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Biomedical subjects

V Diehl

Publications and source records attributed to V Diehl.

At least 109 records · Page 6Linked to original sources
PubMed2001

Polycythemia rubra vera versus secondary polycythemias. A clinicopathological evaluation of distinctive features in 199 patients.

To determine parameters of distinctive value in polycythemia rubra vera (PV) versus secondary polycythemias (SP), a clinicopathological study was performed on 199 patients. These presented with a borderline to marked elevation of the hemoglobin level (> 18 g/dl in men and > 16 g/dl in women). Evaluations of clinical features and bone marrow histopathology were carried out independently. According to the results derived from laboratory data and representative pretreatment trephine biopsies, three groups of patients emerged: group I presenting with the concordant clinical and morphological findings of early to manifest PV (136 patients), group II consisting of 55 patients with the congruent signs and symptoms of SP mostly caused by various chronic bronchopulmonal disorders, and finally eight patients (group III) with divergent findings. Between group I and II patients (PV versus SP), a number of clinical parameters proved to be significantly different. With the exception, of the red cell mass, platelet count, leukocyte alkaline phosphatase, LDH, spleen size, and the erythropoietin level had a significantly discriminating impact. Morphological features of distinctive value consisted of a set of specific lesions. Contrasting SP with an only borderline to slight increase in cellularity associated with a moderate enlargement of the erythroblastic islets, PV was always characterized by a significant increase in hematopoiesis, revealing a trilinear proliferation (panmyelosis). Megakaryopoiesis was strikingly different in PV as compared to SP by displaying clustering and a pleomorphous appearance. i.e., very small and giant megakaryocytes with staghorn-like nuclei were neighboring each other. Moreover, conspicuous alterations of the interstitial compartment were recognizable in SP. These consisted of deposits of cell debris in histiocytic reticular cells, iron-laden macrophages, and a plasmacytosis, implying an inflammatory reaction. These changes were only very rarely observed in PV, as opposed to a minimal to slight increase in reticulin fibers in about 12% of patients. In conclusion, a more elaborate evaluation of bone marrow features resulted in a set of diagnostic criteria with discriminating capacity that should be considered in prospective clinical trials.

Bone Marrow↗
PubMed2001

Therapy-related changes of CD34+ progenitor cells in chronic myeloid leukemia: a morphometric study on sequential trephine biopsies.

In chronic myeloid leukemia (CML), it has been assumed that the number of CD34(+) progenitor cells (PGCs) provides useful diagnostic and prognostic information regarding the evolution of accelerated phase and blastic crisis. However, until now no information is available about changes of this peculiar precursor cell population during therapy or possible associations with the other bone marrow constituents. For this reason, a retrospective clinicopathological study was performed on 83 patients with CML including 209 sequential bone marrow biopsies (intervals ranging between 6 and 143 months) and immunohistological staining of CD34(+) cells (QBEND10), megakaryocyte precursors (CD61), and erythropoiesis (Ret 40f). According to treatment modalities, three different groups of patients could be distinguished that received either monotherapy by interferon-alpha2b (IFN-alpha2b) or hydroxyurea (HU) and a combination of both. In comparison with a control group, morphometry revealed a significant increase in the quantity of CD34(+) PGCs per hematopoiesis (cellularity) in the CML bone marrow before treatment. Independently of treatment modalities and presentation of clinical findings nonresponding patients were generally characterized by a higher amount of progenitors in the initial biopsy specimens. Furthermore, calculation of the CD34(+) cell growth index showed a significant and rapid progression in nonresponding patients and in those developing an accelerated or blastic phase during therapy. This feature was prominently expressed following IFN treatment and related to a failing regeneration of nucleated erythroid precursors. In patients with a myelofibrotic bone marrow at onset no differences in the number of CD34(+) PGCs were recognizable in the pretreatment biopsies. This finding contrasted a significant and gradual change in progenitor cell frequency under treatment and evolving myelofibrosis. Opposed to HU therapy, the latter feature was explicitly detectable in the IFN group. In conclusion, the incidence of CD34(+) PGCs in the CML bone marrow reflects therapeutic efficacy. By demonstrating a significant relationship between fiber content and quantity of CD34(+) cells during treatment, experimental findings concerning the complex functional interactions between the fibrous stroma compartment and progenitor cell differentiation and proliferation are elucidated.

