Molecular and biological role of CD40 in multiple myeloma.
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Antigens, CD↗
Biomedical subjects
J A Katzmann
Publications and source records attributed to J A Katzmann.
CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line.
Myeloma is a neoplasia characterized by the accumulation of malignant plasma cells in the bone marrow. In these studies, we have demonstrated that CD40 is expressed in human myeloma cells and have used a recently established IL-6-dependent myeloma cell line, ANBL-6, to examine the potential function of CD40 expression in myeloma cells. In addition to its expression on the ANBL-6 cells, we show that CD40 is expressed on freshly isolated myeloma cells from seven of seven patients tested. To address the role of CD40 expression in myeloma cells, we have examined the responsiveness of the ANBL-6 cell line to a CD40-specific mAb, G28-5. This cell line has previously been shown to proliferate only in response to IL-6. Of interest in this study, G28-5 also induced proliferation of the ANBL-6 cells. This proliferation was substantially inhibited by an IL-6-neutralizing mAb. Analysis of ANBL-6 cell culture supernatants by ELISA demonstrated that G28-5-stimulated cells secreted significant levels of IL-6, whereas unstimulated cell culture supernatants contained undetectable levels of IL-6. Furthermore, CV-1/EBNA cells expressing the human CD40 ligand also induced the proliferation of the ANBL-6 cell line, an effect that was inhibited by the anti-IL-6 mAb. Lastly, RNA blot analysis demonstrated an increase in IL-6 message in G28-5-stimulated ANBL-6 cells over unstimulated cells. These results indicate that the primary mechanism of anti-CD40-stimulated proliferation of the ANBL-6 cells is the induction of autocrine IL-6 production. Moreover, these data suggest that the expression of CD40 in malignant plasma cells may play a role in tumor cell expansion, possibly by stimulating the induction of autocrine IL-6 secretion.
Antibodies, Monoclonal↗
Early gastric cancer.
Early gastric cancer comprises more than 30 per cent of gastric carcinomas treated in Japan but remains an uncommon entity in the western hemisphere. A retrospective review of 48 patients with early gastric cancer undergoing operative treatment between 1965 and 1984 was carried out. The mean patient age was 70 years, in 31 men and 17 women. Preoperative diagnosis was made in 88 per cent of patients undergoing oesophagogastroduodenoscopy with biopsy but upper gastrointestinal radiography was diagnostic in only 20 per cent. Surgical management consisted of subtotal gastrectomy (86 per cent), total gastrectomy (10 per cent) and wide local excision (4 per cent). The operative mortality and morbidity rates were 0 and 38 per cent, respectively. Mean follow-up was 7.7 years, with 44 per cent of patients still alive. Multivariate analysis disclosed only a healthy Eastern Cooperative Oncology Group score (P = 0.002) and a diploid DNA tumour pattern (P = 0.05) as significant prognostic variables of survival. The overall survival rate of patients with early gastric cancer (70 per cent at 5 years) was equivalent to that of an age- and sex-matched control population.
Aged↗
Phyllodes tumor: clinicopathologic review of 60 patients and flow cytometric analysis in 30 patients.
We reviewed 66 phyllodes tumors of the breast from 60 patients. Our patients included 59 women and one man ranging in age from 16 to 72 years. Fifty patients presented for primary treatment of newly diagnosed breast masses, nine presented with recurrent tumors, and one presented with soft tissue metastases 9 years after bilateral subcutaneous mastectomies and multiple chest wall recurrences of phyllodes tumor. After 0.3 to 53.2 years (mean, 15.5 years) of follow-up, 26 (43.3%) patients are free of disease without recurrence, 26 (43.3%) patients are dead of other (17 patients) or unknown (nine patients) causes, four (6.7%) patients had locally recurrent tumor 0.7 to 2.9 years after lumpectomy and are free of disease 3 months to 12 years after re-excision or simple mastectomy, two (3.3%) patients are lost to follow-up, and two (3.3%) patients died with metastatic disease 1.8 and 7 years after diagnosis. Histologic features and flow cytometric analysis showed no correlation with outcome. Fifty-six breast tumors were biphasic and nine were purely stromal tumors. Twenty-six (47%) biphasic tumors showed stromal overgrowth. Tumor margins were pushing in 20 (39%) and infiltrative in 29 (61%) of 49 evaluable cases. Twenty-one tumors were highly cellular and 17 showed cytologic atypia. Necrosis was identified in 16 tumors. Mitotic rates ranged from 0/10 high-power fields to 48/10 high-power fields. Twenty-four diploid, six aneuploid, three tetraploid, and one polyploid tumor were identified by flow cytometry. S-phase fractions tended to be higher in nondiploid tumors. Neither DNA content nor S-phase fraction correlated with outcome. Our results indicate that most mammary phyllodes tumors, including purely stromal tumors, behave as low-grade, nonmetastasizing neoplasms. Neither histologic evaluation nor DNA content provides reliable clues concerning the natural history of an individual tumor.
