Biomedical subjects
Publications and source records attributed to R S Neiman.
We present a unique case of functional hyposplenism due to massive involvement of the spleen by a rare tumor, an epithelioid hemangioendothelioma, in a 9-year-old girl. To our knowledge, three previous cases of this disorder involving the spleen have been reported, but this is the first associated with functional hyposplenism.
An 18-year-old male with Klinefelter's syndrome presented with a mature teratoma of the mediastinum. He was treated with debulking surgery and brief cisplatin-based chemotherapy. Ten years later, he presented with paraplegia and was found to have an isolated epidural mass. The mass was composed of mature histiocytoid cells reminiscent of those seen in malignant histiocytosis. There was no evidence of medullary dissemination and there was no evidence of recurrence of the germ cell tumor. He received local radiation therapy and a single course of leukemic induction. He remains well 4 years later. This case represents a localized variant of the diffuse histiocytic malignancies associated with malignant mediastinal germ cell tumors.
Flow cytometry studies have shown that high expression of CD34 antigen in patients with chronic myeloid leukemia (CML) is indicative of accelerated or blastic phases. It has also been suggested that similar information can be obtained by CD34 immunostaining of bone marrow biopsy specimens. To test this hypothesis, the authors studied 59 conventionally fixed, paraffin-embedded bone marrow trephine biopsy specimens, representing the three phases of the disease (stable, accelerated, and blast crisis). Immunohistochemical staining for CD34 was performed using QBEnd10, a monoclonal antibody reactive in routine paraffin-embedded tissue. The differences in CD34 positivity among chronic, accelerated, and blastic phases of CML were highly significant (P = .0001). This study demonstrated that CD34 immunohistochemical staining of bone marrow biopsy specimens represents a reliable method for classifying patients with CML and may provide essential diagnostic and prognostic information when a marrow aspirate is unavailable.
Terminal deoxynucleotidyl transferase (TdT) is a nuclear protein widely used as a marker for the diagnosis and classification of acute leukemia. The usual methods for detecting TdT require smears, imprints, or cryostat sections of unfixed tissue. A polyclonal rabbit anti-TdT serum was used to immunostain 54 routinely processed bone marrow sections from patients with acute leukemic disorders, using a recently described antigen-unmasking technique based on microwave oven heating. The specificity of this method of TdT analysis was confirmed by comparing the results obtained with conventional TdT analysis by indirect immunofluorescence. Terminal deoxynucleotidyl transferase reactivity was also evaluated in 44 nonmalignant and normal bone marrow specimens. All cases that were TdT-positive by immunofluorescence (41 of 42 "pre-B" and T-cell acute lymphoblastic leukemia, 2 of 5 acute myeloid leukemia, and 1 of 5 chronic myeloid leukemia in blast crisis) were also positive in paraffin sections. The percentage fluorescence positivity correlated with the percentage of immunoperoxidase stained cells in 44 of 45 cases. The remaining nonneoplastic and normal bone marrow biopsy specimens were TdT-negative. These results show that TdT immunoperoxidase staining of conventionally processed bone marrow specimens can be readily achieved by the use of a simple antigen-unmasking technique and may provide useful diagnostic information particularly in cases in which fresh tissue samples are unavailable.
An immunologically immunosuppressed mouse model of Pneumocystis carinii pneumonia using antibody developed by Dialynas et al. (Immunol. Rev. 74:29-55, 1983) directed to L3T4+ T cells (referred to as L3T4+ antibody) was compared with a corticosteroid-immunosuppressed mouse model. Corticosteroid- or L3T4+ antibody-immunosuppressed BALB/c mice transtracheally inoculated with P. carinii developed severe infections within 5 weeks after inoculation and responded to treatments with an echinocandin B analog, LY302146, or trimethoprim plus sulfamethoxazole so that they had decreased numbers of P. carinii cysts and trophozoites. LY302146 appeared to be more effective in L3T4+ antibody-immunosuppressed mice than in dexamethasone-immunosuppressed mice. Leukocyte populations in lungs of both mouse models during development of infection and during treatment were compared by using immune cell-specific staining. Lungs of L3T4+ antibody-immunosuppressed mice had many more cells detected with pan-B antibody and pan-T antibody than dexamethasone-immunosuppressed mice and the lungs of successfully treated mice had about the same numbers of macrophages as those of nonimmunosuppressed uninfected mice. The immunologically immunosuppressed model will allow study of cytokines and other immune modulators alone and in combination with drugs.
