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Understanding of the granulopoietic system in both normal and diseased states might be assisted by the use of a quantitative modeling procedure that relates the underlying cellular events of granulopoiesis studied in the laboratory to the marrow and peripheral blood picture as it might be seen in the clinic. In this way, the modeling procedure could become both an adjunct to ongoing laboratory research, as well as a means for rationally deciding on modes of treatment for pathologic conditions. The depth and rapid pace of modern granulopoietic research require that the modeling procedure be, on the one hand, detailed enough to permit the inclusion of the pertinent events at the cellular level as they are known today, while on the other hand, remain flexible enough to permit both the modification of any part and the possibility of seeing the predicted consequences of this modification for both the normal and diseased states. A detailed procedure was developed for an hour-by-hour description of the interrelationship of the kinetics of the various marrow cell types with the events in the peripheral blood and tissue spaces. The model was extended to include the toxic effects of a drug (5-fluorouracil) administered according to the protocol of an actual trial with cancer patients, and the temporal pattern of the predicted effects of the drug on the peripheral blood count was compared with that found in the clinic.

Experiments made on the passage of cells through untreated and siliconized glass beads, and on the adhesion and spread of cultured cells on glass and Teflon surfaces show that, in the absence of serum and in its presence in low concentrations, cell adhesion and spread is sensitive to substratum wettability. On the other hand, in the presence of 100% serum, no differences in adhesive parameters are detectable. It is concluded that arguments correlating cell adhesion to surface wettability, and, by inference, surface free energy, are unsubstantiated in 100% serum, which may well approximate to the in vivo situation. The results also show no correlation between parameters of cell adhesion and cell separation, and thereby support the hypothesis that these are different processes.

Two-thousand, five-hundred and twenty-four bacterial isolates were tested against 11 new beta-lactam antibiotics in a prospective study conducted in a cancer center. E. coli, P. aeruginosa, and K. pneumoniae were the most common gram-negative organisms isolated, while S. aureus and Enterococcus were the most common organisms among the gram-positive. The new cephalosporins were more active than the semisynthetic penicillins against E. coli, P. aeruginosa, and K. pneumoniae (p less than 0.001). Mezlocillin had better activity than the other semisynthetic penicillins against most of the gram-negative organisms as well as the enterococci. As a result, mezlocillin was preferred as a beta-lactam agent to be employed with an aminoglycoside as empiric antibiotics for febrile patients with neoplasia.

Sera from a group of patients with ovarian cancer had a statistically significant deficiency of alpha-L-fucosidase activity compared with sera from healthy females or female patients with cervical or breast cancer. Mixing experiments did not identify an inhibitor of alpha-L-fucosidase activity in the sera of ovarian cancer patients. Decreased activity of alpha-L-fucosidases was not associated with stage of disease, tumor burden, histologic type, or grade of differentiation. Unlike alpha-L-fucosidase, beta-man-nosidase and beta-N-acetylglucosamindase in sera of ovarian cancer patients were not deficient in activity. Examination of population data of healthy females and of pedigrees of ovarian cancer patients suggested that the quantitative activity alpha-L-fucosidase in serum was genetically determined. Of 60 healthy females, 4 had low enzyme activity (less than 100 U alpha-L-fucosidase/ml serum), 26 had intermediate activity (100-274 U alpha-L-fucosidase/ml), and 30 had high activity (275 U/ml), whereas of 44 ovarian cancer patients, 11 had low, 29 had intermediate, and 4 had high activity. Application of the Hardy-Weinberg law to these data revealed that low enzyme activity in sera was three times more prevalent in the ovarian cancer group, the allele for this low enzyme activity being two times more common. These observations suggested that deficiency of alpha-L-fucosidase activity in sera of females may be a hereditary condition associated with increased risk for development of ovarian cancer.