Antigens, CD34↗
PubMed2001

Treatment of advanced stage Hodgkin's disease.

Hodgkin's disease remains one of the few malignant diseases which can be cured by modern chemotherapy in most cases even in advanced stages. Adriamycin-containing chemotherapy regimens are considered as the standard therapy which induce long-term remission in about 60-70% of patients. The ABVD scheme, developed by Bonadonna and colleagues in Milan, has a favorable toxicity profile and causes less myelotoxicity, acute leukemia or sterility relative to many previous treatment programs containing alkylating agents. However, 20- 30 % of patients eventually relapse and are then frequently treated with high-dose programs including stem cell transplantation. There are two major goals in advanced Hodgkin's disease: (1) to improve the cure rate and (2) to reduce acute and long-term toxicities. The recent definition of prognostic factors identified patients who are at a high risk of treatment failure as well as those in whom less toxic approaches can be applied. The optimal approach or program has not yet been defined, although new chemotherapy regimens such as BEACOPP and Stanford V with increased tumor response rates have been identified. These new drug combinations are currently analyzed and compared with ABVD in several international trials. While the addition of radiotherapy improved disease control in some trials a survival benefit was not identified and the role of radiotherapy remains controversial. High dose programs remain experimental in advanced stage Hodgkin's disease and should be restricted to prospective clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

The value of bone marrow histology in differentiating between early stage Polycythemia vera and secondary (reactive) Polycythemias.

BACKGROUND AND OBJECTIVES: The diagnostic criteria of the Polycythemia Vera Study Group (PVSG), although generally acknowledged as the gold standard for establishing a diagnosis of polycythemia vera (PV), do not consider bone marrow features. It may, therefore, be speculated that initial-early stages of PV are overlooked. In this retrospective study we tried to investigate whether bone marrow morphology of patients with an only borderline to slight increase in hemoglobin/hematocrit not conforming with the postulates of the PVSG enabled a clear-cut differentiation between PV and secondary (reactive) polycythemias (SP). DESIGN AND METHODS: From a series of 348 patients with a borderline to pronounced erythrocytosis and representative pre-treatment bone marrow trephine biopsies a cohort of 86 cases was selected showing only a borderline increase in hemoglobin (males < 18.5 g/dL, females < 16.5 g/dL). Biopsies and clinical records were evaluated independently and following histologic and clinical work-up a straightforward consensus was reached. The diagnostic impact of histologic findings was tested by means of discriminate analysis of 20 standardized morphologic features based on histochemical and immunohistochemical staining techniques. RESULTS: Bone marrow histopathology in 47 patients diagnosed as having SP was characterized by a minimal to slight increase in cellularity with predominance of the erythroid lineage. Neutrophil granulocytopoiesis was prominent and left-shifted and small to medium-sized megakaryocytes without maturation defects were scattered throughout the bone marrow. There was an increased number of eosinophils, marked perivascular plasmacytosis, histiocytic reticular cells with accumulated cell debris and many iron-laden macrophages. Contrasting this appearance in SP our 39 patients with initial-early stage PV revealed a hypercellular bone marrow with trilineage proliferation (pan-myelosis) showing confluent sheets of erythropoiesis and loose clusters of megakaryocytes. Megakaryocytopoiesis was characterized by a pleomorphous appearance, i.e. giant cells were lying adjacent to small ones, but lacked an obvious cytologic abnormality. There was usually no prominent inflammatory reaction of the interstitial compartment. In ten patients lymphoid nodules were found, but no conspicuous iron deposits and in six patients a borderline to minimal increase in reticulin fibers was present. Following stepwise discriminate analysis of histologic features a set of parameters emerged including increase in megakaryocyte size, perivascular plasma cells, overall bone marrow cellularity and cellular debris. This pattern exerted a significant impact on separation (Wilks' lambda statistics = 0.110, p < 0.0001) of early stage PV from SP. Most patients with SP had an underlying bronchopulmonary condition, frequently associated with heavy smoking or rarely renal pathology. In addition to the histopathologic features, splenomegaly, thrombocyte count, LDH, LAP and erythropoietin levels proved to be different in the two groups of patients. INTERPRETATION AND CONCLUSIONS: Initial-early PV is characterized by a specific pattern of bone marrow histopathology. Clinical features of distinctive impact include splenomegaly, thrombocyte count, LDH, LAP and in particular erythropoietin level. Taking these clinical and histologic findings into consideration, reactive-secondary causes of polycythemia (SP) are clearly distinguishable from autonomous ones (PV).

