Biomedical subjects

G Spitzer

Publications and source records attributed to G Spitzer.

At least 73 records · Page 4Linked to original sources

PubMed1989

A monoclonal antibody cocktail for detection of micrometastatic tumor cells in the bone marrow of breast cancer patients.

We investigated whether monoclonal antibodies (MoAbs) reactive against both acidic and basic cytokeratins alone were sufficient to detect minimal numbers of contaminating epithelial tumor cells in the bone marrow of breast cancer patients. Monoclonal anti-cytokeratin antibodies (AE1 and AE3) were used to stain 14 breast carcinomas by the avidin-biotin-peroxidase technique. Nine tumors (64.3%) showed high reactivity and five (35.7%) showed low or moderate reactivity. Nine MoAbs that proved to be unreactive to light density bone marrow cells by immunoalkaline phosphatase histochemistry were screened for reactivity to breast carcinomas having only low or moderate positivity to cytokeratin antibodies. Three of nine MoAbs showed high percentages of positivity and were selected to supplement the anti-cytokeratin antibodies for immunohistochemical detection of minimal marrow disease in breast cancer patients. A MoAb cocktail was prepared, further tested for reactivity to another five breast carcinomas, and compared with cytokeratin staining alone. The cocktail labeled 100% of carcinoma cells in all the examined specimens. To determine the sensitivity of this panel for detecting minimal numbers of contaminating tumor cells in bone marrow, in vitro mixing experiments were performed. T47D breast carcinoma cells were mixed with bone marrow mononuclear cells at ratios from one tumor cell per 10 bone marrow cells up to one tumor cell per 1 x 10(6) marrow cells, and cytospin preparations were subsequently stained with the MoAb cocktail by the immunoalkaline phosphatase method. Our approach could detect one tumor cell in 1 x 10(5) hematopoietic cells.

Antibodies, Monoclonal↗

PubMed1989

Myeloproliferative disorders: usefulness of X-linked probes in diagnosis.

Myeloproliferative disorders are neoplasms of the pluripotent hematopoietic stem cell. Accurate diagnosis and distinction from reactive processes can be difficult therein with cytogenetic analysis only being useful in a minority of patients. Use of X-linked restriction fragment length polymorphism and methylation analysis has enabled clonal analysis to be performed in up to 50% of females, significantly increasing the proportion of analyzable patients over methods dependent on glucose-6-phosphate dehydrogenase heterozygosity. Using hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase probes, we have demonstrated monoclonality of peripheral blood leukocytes in three females with myeloproliferative disorders who had uninformative chromosomal analysis. This technique greatly enhances the diagnosis of early myeloproliferative disorder.

Adult↗

PubMed1989

Piperazinedione plus total body irradiation: an alternative preparative regimen for allogeneic bone marrow transplantation in advanced phases of chronic myelogenous leukemia.

Twenty-one patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in advanced phases were treated with piperazinedione (PIP), total body irradiation (TBI) and allogeneic bone marrow transplantation. Eleven were in blastic transformation, five were in accelerated phase, and five were in second chronic phase. The median age was 29 years (range, 13-41 years); there were 14 males. All patients but one were rendered aplastic by this regimen. Of these, 17 had hematologic engraftment, recovering granulocytes to 1.0 x 10(9)/l in a median of 28 days (range, 11-52 days). Three patients failed to engraft. Of those who engrafted, five relapsed and died of disease, one relapsed and died of a polymicrobial wound infection, nine patients died of treatment-related complications, including graft-versus-host disease, interstitial pneumonitis and sepsis, and one patient developed large-cell lymphoma 27 months after transplant and died of this 18 months later. One patient relapsed after 31 months died of polymicrobial sepsis at 37 months, and one patient remains disease-free at 54+ months. The 3-year survival rate was 14%. Survival at 1 year was related to having a spleen that did not extend beyond 2 cm below the left costal margin at the time of transplantation, and those with a large spleen at initial presentation relapsed more often. PIP-TBI with allogeneic bone marrow transplantation can induce durable remissions in a small proportion of patients in advanced phases of CML, but it is not superior to cyclophosphamide-TBI in this patient group.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Stimulation of nonclonal hematopoiesis and suppression of the neoplastic clone after treatment with recombinant human granulocyte-macrophage colony-stimulating factor in a patient with therapy-related myelodysplastic syndrome.

A complete hematologic remission was achieved in a patient with therapy-related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism-methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

Adenocarcinoma↗

PubMed1988

Association of the Epstein-Barr virus with lymphoepithelioma of the thymus.

