The control of iron absorption by the gastrointestinal mucosal cell.

Gastrointestinal mucosal factors controlling rates of iron absorption were studied utilizing an in vivo closed duodenal loop technique. Cellular distribution of newly absorbed radioiron was identified by molecular sieve and iron-exchange chromatography of the mucosal cell supernate. In the normal animal, iron rapidly appeared in ferritin, and this fraction accounted for greater than 90% of mucosal supernatant radioactivity after 60 min absorption time. The nonferritin radioiron appeared to be unbound iron salts. In the presence of increased iron absorption induced by iron depletion or hemolysis, the major difference from the normal distribution pattern was an increase in the proportion and quantity of the free iron salts. Incorporation of newly absorbed iron into ferritin did not correlate with the rate of iron absorption. No evidence was found for a specific soluble iron-chelating molecule within the mucosal cell. The nonheme iron content of the mucosal supernates from iron-deficient and hemolyzing animals were significantly lower than in the normal animal.The data are consistent with hypotheses which suggest that iron absorption rates may be controlled in part by the rate of initial iron uptake by the mucosal cell and that a membrane transport mechanism exists which is modulated by the nonheme iron content of the mucosal cell or some portion thereof.

Large cell lymphomas of the stomach: improved prognosis with complete resection of all intrinsic gastrointestinal disease.

Thirty-seven consecutive patients with large cell lymphoma involving the stomach were evaluated between 1974 and 1980. All seven stage IE patients underwent complete resection of the stomach and all patients are alive 21-41 mo after resection. Of 18 stage IIE, 11 underwent complete resection. Two resected patients without postoperative therapy died of their disease. Six patients treated with chemotherapy are alive and well, and two of three patients treated with radiotherapy remain alive without disease. Seven patients had incomplete resection or biopsy, and only one remains alive at 34 mo. Of eight stage IV patients, four had complete resection and chemotherapy without recurrence of their disease. All four patients who were not resected have died of their disease. This study strongly supports the role of early surgery in the management of gastric large cell lymphomas.

The relative value of conventional staging procedures for developing prognostic models in extensive-stage small-cell lung cancer.

Published prognostic models for small-cell lung cancer (SCLC) have either combined limited- and extensive-stage patients or have not included standard anatomic staging information to assess the relative value of the knowledge of specific sites and number of sites of metastases in predicting survival in extensive-stage disease. We studied 136 extensive-stage patients in whom traditional staging procedures were performed and in whom other previously demonstrated significant pretreatment variables were determined. Using the Cox proportional hazards model, when all data were included, three variables were significant: performance status (PS) (P = .0001), number of sites of metastases (P = .0010), and age (P = .0029). A prognostic algorithm was developed using these variables, which divided the patients into three distinct groups. When the anatomic staging data were omitted, the serum albumin (P = .0313) was the only variable in addition to PS (P = .0001) and age (P = .0064) that was significant. An alternative algorithm using these three variables was nearly as predictive as the original. Therefore, in extensive-stage patients, reasonable pretreatment prognostic information can be obtained without using the number or specific sites of metastases as variables once the presence of distant metastases has been demonstrated.

Evaluation of a packaged kit assay of serum ferritin and application to clinical diagnosis of selected anemias.

The reliability of a radioimmunometric assay of serum ferritin concentration by a packaged kit was evaluated. In addition, application of the serum ferritin assay to the clinical evaluation of selected anemias was assessed. When appropriate serum dilutions were utilized, this method was sufficiently reproducible and reliable for application to the clinical laboratory. Serum ferritin was found to be a valuable tool in the differential diagnosis of anemia accompanied by hypoferremia, although iron depletion coexisting with either the anemia of chronic disease or active hepatocellular disease may not be clearly appreciated. The primary advantage of the determination was to help characterize the iron status of the patient with a hypochromic microcytic anemia or hypoferremia who would ordinarly require a bone-marrow examination for iron stores.

The impact of dose intensity of standard chemotherapy regimens in extensive stage small cell lung cancer.