Adolescent↗
Flow-cytometric DNA analysis of stages IB and IIA cervical carcinoma.
The prognostic significance of flow-cytometric DNA analysis was assessed in 375 stages IB and IIA squamous cell carcinoma patients treated with radical hysterectomy and lymphadenectomy at the Mayo Clinic between 1956 and 1985. Paraffin-embedded samples containing at least 20% tumor were dewaxed, rehydrated, stained with propidium iodide, and analyzed. Among 344 assessable samples, 136 (40%) were diploid and 208 (60%) were nondiploid (26 tetraploid, 158 aneuploid, and 24 polyploid). Diploid cases were further subclassified: 25 high proliferative phase (HPP) (S+G2M greater than 20%) and 111 low proliferative phase. No significant correlation was noted between DNA diploid patterns and stage, tumor size, grade, or histotype, but HPP diploid tumors had a significantly higher risk of nodal metastasis. With a mean follow-up period of 150 months, 62 patients died of disease. No significant difference was observed in survival rates (SR) between diploid and nondiploid tumors, but the subset of HPP diploid tumors had a prognosis significantly worse than that of any other group (P less than 0.01). Other significant variables included nodal metastases, parametrial extension, age, and clinical stage. While ploidy patterns did not assign additional risk to node-positive lesions, HPP diploid tumors in node-negative patients were associated with a significantly lower SR. Multivariate analyses in node-negative patients demonstrated that stage, histologic subtype, and HPP diploid patterns retained prognostic independence.
Carcinoma, Squamous Cell↗
Total lymphoid irradiation: a novel and successful therapy for resistant cardiac allograft rejection.
Total lymphoid irradiation (TLI) is a novel type of adjuvant immunosuppression for patients who undergo cardiac transplantation and have refractory allograft rejection during standard immunosuppressive therapy. TLI consists of 6 to 10 fractions of 80 cGy (1 cGy = 1 rad) of irradiation to lymphatic tissues with use of the standard mantle and inverted Y fields. We have used TLI in six patients with biopsy-proven rejection that was refractory to standard treatments, including cyclosporine, azathioprine, antilymphocyte antibodies, and corticosteroids. In five patients, recalcitrant rejection was resolved after completion of TLI, and resolution persisted during long-term follow-up (17 to 30 months; mean, 22.2 months). In each patient, a substantial increase in the CD8 (suppressor T-lymphocyte) subset and elimination of B lymphocytes were demonstrated, findings that also persisted. Side effects were mild and primarily limited to transient leukopenia. In four patients, a readily treated cytomegalovirus reactivation was noted during TLI; thus, a causal relationship was suggested. In recipients of cardiac allografts who have refractory rejection, TLI provides long-lasting amelioration of the rejection profile. This result may be attributable to a relative enhancement of the suppressor T-cell subset and elimination of the B-lymphocyte line. Side effects are minimal, but monitoring for cytomegalovirus activation or reactivation is recommended.
Adult↗
Evaluation of DNA nuclear pattern as a prognostic determinant in resected pancreatic ductal adenocarcinoma.
From a cohort of 72 patients who underwent radical resection for ductal adenocarcinoma of the pancreas between 1951 and 1980, 62 paraffin-embedded specimens were analyzed by flow cytometry. Patients were divided into two groups according to the length of survival: long-term survivors (19 patients who survived 3 or more years after operation) and short-term survivors (43 patients who died within 12 months after resection). In 30 specimens (48%), the nuclear DNA pattern was diploid, whereas 32 were nondiploid (two tetraploid and 30 aneuploid). There were no significant differences in the number of diploid/nondiploid patterns, the fraction of cells in DNA synthetic (S) phase, or the DNA index between the two groups. These data suggest that there is no difference in the DNA content analysis of patients with pancreatic ductal adenocarcinoma when comparing long-term with short-term survivors following resection.