The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial in adult patients with lymphoblastic non-Hodgkin's lymphoma. Thirty-nine patients with no central nervous system (CNS) involvement were treated with an induction cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/L-asparaginase regimen and CNS prophylaxis that included intrathecally administered methotrexate given 6 times and 24 Gy midplane cranial radiation in 12 fractions. Thirty-one patients (79%) achieved a complete remission (CR). Of the 31 patients with CRs, 12 relapsed (39%). CNS relapse occurred in three patients. All patients who entered a CR were treated with maintenance CHOP, cytosine arabinoside (AraC), and methotrexate and subsequently with Ara-C and methotrexate. Life-threatening leukopenia or thrombocytopenia was experienced in 69% of patients in the induction phase and in 70% in the maintenance phase. Nineteen of 39 patients (49%) remain in CR with a followup to 9 years. Bone marrow involvement was associated with a significantly worse survival (P = 0.03).
Assessment of the proliferative index of human bone marrow using immunohistology in tissue sections offers practical advantages over other techniques. It is simpler to perform and can be applied to archival material. Progress in this area has been hampered by technical problems. Ki-67 studies, limited to fresh or frozen tissues, have been contradictory, and the labeling indices have been criticized for being unrealistically low. Proliferating cell nuclear antigen (PCNA) studies have also been considered unreliable because labeling indices include nondividing cells. We stained 82 routinely processed nonneoplastic bone marrow biopsies for Ki-67 equivalent MIB 1 antibody and PCNA/PC10 using a microwave oven antigen retrieval technique. 44.7% +/- 12.0 SD of the bone marrow cells stained with Ki-67/MIB 1. PCNA/PC10 staining gave similar results (50.7% +/- 12.3 SD). Pro- and basophilic erythroblasts, myeloblasts, promyelocytes, myelocytes, and megakaryocytes stained with both monoclonal antibodies in a manner consistent with known morphologic and cytokinetic data. Patients in different clinical groups showed similar mean values, the only exception being a group of cytokine-treated patients, which showed higher values than the other cases. Immunoperoxidase staining of bone marrow sections with Ki-67/MIB 1 and PCNA/PC10 monoclonal antibodies is a reliable method for assessing proliferation of hematopoietic cells.
Terminal deoxynucleotidyl transferase (TdT) represents a useful marker for the diagnosis of acute lymphoblastic leukemia and lymphoblastic lymphoma. It is usually assayed in fresh tissue or cell suspensions by enzyme analysis, immunofluorescence, or immunoperoxidase. We have obtained satisfactory staining for TdT in routinely processed paraffin sections using a recently described antigen retrieval pretreatment based on microwave oven heating of the sections and a polyclonal rabbit anti-TdT serum. With this technique, we assayed paraffin sections from lymph nodes of 91 patients with a variety of malignant lymphomas, including 35 cases of lymphoblastic lymphoma. The specificity of this immunoperoxidase method of TdT analysis was confirmed by comparing the results obtained with conventional TdT analysis by indirect immunofluorescence. Neoplastic cells from 33 of the 35 (94%) patients with lymphoblastic lymphoma were TdT positive with both techniques. All remaining 50 cases of other subtypes of malignant lymphoma were TdT negative. Specificity was further confirmed by demonstrating TdT-positive blasts in paraffin sections of bone marrow biopsies from 44 patients with TdT-positive (by indirect immunofluorescence) acute leukemias and in paraffin sections of extramedullary leukemic infiltrates from eight patients with relapsed acute lymphoblastic leukemia. Other control material studied included eight lymph nodes with Hodgkin's disease, four normal spleen, seven reactive lymph nodes, and 25 nonneoplastic bone marrow samples, all of which gave the expected results, i.e., rare scattered TdT-positive cells in bone marrow and lymph nodes, absence of staining in Hodgkin's disease malignant cells and spleen. Our results confirm that TdT is a specific marker for the diagnosis and classification of lymphoblastic lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)
We report three cases of Hodgkin's disease with coexistent histologic features reminiscent of Castleman's disease. In each case, reactive follicular hyperplasia was prominent and lymphoid follicles contained normal- or small-sized germinal centers. In two lesions, sheets of mature plasma cells and vascular proliferation were present in the interfollicular region, and some of the follicle centers were small, relatively depleted of lymphoid cells, and surrounded by concentric layers of small lymphocytes (so-called onionskin layers). However, unequivocal hyaline-vascular lesions were absent. Both cases were referred with the diagnosis of Castleman's disease, most consistent with the plasma cell variant. Subsequent review demonstrated scattered Reed-Sternberg and Hodgkin cells in the interfollicular region, highlighted by immunohistochemical studies, and the diagnosis of interfollicular Hodgkin's disease was made. In the third lesion, the majority of the lymph node was replaced by Hodgkin's disease, nodular lymphocyte predominance subtype. In the regions not involved by tumor, reactive lymphoid follicles with hyaline-vascular lesions were numerous. This case was also referred with the diagnosis of Castleman's disease, of the hyaline-vascular type. We report these lesions to emphasize that histologic features reminiscent of Castleman's disease may occur in lymph nodes involved by Hodgkin's disease, resulting in diagnostic confusion. Castleman-like histologic features may represent a nonspecific immune response to a variety of immunologic stimuli including, as in these cases, the presence of Hodgkin's disease. The possibility of Hodgkin's disease needs to be considered and excluded before the diagnosis of Castleman's disease is made.