Oncologists often attenuate the doses of chemotherapy drugs in published standard regimens to avoid toxicity. The impact on survival of this practice in patients with extensive stage small cell lung cancer (SCLC) is uncertain. We have compared the outcome of 85 patients treated with a program of cyclophosphamide, doxorubicin, and vincristine to a group of 37 patients treated with conventional regimens of higher dose intensity. The two groups of patients were shown to be equivalent in terms of staging evaluation, response and survival criteria, and pretreatment prognostic factors. The latter was confirmed by applying a published prognostic algorithm. Complete response rates (38% vs 14%) were significantly better with the higher intensity regimens (p = .003). The median survival (39 vs 26 weeks), 1 year survival (32% vs 12%), and overall survival (p = .002) were superior with the full-dose intensity protocols. Myelotoxicity was also greater with the contemporary treatments. Cox proportional hazards analysis, correcting for pretreatment prognostic variables, confirmed the improved survival with conventional doses of therapy (p = .0055). These results support the concept that full-dose intensity chemotherapy provides survival benefit in patients with extensive stage SCLC.

Thrombopoiesis and thrombokinetics--an approach to the evaluation of thrombocytopenia.

Thrombocytopenia is a common clinical disorder with a diverse group of etiologies. Traditionally, the approach to identifying the mechanism of thrombocytopenia has been empirical, primarily due to a lack of clear understanding of normal thrombopoiesis and its control. Additionally, readily available clinical measurements that reflect patterns of altered thrombopoiesis are unavailable. Recent experimental and clinical observations permit us to approach this disorder from a kinetic point of view to classify thrombocytopenia by four mechanistic categories: peripheral destruction and consumption, hypoproliferative thrombocytopenia, ineffective thrombopoiesis, and distributional causes. The application of the measurement of mean platelet size, in conjunction with a bone marrow examination, allows the clinician to more readily identify the cause of a low platelet count in a less empirical manner.

Small cell lung cancer: a problem of tumor heterogeneity.

Small cell undifferentiated carcinoma represents a subtype of lung cancer that possesses biologic and clinical characteristics that make it significantly distinct from other forms. A major impact on the natural history of this disease has been accomplished during the past 15 years, including the potential for cure by non-surgical treatment modalities. Further progress in the management of this disorder has been impaired by a number of factors that appear to be inherent to the biology of the tumor and its clinical features. Analysis of initial clinical trials and more detailed examination of this tumor in vitro have permitted the elucidation of many barriers to curative outcome presently being evaluated at the laboratory and clinical levels. These include clear biologic and morphologic heterogeneity; problems with chemotherapy responsiveness including drug resistance; the potential for combining chemotherapy and radiation modalities; the re-examination of the role of surgical intervention in selected patients; and the need to deal with central nervous system dissemination of tumor cells. Further advances in this disease will be dependent on the successful integration of laboratory and clinical disciplines.

Detection and staging of small cell lung carcinoma with a technetium-labeled monoclonal antibody. A comparison with standard staging methods.

Tumor-associated radiolabeled monoclonal antibodies (MoAb) can detect neoplasms in a variety of settings. The authors conducted a study comparing the ability to detect and stage small cell lung carcinoma by using a Tc-99m labeled monoclonal antibody (NR-LU-10 Fab) (NeoRx Corp, Seattle, WA) with standard staging methods. Standard staging included a physical examination, chest x-ray, a battery of radionuclide scans and/or computerized tomographic studies (head, abdomen, and bone), and bone marrow examination. A total of 22 comparisons were performed in 17 patients (five patients had reevaluations after therapy). Fifty-four (74%) of the 73 lesions defined by standard staging were detected by the radiolabeled MoAb. Seven of eight patients (88%) classified by standard staging as having "limited stage" disease on presentation were concordantly "limited stage" by radioimmunoimaging. One patient deemed "limited stage" by standard staging was correctly upstaged (bone marrow involvement) as a result of the radiolabeled MoAb. Two patients found to have extensive disease at diagnosis were characterized as "limited stage" by the MoAb, for an overall staging accuracy of 0.88. Thirteen of 19 missed lesions were smaller than 2 cm (10 were smaller than 1 cm; 3 measured 1 to 2 cm). This comparative study shows that radioimmunoimaging by Tc-99m labeled NR-LU-10 Fab antibody is capable of complementing standard staging methods used in the evaluation of small cell lung carcinoma.