Adult↗
PubMed2001

The role of ifosfamide in the treatment of relapsed and refractory lymphoma.

Ifosfamide is an alkylating agent with proven efficacy in the treatment of solid tumours and malignant lymphomas. Because it causes only mild to moderate myelosuppression, ifosfamide is often used in combination regimens with other agents. Ifosfamide has been mainly used in therapy of lymphoma as a component of salvage regimens, but high-dose ifosfamide is also effective in the mobilization of peripheral stem cells for treatment of patients with relapsed or refractory lymphoma with regimens containing autologous stem cell transplantation. Based on promising data with a new combination regimen containing idarubicin, etoposide and ifosfamide (IIVP-16) in patients with poor-risk non-Hodgkin's lymphoma, we have performed a phase II study using DIZE (dexamethasone 20 mg i.v. days 1-4, idarubicin 8 mg/m2 i.v. days 1 + 2, ifosfamide 1.0 g/m2 continuous infusion (c.i.) days 1-4, and etoposide 160 mg/m2 c.i. days 1-4) in patients with relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma. In 43 evaluable patients, the response rate was 58%, including 11 complete remissions (CR) and 14 partial remissions (PR). The mean duration of response was 8 months (1-30). Myelosuppression was generally mild with mean duration of neutropenia < 1000/microL of 2.5 days (range 0-18) and thrombocytopenia < 25,000/microL of 1.5 days (0-17). Thus, DIZE is an effective and safe regimen for pretreated patients with aggressive lymphoma. These results appear to compare favourably with other salvage regimens such as IMVP-16 or DHAP. In conclusion, salvage regimens containing ifosfamide can play an important role in patients who are not eligible for high-dose chemotherapies. Moreover, ifosfamide might also have a role in reducing tumour burden and selecting those patients who qualify for HDCT.

Antineoplastic Agents, Alkylating↗
PubMed2000

Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction.

Somatic hypermutation specifically modifies rearranged immunoglobulin (Ig) genes in germinal center (GC) B cells. However, the bcl-6 gene can also acquire somatic mutations during the GC reaction, indicating that certain non-Ig genes can be targeted by the somatic hypermutation machinery. The CD95 gene, implicated in negative selection of B lymphocytes in GCs, is specifically expressed by GC B cells and was recently identified as a tumor suppressor gene being frequently mutated in (post) GC B cell lymphomas. In this study, the 5' region (5'R) and/or the last exon coding for the death domain (DD) of the CD95 gene were investigated in naive, GC, and memory B cells from seven healthy donors. About 15% of GC and memory, but not naive, B cells carried mutations within the 5'R (mutation frequency 2.5 x 10(-4) per basepair). Mutations within the DD were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway.

Apoptosis↗
PubMed2000

Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells.

Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) are thought to be derived from preapoptotic germinal center B cells. However, little is known about the transforming events rescuing the precursor of the H/RS cells from apoptosis. Given the importance of CD95 (Apo-1/Fas)-mediated apoptosis for negative selection within the germinal center, single micromanipulated H/RS cells from 10 cases of cHD were analyzed for somatic mutations within the CD95 gene. Three clonal mutations within the 5' regions were amplified from single H/RS cells in one case. From H/RS cells of another case, two mutations within the last exon coding for the death domain were detected. About half of these H/RS cells carried a monoallelic stop-codon; the remaining tumor cells harbored a monoallelic replacement mutation. Both mutations likely impair CD95 function. Because all these H/RS cells also bear clonal mutations inactivating the IkappaB alpha gene, the IkappaB alpha mutations occurred earlier than those of the CD95 gene in the sequence of transforming events leading to cHD. In conclusion, somatic mutations of the CD95 gene occur in a fraction of cHD cases and may favor the escape of the precursor of the H/RS clone from apoptosis.

Adult↗
PubMed2000

An entirely humanized CD3 zeta-chain signaling receptor that directs peripheral blood t cells to specific lysis of carcinoembryonic antigen-positive tumor cells.

Recombinant T-cell receptors with antibody-like specificity for tumor-associated antigens are successfully used to direct the cytolytic activity of T cells toward tumor cells. Clinical application, however, needs to comply with the low immunogenicity of the recombinant receptor, efficient gene transfer into peripheral blood T cells, and enrichment of receptor-grafted cells. Here, we address these issues and describe an entirely humanized immune receptor for use in adoptive immunotherapy of colorectal carcinoma. The receptor consists of a single-chain antibody (scFv) binding domain specific for carcinoembryonic antigen (CEA), the IgG hinge and CH2/CH3 (Fc) joining region, and the transmembrane and intracellular CD3 zeta signaling chain. To express the receptor in peripheral blood T cells, both GALV envelope and MuLV 4070A pseudotyped retrovirus turned out to be equally efficient, with transduction efficiencies of about 5% to 40%, depending on the lymphocyte donor. Furthermore, receptor-grafted T cells could be 2- to 6-fold enriched by magnetic activated cell sorting, utilizing an antibody directed to the extracellular IgG domain of the receptor. Upon co-culture with CEA(+) tumor cells, receptor-grafted T cells are specifically and efficiently activated to cytolysis and IFN-gamma secretion, demonstrating their feasibility for the adoptive immunotherapy of CEA(+) carcinomas.

Antibody Specificity↗
PubMed2000

European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes.

Paraffin blocks and clinical data from 521 patients with lymphocyte predominance Hodgkin disease (LPHD) diagnosed between 1970 and 1994 were collected from 16 European and United States oncological centers to establish the pathologic and clinical characteristics of a large patient cohort, to determine how frequent T-cell-rich large B-cell lymphoma (TCRLBCL) is among LPHD, and to find differential diagnostic criteria distinguishing between the 2 lymphoma categories. For this purpose, conventionally and immunohistologically stained sections were reviewed by a panel of hematopathologists. The diagnosis of LPHD was confirmed in only 219 of the 388 assessable cases (56.5%). This low confirmation rate was due mainly to the presence of a new variant of classical Hodgkin disease (CHD), which resembled, in terms of nodular growth and lymphocyte-richness, nodular LPHD and, in terms of the immunophenotype of the tumor cells, CHD and was designated nodular lymphocyte-rich CHD (NLRCHD). The nodules of LRCHD consisted-as in nodular LPHD-predominantly of B cells but differed from those present in LPHD in that they represented expanded mantle zones with atrophic germinal centers. Clinically, patients with LPHD and NLRCHD showed similar disease characteristics at presentation but differed in the frequency of multiple relapses and prognosis after relapse. Patients with LPHD and NLRCHD clearly differed from patients with CHD with nodular sclerosis or mixed cellularity, as they presented with an earlier disease stage and infrequent mediastinal involvement. As 97% of the LPHD cases showed a complete or partial nodular growth pattern, their differentiation from TCRLBCL was a rare problem in the present series. (Blood. 2000;96:1889-1899)

Adolescent↗
PubMed2000

["Lean management" in hospitals: potentials and limitations].

