Klaus Wilms

Malignant lymphomas of the upper gastrointestinal tract. Results of a prospective study in 103 patients

Background. There is a discrepancy between the incidence of gastrointestinal involvement by malignant lymphomas, as established in postmortem studies, and the rareness of the corresponding clinical diagnosis.

Differences in endoscopic and clinicopathological features of primary and secondary gastric non-Hodgkin's lymphoma ☆ ☆☆ ★ ★★

BACKGROUND Lymphomatous neoplasia of the stomach is initially seen either as primary gastric B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) or as nodal non-Hodgkin s lymphoma (NHL) secondarily involving the GI tract. One hundred seventy-six patients with primary gastric NHL (low grade, n = 65; high grade, n = 111) and 29 with secondary gastric NHL (low grade, n = 19; high grade, n = 10) were studied to evaluate whether differences in pathogenesis are associated with distinct clinical and endoscopic features. METHODS Clinical features, tumor size, localization, and growth pattern were analyzed by means of esophagogastroduodenoscopy; grading was determined with histologic examination. RESULTS The analysis of various clinical symptoms and endoscopic findings revealed a relationship between the occurrence of abdominal pain, vomiting, and unifocal growth pattern with an affiliation to the group with primary gastric NHL (p < 0.001), whereas tumor localization in the gastric fundus was predominantly found in secondary gastric NHL (p < 0.001). An equation has been generated that may help to predict affiliation to primary or secondary gastric NHL with an accuracy of 96%. CONCLUSIONS Our results indicate that careful pretreatment analysis of clinical and endoscopic findings may be helpful in the diagnosis of primary or secondary gastric involvement by NHL, although reliable discrimination still requires histologic verification.

γ/δ Receptor-expressing T-cell clones from a cutaneous T-cell lymphoma suppress hematopoiesis

SummaryRecently we described a cutaneous T-cell lymphoma expressing the γ/δ T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patients bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating γ/δ T-lymphoma cells we established T-cell clones bearing the γ/δ T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these γ/δ T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of α/β T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-γ,since it was detectable in high amounts in the SN of these γ/δ T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN-γ antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-γ, which is secreted in high amounts from γ/δ T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.

Immunohistology of Graft-Versus-Host Disease Mediated Skin Lesions and its Correlation to a Large Granular Lymphocyte Surface Phenotype and Function*

SummarySkin lesions of five patients presenting with acute and chronic Gvhd after bone marrow transplantation were analyzed on frozen tissue sections using selected monoclonal antibodies against various T-cell determinants and HLA-antigens in order to define immunological phenomena characteristic for cutaneous damage seen in various GvHD states. Four of these patients showed marked increase of a certain T-cell subpopulation positive for HLA-D region products in the upper dermis. A considerable number of these T-cells seemed to show cytotoxic reactivity on the basal cell layers of the epithelium and to correlate with the appearance of an OKT4−, OKT8+, HLA-DR+ T-cell subset in the peripheral blood presenting natural killer (NK) cell like activity on various targets. Ia antigen expression on keratinocytes observed in one patient with chronic GvHD could result from a rapid and irregular turnover of epidermal cells affected by continuous stimuli of these T-cells. Further immunological studies on skin biopsies of patients with different states of GvHD and autoimmune diseases may lead to valuable diagnostic criteria for an early and accurate assessment of various skin lesions in patients after bone marrow transplantation.

Tissue-specific inhibitor of lymphocyte proliferation extracted and purified from calf spleen. Biological and chemical properties.

ZusammenfassungEin teilweise gereinigter Kalbsmilzextrakt — bisher als gewebespezifischer, artunspezifischer, reversibel und nicht toxisch wirkender (chalonähnlicher ?) Inhibitor der Lymphozytenproliferation beschrieben —wurde weiter charakterisiert. Unsere Ergebnisse zeigen, daß der Inhibitor in der G1-phase ansetzt. Die inhibierende Aktivität ist hitze-, trypsin- und ribonukleaseresistent. Es handelt sich offensichtlich um ein saures Molekül, das nicht an Ribonukleinsäure gebunden ist. Diese Eigenschaften werden mit den Eigenschaften von gewebespezifischen Inhibitoren der Lymphozytenproliferation anderer Autoren verglichen.SummaryA partly purified calf spleen extract which inhibits lymphocyte proliferation in a tissue-specific, species-nonspecific, nontoxic, and reversible way, and may thus contain a chalone-like activity, has been further characterized. Our results show that the inhibitor works in G1-phase. The activity is resistant to heat, trypsin- and ribonuclease-treatment. It appears to be an acidic molecule and it does not appear to contain ribonucleic acid. These properties are compared to the characteristics which have been described for tissue-specific inhibitors of lymphocyte proliferation by other authors.

Granulocytic differentiation of HL-60 cells is not regulated by DNA de novo methylation

SummaryDNA cytosine methylation and transcription of specific genes are inversely correlated. In granulocytic differentiation of HL-60 cells there is a distinct down regulation of the c-myc protooncogene expression, which is probably a causal mechanism. With differentiation of HL-60 cells we found no restriction enzyme fragment length polymorphism (RFLP) within the c-myc proto-oncogene, which indicates that there is no loss of regulatory elements (e.g., TATAA boxes within the first exon). Furthermore, we found no de novo methylation in this region. Methylation of other DNA regions, which could influence c-myc expression, is also not necessary for differentiation, as was shown by inhibition of DNA methylase. L-Ethionine and S-adenosyl-L-homocysteine are both potent inhibitors of DNA methylase and do not influence proliferation of HL-60 cells, as shown by FACS analysis.