The ETS oncogene family member PU.1 is a transcriptional activator that is dysregulated by Friend erythroleukemia virus insertion. Northern analysis found that PU.1 is highly expressed in cells of myeloid and B-lymphoid origin, but not expressed at all in a number of nonhematopoietic tissues. Interferon-gamma and retinoic acid downregulated PU.1 expression in marrow macrophages. In situ immunohistochemistry found that PU.1 is expressed only in early granulocytic and erythroid cells and megakaryocytes, but not in mature erythroid cells, mature granulocytes, endothelial cells, or osteocytes. Thus, its expression pattern makes PU.1 a candidate for a genetic determinant of lineage commitment and stage progression in blood cell development. It also lends insight into how PU.1 might play a role in Friend virus erythroleukemia.
BACKGROUND: Patients with mediastinal germ cell tumors (MGCT) have a high incidence of hematologic malignancies unrelated to cytotoxic chemotherapy. It has been suggested that these leukemic conditions originate from a MGCT progenitor cell capable of undergoing non-germ cell (hematopoietic) differentiation. METHODS: To assess this hypothesis, histologic material from six patients with MGCTs associated with leukemia was examined using monoclonal and polyclonal antibodies capable of labeling cells of the different marrow cell lineages. RESULTS: Morphologically identifiable hematologic cells were found within the yolk sac tumor component of the MGCT in four of these patients. In three of the four cases, the cells consisted of poorly differentiated blast cells, whereas in the fourth, clusters of erythroblasts were identified. The leukemic cells within the MGCT and in the bone marrow had similar morphology, constant expression of the early progenitor cell marker CD34, and variable expression of more mature myeloid, monocytic, erythroid, and megakaryocytic markers. Three cases expressed p53, a nuclear protein associated with neoplastic transformation in a wide range of malignancies, including testicular cancers, but which rarely is reported in leukemias. Karyotype of the leukemia was assessed in five cases: two showed an i(12p), a cytogenetic marker of GCT not identified in the usual cases of leukemia. CONCLUSIONS: The results support the hypothesis that these leukemic conditions originate in the MGCT through a mechanism of differentiation from a yolk sac tumor-derived progenitor cell, with subsequent homing to the marrow.
Lymphoma arising in the liver is uncommon in adults and rare in children. A 12-year-old boy with hepatomegaly and jaundice had a calcified intrahepatic large-cell lymphoma of B-cell origin that expressed bcl-2 protein and had near-tetraploid chromosome number with a t(8;14) (q24;q32) and a homogeneously staining region (HSR). This tumor, only the fourth example of primary hepatic lymphoma in a child, has the rare finding of an HSR before treatment and is the first human lymphoma with t(8;14) that expresses bcl-2 protein. In addition, the demonstration of extensive calcification in the tumor by computed tomography scan is highly unusual for lymphoma. Lymphoma must be considered in the differential diagnosis of primary liver tumors in children and adults, especially if the serum alpha-fetoprotein level is normal.