We have observed that the ammonia levels in mammalian cell culture media are 10 to 100 times the mean level found in the blood of normal humans. At the moment of formulation of culture medium, the major source of ammonia is the serum component. Ammonia levels exceeding 5,000 μg/dl of NH 3 -N have been detected in stored serum samples. Upon storage, of complete culture media, significant quantities of ammonia were generated by the decomposition of glutamine and serum. The rates of generation of ammonia, in stored culture media, ranged from 0 to 89 μg/dl/day of NH 3 N depending on the temperature of storage (−80 °C to 37 °C).

Hydroxyurea was evaluated as a possible radiation sensitizer in 130 evaluable women with Stages IIB and IIIB (International Federation of Gynecology and Obstetrics) carcinoma of the uterine cervix. This was a prospective double-blind randomized study in which hydroxyurea or placebo was compared in conjunction with continuous or split-course radiation therapy. Of all patients with Stage IIB cancer without biopsy proof of aortic node metastasis, a significant improvement in survival (P less than 0.01) was achieved in the hydroxyura group (74.0%) as compared to the patients receiving placebo (43.5%). In women with Stage IIIB cervical cancer there was a trend toward longer survival in those receiving hydroxyurea (52.1%) as compared to those receiving placebo (33.3%). However, there was a statistically significant improvement in survival in those women with Stage IIIB cervical cancer who had staging done at operation, were found to have negative para-aortic nodes, and subsequently received continuous radiation therapy (90.9%) as compared to those receiving split-course therapy (29.4%) (P = 0.005).

Thyroid function was evaluated in a consecutively treated group of children and adolescents with Hodgkin disease who received incidental radiation to the thyroid gland. Ten of 27 (36.7%) were found to have elevated concentrations of thyroid-stimulating hormone (TSH). Two groups of patients had an increased incidence of thyroid dysfunction - those who had not had a pretreatment lymphangiogram and those who were less than 13 years of age at the time of neck irradiation. The estimated percentage of patients who did not have a pretreatment lymphangiogram who will develop TSH elevation was 67.7% and of patients who were 13 years of age or less when irradiated, 64.8%. Thyroid dysfunction developed in 6/7 patients who had both of these risk factors present.

A new simplified system for updating a cancer registry has been developed in the Biostatistics Department of Roswell Park Memorial Institute. It was designed to serve the needs of maintaining a registry for a cooperative cancer research group. The Data-Update Procedure at a Remote Terminal (DUPART) system has general value for registry applications.

Data from isotopic uptake experiments were used to measure calcium fluxes and compartment sizes in ascites tumor cells. The data were analyzed with two kinetic models, A and B. In 80% of the experiments model A, which is based on one exchangeable calcium compartment, was rejected in favor of Model B, which predicts two exchangeable compartments. A statistical evaluation of the model's performance, when fit to the experimental data was used to select between the two models. The results show that calcium was distributed between three cellular compartments in the ratio, non-exchangeable (88%): rapidly exchanging (7%): slowly exchanging (5%). The undirectional fluxes suggested that calcium transport could be described as a series system with the temporal sequence: environment ⇄ rapidly exchanging ⇄ slowly exchanging.

A mathematical model is developed in order to examine the relationship between the spread of cancer and the movements of the constituent cells of the tumor. A distinction is made between the “visible” and the “invisible” spread of cancer in an area of tissue in terms of the number of tumor cells located in this area. The relevance of this distinction for the cure of cancer by surgical excision of the visible tumor is examined in some detail for the geometry of uterine cancer. The movements of the tumor cells are classified into (a) those which occur in the intercellular spaces (from ameboid movements, tumor pressure, etc.) and (b) those which are due to convection in the small vessels of the vascular system. The effect of these two types of movement on the spread of the cancer is examined by means of computer pictures generated from the mathematical model.