Little attention has yet been payed on establishing modern and competitive organizational structures in German hospitals. In this paper, we attempt to apply elements of lean management to the work of physicians working in an inpatient setting. Traditional ways of communication and their disadvantages are discussed. These include loss of motivation, bureaucratic structures and a lack of interdisciplinary cooperation. Using Maslow's theory of motivation, possible improvements are discussed, such as the reduction of restrictive job characteristics, an increase of physicians' spheres of competence and the use of their innovative potentials. These suggestions are explained using practical examples. The aim of the study is to contribute to quality management in hospitals by increasing personal responsibilities according to lean management.

Germany↗
PubMed2000

Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group.

To determine prognostic factors and treatment outcome, patients with primary progressive Hodgkin lymphoma (HD) registered in the database of the German Hodgkin Lymphoma Study Group (GHSG) were analyzed retrospectively. Detailed records from randomized prospective multicenter trials performed between 1988 and 1998 of 3807 patients recruited in these trials were reviewed. The median age of the 206 patients available was 34 years (range, 16-71). Fifty-seven patients (28%) in intermediate stage and 149 patients (72%) in advanced stage developed progressive disease (PD). One hundred and fifty-three patients (74%) were treated with salvage chemotherapy, 47 patients (23%) with salvage radiotherapy, and 6 patients (3%) did not receive any therapy due to rapid PD. Seventy patients (34%) were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. The 5-year freedom from second failure (FF2F) and overall survival (OS) for all patients were 17% and 26%, respectively. The 5-year FF2F and OS for patients treated with HDCT were 31% and 43%, respectively. In multivariate analysis low Karnofsky performance score at the time of progression (P <.0001), age above 50 years (P =.019), and failure to attain a temporary remission on first-line treatment (P =.0003) were significant adverse prognostic factors for OS. Patients with none of these risk factors had a 5-year OS of 55% compared with 0% for patients with all 3 of these unfavorable prognostic factors. Although HDCT is a reasonable option for selected patients with primary progressive HD, the majority did not receive HDCT. Interestingly, salvage radiotherapy gave promising results in patients with localized PD. (Blood. 2000;96:1280-1286)

Adolescent↗
PubMed2000

[Long-term toxic sequelae of the treatment of Hodgkin's disease].

In recent years, continuous optimization of therapy has decisively improved the prognosis of Hodgkin's disease. However, this improvement in overall survival has also led to an increase in several possible late effects which the clinician must be aware of. Due to the appearance of chronic fatigue symptoms, cardiopulmonary problems, hypothyreosis and damage to the gonadal system including azoospermia and ovarian insufficiency, the mostly young patients often suffer a persistent reduction in quality of life. In addition, the increased incidence of second malignancies following successful primary treatment presents a considerable problem. While complete remission and prolonged survival were previously the main objectives in the therapy of malignant lymphomas, reduction or avoidance of toxicity is now becoming more and more central. This development has led to the increasing importance of late sequelae and quality of life as endpoints in modern therapy trials in oncology.

Adult↗
PubMed2000

Spontaneous regression of HIV associated T-cell non-Hodgkin's lymphoma with highly active antiretroviral therapy.

A subcutaneous, T-phenotypic anaplastic large cell lymphoma (CD30/Ki1-positive, EBV positive) was diagnosed in a HIV-infected bisexual man. Without chemotherapy the patient had a sustained long-term remission of this tumor (more than three years) after the initiation of highly active antiretroviral therapy. By PCR analysis of T-cell receptor beta gene rearrangements the tumor was found to be oligoclonal. Improvement of cellular immune function by antiretroviral therapy is the only recognizable factor which may have led to tumor remission. This hypothesis is supported by parallels to EBV associated polyclonal lymphoproliferation in allogeneic transplantat recipients where regression of lymphoma can be induced by reducing immunosuppressive therapy.

Anti-HIV Agents↗