Radionuclide imaging of bone marrow metastases with a Tc-99m labeled monoclonal antibody to small cell lung carcinoma.

The detection of metastatic disease confined to the bone marrow compartment has in the past been technically limited. We have identified excellent imaging of bone marrow metastases during the evaluation of a Tc-99m labeled monoclonal antibody (NR-LU-10 Fab) (NeoRx Corp., Seattle, WA). This occurred during a study to assess the monoclonal antibody's ability to detect sites of small cell cancer (primary and metastatic). The study by design compares areas seen by the monoclonal antibody scan with those found by standard staging methods in patients with small cell lung cancer. Standard staging included chest x-rays, bone scans, CT studies of the abdomen, and histologic examination of the bone marrow. Fifteen patients have been evaluated, four on two occasions, for a total of 19 monoclonal imaging studies. Metastasis to the marrow compartment was identified by the monoclonal imaging in all patients whose bone marrow biopsies were positive for small cell carcinoma, and it was primarily responsible for the eventual detection of extensive disease (marrow involvement) in one patient. Thus it appears that compartmental bone marrow imaging for metastatic disease is possible with immunoscintigraphy.

Unidirectional uptake of iron across intestinal brush border.

To define the significance of the uptake step by unidirectional uptake of iron was measured on proximal small intestintestinal segments from Nembutal-anesthetized rats. The method employed a nonabsorbable marker of adherent incubating medium, and the studies were performed during the linear time period of instantaneous uptake. Uptake was linear over the concentration range 0.1-10 mM, from three iron complexes. The rate varied with the bioavailability of the iron in each complex. The Q10 was 1.0-1.3. Uptake rates were similar in all segments of small intestine. Uptake was not increased in segments from iron-deficient animals or rats with hemolytic anemia. Cobalt did not inhibit the uptake rate. These studies demonstrate that the uptake of nonheme iron by the small intestinal mucosal cell is by passive diffusion and further indicate that the uptake step does not contribute significantly to the mucosal control of iron absorption.

Influence of hemoglobin phenotype on the mean erythrocyte volume.

The influence of the hemoglobin (Hgb) phenotype on mean erythrocyte volume was re-examined in the light of recent evidence indicating a poor correlation between manual and more precise automated methods of measurement. The present studies identified a 17.6% frequency of microcytosis in a population of nonanemic Black males, a value higher than previously appreciated. In addition, it was shown that the frequency of microcytosis was also a function of the Hgb phenotype. Thus, 9.4% of Hgb AA, 18.6% of AS and 26.5% of AC subjects had microcytic erythrocytes. The data presented are consistent with the hypothesis that both the alpha-gene complement and the beta-chain phenotype contribute to the erythrocytic mean corpuscular volume and that the frequency of microcytosis in a patient population is a function of both of these variables.

Malabsorption and defective utilization of iron in three siblings.

Three siblings had iron deficiency anemia without evidence of reduced iron intake or gastrointestinal blood loss. They failed to respond to oral iron therapy, and malabsorption of oral medicinal iron was demonstrated in two of the children. All three had a partial but incomplete hematologic response to intramuscular iron dextran treatment. There was no evidence for other well-defined causes of hypochromic microcytic anemia or for a generalized disorder of intestinal absorption. These three patients appear to have a familial disorder characterized by impaired iron absorption and utilization, similar to that observed in the mk/mk mouse.

An eosinophilic fibrohistiocytic lesion of bone marrow in a patient with Hodgkin's disease. A potential for morphologic confusion.

The eosinophilic fibrohistiocytic lesion of bone marrow (EFLBM) is characterized by collections of elongated "fibrohistiocytic" cells in association with lymphocytes, eosinophils, and plasma cells. The fibrohistiocytic cells are mast cells, and many investigators include this lesion (EFLBM) as a localized form of mastocytosis. The etiology and clinical significance of these lesions remains unclear. The morphologic features of these lesions point to a wide differential diagnosis that includes Hodgkin's disease. Currently, however, there are no recorded cases of well-defined Hodgkin's disease with these lesions. A case of Hodgkin's disease in which such lesions complicated the interpretation of serial bone marrows is reported. This case illustrates how the presence of these lesions could potentially influence therapeutic intervention.