Carcinoma, Intraductal, Noninfiltrating↗
Relationship of nuclear DNA content to clinical and pathologic findings in patients with primary hepatic malignancy.
BACKGROUND: Nuclear DNA content of a variety of tumors has proven valuable as a prognostic indicator. The purpose of this study was to analyze patterns of DNA content in primary hepatocellular carcinoma and to correlate ploidy status with patient survival. METHODS: The relationship of nuclear DNA content to host and tumor characteristics was analyzed in 46 patients with primary hepatic malignancy who had undergone resection with curative intent between 1975 and 1985. RESULTS: Flow cytometric measurement of tumor DNA content revealed a diploid pattern in 33%, tetraploid or polyploid in 30%, and aneuploid in 37% of cases. There was no significant correlation between tumor DNA content and demographic or pathologic findings in the patients studied. Moreover, there was no difference in survival between patients with diploid versus nondiploid tumors. CONCLUSIONS: These findings suggest that tumor DNA content has no prognostic value in patients with primary hepatic malignancy.
Carcinoma, Hepatocellular↗
T cell depletion using anti-CD2 coated magnetic beads simplifies the detection of peripheral blood plasma cells.
The detection of peripheral blood plasma cells is clinically important, but difficult to perform by use of routine smears. To simplify the detection process, the peripheral blood T cells from ten patients with known active multiple myeloma were depleted using anti-CD2 coated magnetic beads. In all cases, there was enrichment of the immunoglobulin (Ig) positive cells after T cell depletion (mean enrichment factor, 3.4; median, 3.2; range, 1.2-5.1) with a mean pre-bead %Ig+ cells of 7.3 compared to 20.4 for the post-bead sample (p = 0.005). The monoclonal plasma cells were similarly enriched and more easily enumerated on the microscope slides prepared from the T cell depleted sample.
Antigens, Differentiation, T-Lymphocyte↗
DNA content flow cytometry as a prognostic factor for node-positive breast cancer. The role of multiparameter ploidy analysis and specimen sonication.
The DNA content was analyzed in paraffin-embedded material from 167 patients with node-positive breast cancer to learn whether specimen sonication and multiparameter ploidy analysis (MPPA) (using DNA content and light scatter) could improve the strength of ploidy as a prognostic variable. Sonicated specimens were found to have fewer aggregates, a lower percentage of cells in S-phase (%S) and G2M phase than the corresponding nonsonicated specimens. The results using MPPA predicted the prognosis better because they allowed detection of small aneuploid peaks in histograms classified as diploid or tetraploid using DNA content alone. Ploidy was a significant univariate factor, and patients with tetraploid tumors had the best survival. In the multivariate analysis, if other routine factors were examined preferentially, ploidy and %S did not provide additional prognostic information for survival. This study of paraffin-embedded breast cancers suggested that sonication and MPPA may improve the ploidy analysis in certain cases and that tetraploidy may be a favorable ploidy pattern in this group.
Breast Neoplasms↗
DNA ploidy and cell kinetic measurements as predictors of recurrence and survival in stages B2 and C colorectal adenocarcinoma.
DNA content and cell proliferation were measured by flow cytometry on paraffin-embedded Stage B2 or C colorectal adenocarcinomas from 694 patients enrolled in adjuvant trials conducted by the North Central Cancer Treatment Group. Patients with diploid tumors had a higher survival rate than those with nondiploid tumors (P less than 0.001). The proliferation index (the sum of the percent of cells in S-phase plus those in G2M phase) was also a strong prognostic factor (P less than 0.001). The ploidy and proliferation data were combined, and the patients in the favorable group (diploid and low proliferative index) had a 5-year survival of 74% compared with 54% for the unfavorable group (high proliferative index or nondiploid, P less than 0.001). This grouping was prognostic for survival in B2 (P less than 0.001), C (P = 0.013), colon (P less than 0.001), and rectal (P = 0.026) patient subsets. This study indicates that cell kinetic parameters are important and independent prognostic factors for Stages B2 and C colorectal cancer.