Effect of human fibroblast interferon on natural killer cell activity: stimulation in vitro and inhibition in vivo.

SummaryThis paper describes the influence of human fibroblast interferon (IFN-β) on the cytotoxic activity of natural killer cells (NK) in vitro and in vivo using the blood of healthy donors and myeloma patients. IFN-β stimulates NK activity against all target cells tested in vitro in a dose-dependent way up to 250% of pretreatment values. At higher IFN concentrations, stimulation returned to baseline values. Stimulation was most pronounced in the lowest lymphocyte to target cell ratio. 1- to 2-h preincubation of effector cells with IFN was enough to achieve maximal stimulation. The effector cells of IFN-treated myeloma-patients, or patients with herpes zoster, showed a clear reduction of toxicity against all cells tested during the first infusion, as compared to the pretreatment values.ZusammenfassungDie zytotoxische Aktivität der natürlichen Killerzellen (NK) wurde bei gesunden Spendern und Patienten mit Plasmocytom unter dem Einfluß von humanem Fibroblasteninterferon (IFN-β) in vitro und in vivo gemessen. IFN-β steigerte die NK-Aktivität gegenüber allen getesteten Zielzellen in vitro dosisabhängig bis zu 250% des Ausgangswertes. Bei weiterer Erhöhung der IFN-Konzentration nahm die Stimulation wieder ab. Die Stimulation war bei niedriger Lymphozyten-Zielzell-Relation am deutlichsten zu sehen. Eine 1- bis 2stündige Präinkubation der Effektorzellen mit Interferon reichte aus, um die maximale Stimulation zu erreichen. Wurde der Einfluß von IFN-β auf NK-Zellen in vivo im Blut von Interferon-behandelten Patienten mit Plasmocytom gemessen, zeigte sich eine deutliche Verminderung der Toxizität gegenüber allen getesteten Zielzellen während der ersten Infusion im Vergleich mit dem Ausgangswert vor Interferon-Therapie.

Therapieergebnisse bei Lymphogranulomatose im Stadium IIIB und IV mit einem modifizierten MOPP-Schema

SummaryIn a retrospective study 80 patients with Hodgkins disease of stage III B (n = 32) and IV (n = 48) were investigated, who had been treated with a modified MOPP regimen. 28 patients (35%) were previously untreated. A complete remission was reached in 51 patients, a partial remission in 16, and 13 patients failed to respond. 16 patients had died in the observation period. Complete remissions were twice as frequent with 90% in stage III as compared with 45% in stage IV. The group of patients surviving 4 years was 92% in stage III and 62% in stage IV.ZusammenfassungIm Rahmen einer retrospektiven Studie wurden 80 Patienten mit Lymphogranulomatose im Stadium III B (n = 32) und IV (n = 48) untersucht, die mit einem modifizierten MOPP-Schema behandelt worden waren. Nur 28 Patienten (35%) waren nicht vorbehandelt. 51 Patienten erreichten eine Vollremission, 16 Kranke eine Teilremission, bei 13 Patienten versagte die Chemotherapie. 16 Kranke verstarben im Beobachtungszeitraum. Vollremissionen waren im Stadium III mit 90 % doppelt so häufig wie im Stadium IV mit 45 %. Der Anteil der Patienten, die 4 Jahre überlebten, betrug im Stadium III 92% und im Stadium IV 62%.In a retrospective study 80 patients with Hodgkins disease of stage III B (n = 32) and IV (n = 48) were investigated, who had been treated with a modified MOPP regimen. 28 patients (35%) were previously untreated. A completed remission was reached in 51 patients, a partial remission in 16, and 13 patients failed to respond. 16 patients had died in the observation period. Complete remissions were twice as frequent with 90% in stage III as compared with 45% in stage IV. The group of patients surviving 4 years was 92% in stage III and 62% in stage IV.

Nuclear Topoisomerase II Activity Changes During HL-60 Leukemic Cell Differentiation: Alterations in Drug Sensitivity and pH Dependency

We have studied the effect of dimethyl-sulfoxide(DMSO)-induced granulocytic differentiation on the sensitivity of HL-60 cells to various cytotoxic topoisomerase II inhibitors: (i) undifferentiated HL-60 cells are highly sensitive to etoposide, while differentiated HL-60 cells are 700-1000 fold resistant to etoposide, (ii) undifferentiated HL-60 are 50-100 fold resistant against 4-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) when compared to the differentiated HL-60 cells, (iii) the addition of mAMSA to the medium inhibits granulocytic differentiation of HL-60 cells. This change in resistance pattern is probably due to an alteration of topoisomerases since distinctive iso-activites of topoisomerase can be discriminated on the basis of the pH profile, which alters markedly during differentiation. In an etoposide-resistant HL-60 cell line we found a reduced topoisomerase activity at pH 7.8/7.9. This topoisomerase iso-activity is obviously involved in etoposide cytotoxicity.

Bone marrow transplantation for acute leukemia in second or subsequent remission.

SummaryTwenty-one patients with acute leukemia in second to fifth remission were treated with bone marrow transplantation: 19 patients with transplants from HLA-matched siblings and two with transplants from identical twins. Twelve patients survived from 15 to 1,625 days after transplantation: six of 11 in the ALL group and six of 10 in the AML group. Recurrence of leukemia after marrow transplantation occurred in five patients. The cause of death in five patients was infection, in two patients combined with graft-versushost disease. Long-term disease-free survival can probably be achieved in 30%–35% of all patients with acute leukemia who receive a marrow transplant in second or subsequent remission.