A 30-year-old woman with the histologic diagnosis of lymphoepithelioma of the thymus is reported on. Investigation of Epstein-Barr serology showed evidence of infection, and Southern blot analysis showed the presence of the viral genome in the tumor specimen. The patient achieved complete remission after treatment with combination chemotherapy, autologous bone marrow transplant, and radiotherapy. These findings suggest that lymphoepithelioma of the thymus may have a viral pathogenesis similar to that of nasopharyngeal carcinoma.

Adult↗

PubMed1988

Antitumor activity against human tumor samples of cis-diamminedichloroplatinum(II) and analogues at equivalent in vitro myelotoxic concentrations.

We compared the antitumor activity of cis-diamminedichloroplatinum(II) (cisplatin; CDDP) with three CDDP analogues: cis-diammine-1,1-cyclobutanedicarboxylateplatinum(II) (CBDCA), N-methyliminodiacetato-1,2-diamino(cyclohexane)platinum(II) (MIDP), and N-(2-hydroxyethyl)-iminodiacetato-1,2-diamino(cyclohexane)platinum (II) (HIDP). Fresh human tumor samples in the adhesive tumor culture system were utilized for this comparison. The equitoxic concentrations of all four drugs were derived based on their inhibitory activity against human bone marrow samples. For these normalized concentrations, CDDP proved to have a higher cytotoxic activity than its analogues. CBDCA's in vitro activity had a significant correlation with CDDP activity (r = 0.67) in vitro. However, the structurally similar substances MIDP and HIDP demonstrated a much greater degree of association (r = 0.90). Our data suggest that CBDCA, HIDP, and MIDP have overall less activity than CDDP when tested at equitoxic in vitro concentrations. Close association between CDDP and CBDCA also reflects known clinical experience with these two drugs, suggesting the method of comparison used here is probably appropriate. These conclusions, however, must be validated by clinical trials.

Bone Marrow↗

PubMed1988

High colony-forming efficiency of primary human tumor cells cultured in the adhesive-tumor-cell culture system: improvements with medium and serum alterations.

The colony-forming efficiency (CFE) of primary human tumor cells cultured in the adhesive-tumor-cell culture system (ATCCS) using Ham's F12 (F12) or Eagle's minimum essential medium, alpha modification (alphaMEM) and culture medium supplemented with either swine, equine or bovine sera were compared. AlphaMEM supplemented with equine serum provided the highest CFE of the combinations. The CFE increase due to the change from F12 to alphaMEM was approximately 5-fold, and the increase due to the change in serum from swine to equine was approximately 2-fold. Cytokeratin staining showed that this increase was not due to fibroblast growth. The high-average CFE with alphaMEM, approximately 3%, means that an inoculum of only 2 X 10(3) cells is needed to achieve formation of approximately 65 colonies in control cultures, thereby increasing the performance of this system when used in a chemosensitivity assay.

Cell Adhesion↗

PubMed1988

In vitro activity of amonafide against primary human tumors compared with the activity of standard agents.

Amonafide, one of a series of benz[de]-isoquinoline-1,3-dione compounds, is now entering phase II clinical trials in this country. We tested amonafide, exposed continuously for 5 days, at four different concentrations against 56 primary human tumors in vitro. The drug concentration range used was based on amonafide's inhibitory activity against human bone marrow cells. The antitumor activity of 5-fluorouracil, mitomycin C, cisplatin, and etoposide against tumors from this panel of 56 was compared with that of amonafide at in vitro concentrations equitoxic against human bone marrow cells. Amonafide was active against only 12% of tumors compared with standard agents, which were active against more than 40% of tumors in the human bone marrow inhibitory range. Our data suggested that amonafide is less likely to be clinically active against human solid tumors than the standard agents.

Adenine↗

PubMed1988

A comparison of marrow transplantation with chemotherapy for adults with acute leukemia of poor prognosis in first complete remission.

From July 1980 to November 1985, 109 patients with acute myelogenous and lymphoblastic leukemia who had reached a complete remission (CR) following induction treatment were assigned to a study comparing marrow transplantation with chemotherapy as a postremission treatment. Sixty-nine patients did not have a human leukocyte antigen (HLA)-identical donor, and therefore served as chemotherapy controls; 40 patients had HLA-identical donors, and therefore were assigned to the transplant arm. Of these, 23 were transplanted in first remission and 17 were not. Ten of these 17 were subsequently transplanted in relapse. Initially, only patients with poor prognosis determined by a predictive model were entered into the study. Subsequently, patients with moderately poor prognosis were admitted. Comparing the chemotherapy group with the patients transplanted in first CR, significant control of leukemia relapse in transplanted patients was seen in the subgroup with acute myelogenous leukemia (AML) (P less than .1), and acute lymphoblastic leukemia (ALL) (P less than .01), in the poor (P = .01) and intermediate subgroup (P = .01), and in the good-prognostic groups (P = .05). The survival was affected significantly in only the poor and intermediate subgroups. The use of predictive models might help to select patients for whom bone marrow transplantation is appropriate in first remission and those for whom bone marrow transplantation can be left as the initial treatment of relapse. Predictive models could further be helpful in comparing studies performed at different transplant centers.