Adenocarcinoma↗
Symptomatic subependymoma: a clinicopathological and flow cytometric study.
Twenty-one intracranial subependymomas were reviewed with regard to presentation, diagnosis, operative findings, and long-term follow-up data. The histopathological features were critically reviewed, and deoxyribunucleic acid analysis was performed by flow cytometry. The patients' mean age was 48.5 years (range 32 to 72 years). In 14 cases the tumor was located in the fourth ventricle, in six within a lateral ventricle, and in one in the third ventricle with extension into the lateral ventricle. Radiographic characteristics included isodensity with minimal enhancement on computerized tomography, frequent dystrophic calcification, and isointensity on T1-weighted or slight hyperintensity on T2-weighted magnetic resonance images. The predominant histological features in all cases were those of classic subependymoma. Nonetheless, pathological examination showed a minor (less than 20%) ependymoma component in five cases, significant cytological atypia in seven, mitoses in 11, endothelial prominence in four, and focal hemorrhage-associated necrosis in two. Flow cytometry revealed a diploid pattern in 12 patients, tetraploidy in two, and aneuploidy in one. Two patients died in the perioperative period. Of the remaining 19, 12 underwent gross total resection (two of whom received postoperative irradiation) and seven underwent subtotal resection (five of whom received irradiation). None of the 12 non-irradiated patients developed tumor progression or died of direct tumor-related causes. Of the seven irradiated patients, follow-up imaging studies demonstrated their tumors to be radioresponsive, particularly with doses of 5000 cGy or greater. Despite the presence of cytological atypia and mitotic activity in the majority of cases, the prognostic effects of such factors as tumor location and the extent of surgical resection outweighed those of the standard histopathological parameters. Routine postoperative irradiation is not recommended, but should be reserved for cases with a symptomatic residual or recurrent subependymomas following surgery.
Adult↗
Models of S-phase determination in lymphomas from flow cytometric DNA content histograms: comparison with the bromodeoxyuridine labeling index.
The estimated S-phase fraction (%S) of non-Hodgkin's lymphomas has been demonstrated to be of prognostic value. The %S can be determined by labeling index (LI) techniques or by various mathematical models applied to DNA content histograms. We performed DNA content analysis and a slide-based bromodeoxyuridine immunofluorescence LI on split samples from 117 biopsy specimens suspicious for lymphoma. The LI was compared with the %S determined by two computer models (rectangular and polynomial) with and without debris subtraction, and a manual gates computer model. In the 93 DNA diploid cases, the rectangular models had the highest correlation with the LI (R = 0.88). In the 24 aneuploid cases, the manual gates model was the most useful because of a high correlation with the LI (R = 0.70) and its ability to be used in most cases (23/24). The polynomial models had limited usefulness because they generally gave a higher %S than the LI and could be fitted in less than half of the DNA aneuploid histograms. These results suggest that in situations where the LI is not possible, an accurate %S estimate can usually be obtained with either a rectangular or manual gates model.
Bromodeoxyuridine↗
Subependymal giant cell astrocytoma: a clinical, pathological, and flow cytometric study.
Of 345 patients with tuberous sclerosis complex evaluated at the Mayo Clinic from 1950 to 1989, 23 were identified as having brain tumors. In 20 of the 23, histological or clinical evidence showed the tumor to be a subependymal giant cell astrocytoma. A search of the Mayo Clinic tissue registry yielded 73 giant cell-containing astrocytomas and intraventricular gliomas exclusive of ependymomas. Reexamination revealed no further examples of subependymal giant cell astrocytoma in patients without features of the tuberous sclerosis complex. Considerable histological variation was observed in the 15 subependymal giant cell astrocytomas subjected to critical microscopic review. It is of note that no correlation was noted between either the histological features, such as atypia, mitoses, endothelial proliferations, necrosis, or the flow cytometric characteristics and the clinical course or the survival time of the patients.
Adolescent↗
Effect of sonication on paraffin-embedded tissue preparation for DNA flow cytometry.
