxoid only. All the control animals had multiple lung foci of neoplastic cells ten days after seeding, as has been previously observed, and CG antibodies were undetectable. In contrast, a significant titer of anti‐CG was found in all preimmunized animals. At the same time, the pretreated animals rarely had a few small neoplastic nodes in the entire lung sections at the standard 8–10 days post‐seeding. The protective effects of preimmunization with CGβ‐tt were further demonstrated by the animals living 20 days post‐seeding, the absence of lung pathology in the ones killed thereafter, and by six animals that were left alive and have not shown any deterioration for more than six months after the administration of the cell suspension.

Treatment recommendations for anaplastic oligodendrogliomas that are codeleted.

Abstract: Anaplastic oligodendroglioma (AO) is a rare malignant tumor occurring in adults. Despite early indications of chemosensitivity, no clinical trial had demonstrated a benefit of chemotherapy beyond that of radiotherapy alone. Now, however, the Radiation Therapy Oncology Group (RTOG) 9402 and the European Organisation for Research and Treatment of Cancer (EORTC) 26951 studies investigating PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine) and radiation therapy vs radiation alone both show improved outcomes in patients with the 1 p/19q codeletion who received PCV and radiation therapy. These differences were detected with additional follow-up after publication of the initial results in 2006, when no differences in survival were detected. The two studies have also validated the use of the 1p/19q codeletion as a predictive biomarker in AO. Many will debate the wisdom of adopting PCV therapy as standard of care because of the greater toxicity of PCV compared with temozolomide (Temodar). Nonetheless, although important questions still remain regarding chemotherapy choice, sequence, and dosing, the answers to which will require additional large phase III trials, radiotherapy alone is no longer appropriate therapy for 1p/19q codeleted AOs.

Effects of antibodies to choriogonadotropin in malignant growth

SummaryWe have studied the effects of preimmunization with a conjugate of the β-subunit of choriogonadotropin and tetanus toxoid (CGβ-tt) on the growth of the implanted R 3230 AC mammary adenocarcinoma (in Fischer 344 rats) and the implanted 5123 1-1 hepatoma (in Buffalo rats) after 20 days, in order to determine if the in vivo production of antibodies against CG could modify the relationship between host and malignant growth. The results obtained demonstrated that active immunization against CG retarded significantly (P<0.01) the growth of the two transplantable tumors. Anti-CG antibodies were also determined and constantly found in the sera of all the preimmunized rats of both strains while no antibodies to CG were found in the control animals.We have studied the effects of preimmunization with a conjugate of beta-subunit of choriogonadotropin and tetanus toxoid (CG beta-tt) on the growth of the implanted R 3230 AC mammary adenocarcinoma (in Fischer 344 rats) and the implanted 5123 1-1 hepatoma (in Buffalo rats) after 20 days, in order to determine if the in vivo production of antibodies against CG could modify the relationship between host and malignant growth. The results obtained demonstrated that active immunization against CG retarded significantly (P less than 0.01) the growth of the two transplantable tumors. Anti-CG antibodies were also determined and constantly found in the sera of all the preimmunized rats of both strains while no antibodies to CG were found in the control animals.

Expression of human choriogonadotropin-like material correlates with metastatic phenotype of R3230 AC rat adenocarcinoma.

Human choriogonadotropin (hCG)-like material has been found in variable amounts on the surface of cells of human and animal tumors. Intravenous injection of R3230 AC rat adenocarcinoma cells, one of the models investigated, results in multiple lung foci seeding. We analyzed the phenotypic diversity of this tumor by cloning and culturing two distinct cell subpopulations from a cell culture of this tumor, hereafter called OR or original cell culture. One was obtained after repeated exposure of the OR to increasing concentrations of concanavalin A and wheat germ agglutinin. A single clone was isolated and was named lectin-resistant (LR) cell line. The LR cells did not metastasize but maintained stable tumorigenicity and morphology over at least 10 passages. A second cell line was obtained by repeated passage and injection of cells from a single metastatic node. After repeating the process five times, a single clone of cells was selected from the final variant and was called lung metastatic (LM) cell line. The LM cultured cells maintained stable tumorigenicity, morphology, and metastatic properties for no more than 10 passages. OR, LR, and LM cells were assessed by their doubling time (DT), chromosome counts, and hCG immunocytochemistry. The results demonstrated that the LM cell line had a higher chromosome count than the LR and the OR cell lines, and its DT was the shortest. Immunocytochemistry of the transplanted OR neoplasm showed scattered expression of the hCG-like material. By the same techniques a complete lack of reactivity of the LR cells was found. However, almost all cells of the LM line were strongly positive for hCG-like material. After a few passages, the great majority of the LM cells also became unreactive. Our data demonstrate: (i) the existence of marked heterogeneity of the expression of hCG-like material in the primary tumor cell population; (ii) that the expression of hCG-like material correlates with the metastasizing capacity of the cells; and (iii) that there is a phenotypic instability for the expression of hCG-like material by tumor cells when maintained in vitro.

Aldolase isoenzyme patterns during human ontogeny and in lung, kidney and breast cancer.

Enzyme patterns characteristic of fetal tissue have been noted in some experimental tumor models, particularly in hepatomas. In this study we undertook to determine whether biochemical evidence of a similar reversion could be detected in tumors of other human organs. As marker, we chose to use the aldolase isoenzymes A, B and C, for which distinct adult and fetal tissue patterns have been described. Using monospecific antibodies, we determined the aldolase isoenzyme pattern in a variety of human organs ranging in age from 14 to 40 weeks of gestation, in the 2- to 3-month postnatal period and in adults. In addition, 19 breast cancers, 19 primary lung cancers and 8 kidney cancers were examined. Our studies on breast cancer revealed three apparently distinct groups -- one showing primarily the A isoenzyme type (6 cases), a second containing mainly A with considerable quantities of B and C isoenzymes (9 cases) and a third group (4 cases) which may contain a different isoenzyme altogether since the combined activity of the three known forms was less than 100% in each case. In lung cancer, fetal characteristics could be substantiated since in fetal and adult lung tissue, the isoenzyme pattern is almost identical; 3 out of 19 cases showed substantial quantities of the B isoenzyme. In kidney tumors, a reversion to the A form with an appreciable fraction of the C form was found, which is similar to the fetal pattern.

Patterns of Amino-acid Inhibition of Alkaline Phosphatases as an Aid in Cancer Diagnosis

(1) The amino acid inhibition of alkaline phosphatases is a concentration-dependent, reversible process. (2) Isoenzymes from different organs and tumours have definite and reproducible patterns of ami