Adolescent↗

PubMed1988

Enhancement of growth of primary metastatic fresh human tumors of the nervous system by epidermal growth factor in serum-free short term culture.

Using the adhesive tumor cell culture system, we studied the effect of epidermal growth factor (EGF) on 16 primary and 7 metastatic fresh human tumors of the nervous system cultured in serum-free and serum-supplemented media at low cell density. In serum-free conditions, EGF significantly enhanced the growth of glial tumor cells. This positive effect was less pronounced for metastases to the brain. No significant enhancement was observed for the other tumor types (primitive neuroectodermal tumors and various tumors of neuroepithelial/mesenchymal origin). The addition of serum obscured this effect of EGF, even at the lowest cell densities. In 7 tumors, the simultaneous addition of platelet-derived growth factor did not enhance the EGF response. Subtypes of brain tumors respond to EGF in vitro under serum-free conditions.

Brain Neoplasms↗

PubMed1988

Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia.

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4-hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.

Antineoplastic Agents↗

PubMed1988

myc and sis expression in acute myelogenous leukemia.

Several oncogenes have been reported to be expressed in normal and malignant hematopoietic cells. Since these studies have almost exclusively been done by Northern and dot blot hybridization techniques using mixed populations of cells, any conclusions concerning quantitative changes in gene expression are difficult to document. We have developed a rapid and sensitive RNA-in situ hybridization technique permitting detection of as few as five copies of mRNA per cell. Using this technique we have studied the expression of two genes, c-myc and c-sis, in acute leukemia patients as well as hematologically normal individuals. We have found that expression levels of myc and often sis are higher (greater than 5-fold) in hematopoietic cells obtained from leukemia patients than in normal hematopoietic cells. In regenerating marrow, there is a dramatic increase in the frequency of cells expressing myc at the level of five to 10 copies without the presence of any cells expressing myc at the high levels found in acute leukemia. This is completely different from leukemic remission marrow in which we find a subpopulation of cells which express myc at very high levels. At this time, the leukemic origin of this abnormal cell population is likely because of the close correlation we find between gene overexpression and leukemic phenotype as identified by double-labeling experiments. It appears that gene overexpression may be a more sensitive or an earlier marker for leukemic cells and that such an assay could be used in the detection of residual disease.

Bone Marrow↗

PubMed1988

Drug and radiation sensitivity testing of primary human tumor cells using the adhesive-tumor-cell culture system (ATCCS).

In summary, the ATCCS is an efficient culture system which grows clonogenic cells from greater than 80% of human cancers. The ATCCS supports the growth of malignant cells from human cancers. The ATCCS shows classical drug and radiation survival curves which routinely achieve over 1 log of kill. The ATCCS has high CFE and permits sensitivity testing from small samples. Clinical correlations for the chemosensitivity assay were satisfactory. Radiosensitivity in vitro correlates with tumor histology.

Cell Adhesion↗

PubMed1987

Involvement of chromosome 7 in primary lung tumor and nonmalignant normal lung tissue.

By using the newly developed adhesive tumor cell culture system, we analyzed the chromosomal constitutions of primary lung tumor and nonmalignant normal lung tissue from 10 previously untreated patients with non-small cell lung cancer. Chromosomal analyses were successfully carried out in banded chromosome preparations from 10 tumor and 8 normal lung tissue samples. All analyzed tumor and normal lung tissue samples had a predominantly normal diploid chromosome number. However, there was at least one structural or numerical alteration in every tumor and lung tissue sample analyzed. Chromosomes 1, 3, 4, 6, 7, 8, 9, 12, 15, and 20 were more often involved in rearrangement. The most consistent finding was trisomy 7; 4 patients had trisomy 7 in both tumor and normal lung tissue, and another 2 had this anomaly in tumor tissue only. Of the 4 patients without trisomy 7, 2 had a homogeneously staining region in the short arm of chromosome 7 in tumor tissue. Phytohemagglutinin-stimulated peripheral blood lymphocytes from 7 patients, including 5 patients with trisomy 7 in tumor tissue, did not show trisomy 7. These cytogenetic data suggest that chromosome 7 may be associated with lung cancer development and that trisomy 7 may be the hallmark of premalignant changes, at least in a subgroup of patients with non-small cell lung cancer.