Effect of the radiolabel mediator tropolone on lymphocyte structure and function.

The in vitro use of the radioisotope indium 111 (111In) was examined as a radiolabel for lymphocytes obtained from both normal individuals and patients with a variety of lymphoid malignancies. Successful cell labeling requires a chelator. The traditional agent oxine, has proved to be toxic to the lymphoid lineage. Cellular uptake of 111In mediated by the chelator oxine was compared with that of a new chelator, tropolone. Oxine provided better labeling efficiency (48%) than tropolone (35%) for the labeling of normal lymphocytes. By contrast, lymphocytes from patients with chronic lymphocytic leukemia had a nearly twofold greater labeling efficiency when tropolone was substituted for oxine. Further studies demonstrated that tropolone induced functional injury to lymphocytes when mitogenic response to concanavalin A, pokeweed mitogen, and phytohemagglutinin was assessed. Similar toxicity was found when tropolone was compared with oxine. In addition, tropolone produced damaging structural changes seen by both scanning and transmission electron microscopic examination. These changes were both variable and not predictable. Shortening of the incubation time of the chelator with the cell provided the least amount of cellular injury. These findings suggest that tropolone be used as an alternative mediator of lymphocyte labeling with 111In only under critically defined conditions.

Treatment of cutaneous sclerosis and aplastic anemia with antithymocyte globulin.

We administered antithymocyte globulin to a 52-year-old man with cutaneous sclerosis (scleroderma) and severe aplastic anemia for treatment of the aplastic lesion. The use of this therapy resulted not only in marrow recovery but also in resolution of the sclerosis. This observation indicates that T lymphocytes, their products, or both, are important factors in the pathogenesis of cutaneous sclerosis. Furthermore, the success of this treatment could play a role in future investigations involving the treatment of scleroderma and scleroderma-like conditions.

Therapeutic plasma exchange in the immune hemolytic anemias and immunologic thrombocytopenic purpura.

Thus, plasma exchange appears to have a potential but limited role in the care of antibody mediated injury of red cells or platelets. Its clearest indication appears to be in those uncommon instances of warm antibody mediated hemolysis with a highly fulminant course where the classical therapeutic measures do not have adequate time for effect. Similarly, such therapy appears to have significant potential in cases of acute immunologic thrombocytopenic purpura where some clinical contraindication to steroids, immunosuppressive agents or splenectomy exists. Acute ITP of pregnancy may provide another important setting for such a therapeutic approach. Finally, plasma exchange has been shown to provide temporary clinical stability in cases of chronic cold agglutinin disease.

Effects of cancer chemotherapy on the human aerobic oropharyngeal flora.

Since various agents used in cancer chemotherapy exhibit antimicrobial activity in vitro, we performed sequential quantitative cultures of saline gargles obtained from patients receiving cancer chemotherapy to determine if such chemotherapy alters the composition of the aerobic oropharyngeal flora. When we compared results of cultures obtained from 12 patients just before and at various times after receiving courses of cancer chemotherapy, we observed small, though significant reductions in the numbers of total bacteria, alpha-hemolytic streptococci and inhibitory streptococci two to seven days after courses of chemotherapy. A concomitant increase in the percentage of patients colonized by gram-negative bacilli occurred. Of the chemotherapeutic agents used to treat our subjects, only doxorubicin exhibited antimicrobial activity in vitro. All four alpha-hemolytic streptococci, but none of the seven strains of gram-negative bacilli examined, were inhibited by doxorubicin at concentrations of less than or equal to 12.5 mg/l. Doxorubicin had a modest enhancing effect on in vitro adherence of gram-negative bacilli to human embryonic lung cells. These data suggest that cancer chemotherapy might play a role in colonization of cancer patients by gram-negative bacilli by creating a microbiologic vacuum conducive to such colonization. In this way, cancer chemotherapy might contribute to the high incidence of gram-negative bacillary pneumonia among patients with malignant neoplasms.