p53 overexpression was studied immunohistochemically in paraffin-embedded bone marrow biopsies using a recently described technique for antigen retrieval based on microwave oven heating of paraffin sections. Using a monoclonal antibody (PAb1801) that reacts with human cellular p53, nuclear staining was detected in 7/11 (63%) therapy-related myelodysplastic syndromes and in 3/4 (75%) therapy-related acute myeloid leukemias. Conversely, staining for p53 was seen only in 9/40 (22%) cases of "primary" hematologic conditions (P < 0.007); these included myelodysplastic syndromes [#2], acute myeloid leukemia [#4], and chronic granulocytic leukemia in accelerated phase or blast crisis [#3]. Biopsies of normal controls and of chronic granulocytic leukemia in stable phase were consistently p53(-). Nine of the 10 karyotyped p53(+) acute myeloid leukemia/myelodysplastic syndrome cases showed complex cytogenetic findings with frequent involvement of chromosome 5 and/or 7. Only four of the 33 karyotyped p53(-) cases showed similar cytogenetic changes. Chromosome 17 involvement was present in four of 13 (31%) cytogenetically assessed p53+ cases, but in none of the p53(-). In univariate analysis, p53 expression in both MDS and AML was significantly associated with shorter survival. The frequent overexpression of p53 in therapy-related myelodysplastic syndromes, therapy-related acute myeloid leukemias and in accelerated phase/blast crisis, chronic granulocytic leukemia and its strong association with complex karyotypes suggests an important role of this gene in the pathogenesis of these leukemic conditions.
Explore the source record for details and available documents.
A case-control study was conducted to assess the effect of occupational exposures on the risk of non-Hodgkin's lymphoma. Interviews were conducted with 303 persons with non-Hodgkin's lymphoma newly diagnosed from January 1, 1980, to May 31, 1982, among residents of the Boston, MA, metropolitan area and 303 age and gender matched controls. The study found an increased risk of disease among persons employed in the agriculture, forestry, and fishing industry [relative risk (RR) = 3.0]; the construction industry [RR = 2.1]; and the leather industry [RR = 2.1]. The particular job groupings at increased risk were plant farmers and gardeners (RR unbounded); painters and plasterers (RR = 6.0); and carpenters, brick and stone masons, plumbers, and roofers (RR = 12.0). Although other exposures may have led to these increased risks, the findings in this study are consistent with an increased risk of non-Hodgkin's lymphoma for workers who may be exposed to chlorophenols or phenoxyacetic acids.
One hundred and forty one patients were treated in a combined Eastern Cooperative Oncology Group and Southwest Oncology Group phase-III study evaluating low-dose cytarabine (LDAC) versus supportive therapy for the treatment of myelodysplastic syndrome (MDS). Patients were randomized to either cytarabine 10 mg/m2 subcutaneously BID or supportive therapy. Central pathology review was required. All patients were classified according to the FAB criteria for MDS. The overall concordance rate for the MDS subtype was 52%, and 25 patients were pathology exclusions, including 20 with AML. The overall response rate to a single cycle of LDAC was 32%, with 11% complete and 21% partial responses. The median duration of response was 5.9 months, with a range of 1.4-33.5 months. Responses were seen in all subtypes. Infections were more common in the LDAC arm. There was no difference in the time to progression or the overall survival for patients treated with LDAC or supportive therapy. The incidence of leukemic transformation was similar in both arms at 15%, but it differed according to the MDS subtype. Patients receiving LDAC had a decreased transfusion requirement after 3 months. There was a significant correlation between the degree of cytoreduction after receiving a single cycle of LDAC and survival. This survival difference was most marked in patients with the RAEB and RAEB-T subtypes. Although LDAC produced responses in all subtypes of the MDS, there was no effect on overall survival or transformation to AML. However, selected patients benefited from a single cycle of LDAC with durable responses. A cytoreductive effect appears to be required for a durable response. Future studies should include pathology review and must address the clinical and biological heterogeneity of MDS.
As human immunodeficiency virus (HIV) infection spreads into the heterosexual population, perinatally acquired HIV infection will increase in incidence, and knowledge of the mechanism of this transfer is important. We have used immunoperoxidase techniques to detect HIV p24 antigen in formalin-fixed, paraffin-embedded placental tissue from nine known HIV serologically positive mothers. In four of these cases we have detected evidence or viral antigen in placental Hofbauer cells, vascular endothelium, or intermediate trophoblast. The implications for understanding the mode of transfer of infection to the fetus are discussed.
PURPOSE: Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkin's lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS: Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS: Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION: Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.