Aged↗

PubMed1987

Use of carcinoembryonic antigen in small cell lung cancer. Prognostic value and relation to the clinical course 1.

Carcinoembryonic antigen (CEA) was measured in 147 patients at diagnosis of small cell lung cancer; 17% of patients with limited disease and 51% with extensive disease had an abnormal CEA level (greater than 10 ng/ml). The median level was higher in extensive than in limited disease (11 ng/ml and 5.8 ng/ml, respectively; P less than 0.001). Multivariate analysis showed CEA level greater than or equal to 50 ng/ml to be an adverse prognostic factor (P = 0.02); median survival at this level was shorter than at less than 50 ng/ml (7 and 46 weeks, respectively; P = 0.002). No consistent directional changes of follow-up CEA values were observed in patients with initially normal CEA levels, but normalization of levels occurred in complete responders. We recommend that CEA be measured in this disease at diagnosis as an additional prognostic factor and that patients with abnormal initial CEA levels have follow-up measurements to aid in evaluating response.

Carcinoembryonic Antigen↗

PubMed1987

High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma.

Adult patients with advanced non-Hodgkin's lymphoma in whom conventional chemotherapy has failed are seldom cured thereafter. We studied 100 such patients with intermediate-grade or high-grade non-Hodgkin's lymphoma who were subsequently treated with high-dose chemotherapy (61 patients) or high-dose chemotherapy plus total-body irradiation (39 patients), with bone marrow transplantation used for hematologic support. Thirty-four patients had disease that had been refractory to primary chemotherapy, and 66 patients had had a complete remission with primary chemotherapy but later relapsed. Before autologous bone marrow transplantation and high-dose chemotherapy, the 66 relapsed patients had also received conventional salvage chemotherapy; 22 had had no response or had had disease progression (a response termed "resistant relapse"), and 44 patients had responded partially or completely (a response termed "sensitive relapse"). After high-dose therapy and bone marrow transplantation, the actuarial three-year disease-free survival was zero in the refractory group, 14 percent in the resistant-relapse group, and 36 percent in the sensitive-relapse group. Patients who had had a complete remission in response to initial chemotherapy had a higher disease-free survival rate than those who had not (P less than 0.001), and patients with sensitive relapse had a higher disease-free survival rate than those with resistant relapse (P less than 0.003). These results should be considered in the planning or interpretation of trials of salvage chemotherapy in adults with non-Hodgkin's lymphoma.

Adolescent↗

PubMed1987

High dose cyclophosphamide, BCNU, and VP-16 (CBV) as a conditioning regimen for allogeneic bone marrow transplantation for patients with acute leukemia.

A high dose combination chemotherapy regimen (CBV) consisting of cyclophosphamide (1.5 gm/m2 day 1 to day 4); BCNU (300 mg/m2 day 1) and etoposide (100 mg/m2 every 12 hours for 6 doses), followed by bone marrow transplant from human leukocyte antigen (HLA) identical sibling donors, was evaluated in 29 patients in whom acute leukemia was in relapse or remission. Engraftment of donor cell type occurred in all but one of 21 patients, in whom marker differences between donor and recipient were established. Two of 11 patients transplanted during relapse of the disease, lived beyond 1 year after bone marrow transplantation. One patient died free of leukemia, 41 months after transplantation of meningitis. Two of seven patients transplanted during the second remission of the disease, are alive and free of leukemia at 42+, and 8+ months. All patients transplanted during the third or fourth remission of the disease have died from either a further relapse, or transplant related causes. The low incidence of organ toxicity with CBV allows for further dose escalation of its drug components.

Acute Disease↗

PubMed1987

Biological effect of epidermal growth factor on the in vitro growth of human tumors.

The effect of epidermal growth factor (EGF) on the in vitro growth of 186 malignant human tumor specimens (45 melanomas, 32 sarcomas, and 56 lung, 16 gynecological, 14 breast, 12 genitourinary, and 11 gastrointestinal carcinomas) was evaluated in the cellular adhesive matrix human tumor culture system supplemented with transferrin, insulin, hydrocortisone, and estradiol. EGF increased tumor growth by at least 50% in 81% of the 186 tumors and by over 100% in 54%. The enhanced growth induced by EGF was related to an accelerated cellular division independent of tumor type and not to an increase in the actual number of clonogenic units. The drug concentrations of cell cycle-independent Adriamycin and cisplatin needed to achieve a 90% tumor cell kill were not altered by the responsiveness of the tumor to EGF.

Antineoplastic Agents↗