Since the publication of paraffin block extraction procedures, flow cytometric analysis of DNA ploidy and S-phase of tumor specimens has been widely applied. DNA aneuploidy, DNA tetraploid (elevated G2/M), and elevated S-phase are clinically significant in some tumor systems. True DNA tetraploid cell lines will contain a large 4c population and perhaps an 8c population; samples with cell aggregates will also contain a 6c population. Microscopic examination of samples having a 6c peak revealed nuclei with adhering debris and doublets, triplets, and larger nuclear aggregates. After sonication, a uniform suspension of single nuclei without adherent debris was seen. In addition to reducing the percent of G2/M cells, sonication also reduced S-phase percent such that it was closer to the bromodeoxyuridine labeling index. The DNA ploidy classification of specimens was also compared pre- and post-sonication. Four of 96 breast cancer samples changed classification; all were specimens in which the histogram became cleaner and a small DNA aneuploid peak became apparent after sonication.
Breast Neoplasms↗
Beta 2-microglobulin predicts survival in primary systemic amyloidosis.
PURPOSE: The study assessed whether beta 2-microglobulin levels predict survival or response in patients with primary systemic amyloidosis without associated multiple myeloma. PATIENTS AND METHODS: The study group consisted of 131 untreated patients with biopsy-proven primary systemic amyloidosis diagnosed and evaluated at the Mayo Clinic. No patient had multiple myeloma. The minimum follow-up of surviving patients is 8 years. No patient was lost to follow-up. RESULTS: The median survival of patients with an increased beta 2-microglobulin level was 10.8 months, compared with patients with a normal beta 2-microglobulin level (less than or equal to 2.7 micrograms/mL, 0.23 mumol/L) of 32.9 months (p less than 0.001). In a multivariate proportional-hazards model, the best model included congestive heart failure (p less than 0.0001) and increased beta 2-microglobulin levels (p less than 0.05). After adjustment for the presence of congestive heart failure, beta 2-microglobulin level remained significant. When the analysis was restricted to those patients with normal renal function, the median survival of those with an elevated beta 2-microglobulin level was 9.1 months versus 39.4 months for those with a normal level (p less than 0.001). The serum level of beta 2-microglobulin was increased in patients with nephrotic-range proteinuria with or without renal insufficiency (p = 0.05). CONCLUSION: The serum beta 2-microglobulin level should be measured routinely in all patients with primary systemic amyloidosis because it provides a useful objective factor to identify subsets of patients with this disease who have unfavorable outcomes.
Adult↗
A new murine monoclonal antibody for the diagnosis of erythroleukemia.
The authors have developed a murine monoclonal antibody, RC-82.4, against an antigen expressed by a human erythroleukemia cell line OCI-MIR. The antibody reacts with an antigen expressed by proerythroblasts, normoblasts, and some reticulocytes but not expressed in erythrocytes, granulocytes, monocytes, megakaryocytes, plasma cells, or lymphocytes. The authors have established an immunocytochemical method for studying bone marrow smears with RC-82.4. By studying bone marrow smears from 11 patients with M-6 erythroleukemia and 104 patients with various other hematologic and nonhematologic malignancies, the authors have found that RC-82.4 has great sensitivity and specificity in recognizing erythroid differentiation in blasts. The authors have used RC-82.4 and antihemoglobin antibodies to identify erythroblasts in acute and secondary acquired cases of erythroleukemia that would have been unclassifiable by morphologic and all other conventional cytochemical and immunocytochemical criteria.
Adult↗
Rapid immunotyping of B-cell non-Hodgkin's lymphomas by flow cytometry. A comparison with the standard frozen-section method.
The authors compared immunotyping (IT) results obtained by both standard frozen section (FS) and flow cytometry (FC) methods on 218 biopsies suggestive of lymphoma to learn the advantages of each method. The independent interpretations of the FS and FC IT results were concordant in 93% (202 of 218) of cases. The 16 cases with discordance were reviewed and seven causes for discrepancy found: methodologic problems, focal lymphomatous involvement, more sensitive light chain detection by FC, inadequate sample for FC, interpretation error, sample mislabeling for FC, and unexplained. Eleven of the concordant B-cell non-Hodgkin's lymphomas (NHLs) studied by FC did not have a kappa:lambda ratio of 3 or greater or 0.5 or less and were shown to express light chain restriction by a D-value of 15 or greater with the use of statistical analysis of the kappa and lambda histograms or by multiparameter analysis of large versus small cells. The authors found both methods to be effective for phenotyping lymphomas, however, each has distinct features, making them complementary in their applications.
Antibodies, Monoclonal↗