Biologists, in the laboratory, see cancer cells as individual entities while physicians, in the clinic, see them as tumor masses. A mathematical model is described which bridges the relationship between the observations in the clinic and the underlying movements of the individual tumor cells. For this purpose the model is developed according to the protocol of an actual study of patients with cancer of the endometrium and includes the effect of preoperative radiation treatment in reducing the visible size of the tumor. In this way it is possible to obtain a quantitative estimate of the radiation effect. The model is also used to estimate the motility of tumor cells in vivo and this is compared with measurements obtained in the laboratory. A short discussion is presented of how mathematical models could become useful tools for bridging the gap between discovery in the laboratory and application in the clinic.

The contact interaction between cells and thewalls of microchambers through which the cells are passing are quantitated in terms of parameters which are estimated from macroscopic experimental data. For this purpose, an analysis is made of the internal geometry of glass bead-columns. A mathematical model is presented which describes the passage of cells down the column. This model relates the temporal pattern of the number of cells entering and leaving the bead-column to the “dynamic adhesive” properties of a cell as it passes through a microscopic section of the bead-column.

A prospective trial was initiated in 1972 utilizing Depo-Provera in women with metastatic or recurrent endometrial adenocarcinoma to evaluate if the objective response and survival would be significantly improved in comparison to patients previously treated with Delalutin at a similar dose. One hundred fourteen patients were included in the study: 70 received Delalutin and 44 Depo-Provera. There was no significant increase in the objective response or survival between the Delalutin or Depo-Provera patients. Of the 114 patients, 15.8% achieved an objective response, with 7.0% being complete responders. There was no significant increase in objective response to Delalutin or Depo-Provera in relationship to the size of the tumor masses, the number of metastases, site of metastases, histologic grade of the primary, histologic grade of recurrence or metastases, or prior radiation therapy. The only significant correlate was that patients whose disease recurred 3 or more years after the initial therapy had a significant (P = 0.01) increase in response (33.3%) compared to those with recurrence less than 3 years after their original treatment (8.3%).

A possible genetic link has been suggested in several dermatologic diseases. An increased incidence of HLA-A10 and HLA-B13 has been reported in pemphigus vulgaris, HLA-B17 and HLA-B13 in psoriasis, and HLA-B5 in Behcet syndrome. 1 HLA-B8 has been reported in 70% to 88% of dermatitis herpetiformis cases and in 90% of adult celiac disease cases, 2 which is suggestive of a close association between these two diseases. The purpose of this study was to determine the HLA phenotype frequencies in a group of white patients with bullous pemphigoid (BP). Subjects and Methods Nineteen white patients with BP were studied. All had typical clinical disease and subepidermal bullae and all demonstrated the presence of immunoglobulins and/or C3 along the basement membrane zone (BMZ) of peribullous skin, as previously described. 3 HLA typing was performed by Amos microcytotoxicity tests 4 with the use of 70 anti-HLA antisera. Similar tests were performed on

To the Editor.— The reported discovery rates of breast cancer among asymptomatic women between 35 and 75 years of age screened for the first time by mammography range from three to eight times the annual incidence of the disease in the US female population in this age category. It remains to be clarified whether all these cases reported by the 27 national breast cancer detection centers sponsored by the National Cancer Institute would, if they remained undetected, have gone on to become lifethreatening cases of clinical breast cancer. However, the fact remains that these cases are reported to the public health authorities and are incorporated in the local and national statistics for the incidence of breast cancer. These reported discovery rates imply that if, say in 1984, mammography is used to screen 25% of the female population at risk (almost 80% of the female population aged 35 to 64 years

The physician sees the breast cancer patient only after her disease has had a complex history of growth and possible spread. The development of the disease can be characterized by the tumor doubling time, the risks of local and distant spread, and the patient's delay in seeking medical assistance. These parameters can be estimated from the physician's observations of the size of the tumor in the breast and the degree of local and distant spread. For this purpose a comprehensive mathematical model is developed which describes the development of the cancer from the appearance of the first cell to the possible occurrence of a distant metastasis. The model also accounts for the limitation on the minimum size of the tumor before it could be detected and for the effect of surgical intervention by the physician on the development of a recurrence of the disease. A simple extension of the model permits a quantitative test of a two-disease hypothesis of breast cancer.