Cooperative trials of Hodgkin's lymphoma in the Federal Republic of Germany.
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Biomedical subjects
Publications and source records attributed to U Rühl.
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A female patient is described with highly echogenic splenic nodes found in routine diagnosis. After CT and angiography a splenectomy was carried out. The histological finding of sea blue histiocytes and the extended family history suggested a subtype of Niemann-Pick disease. Biochemical lipid analysis of the spleen confirmed Type-C Niemann-Pick disease. Niemann-Pick disease and its subtypes are discussed briefly.
In a national multicenter trial in the Federal Republic of Germany, patients with Hodgkin's lymphoma in stages I, II and IIIA presenting with large mediastinal tumor (MT), extranodal (E), or massive spleen (S) involvement received a combined modality treatment with 2x (COPP + ABVD) followed by 20 or 40 Gy EF radiation (HD1 protocol). By October 1987, 89 patients aged 15-60 years had finished therapy and were evaluable for response. Of these 74 (83%) achieved complete remission (CR). After 3 years freedom from treatment failure (FFTF) is 80% (+/- 8%, 95% confidence interval) and survival (SV) 92% (+/- 6%, 95% confidence interval). In a univariate and multivariate analysis using FFTF as endpoint we could not identify any particularly prominent prognostic risk factor among the following examined: stage, constitutional symptoms, MT, E stage, S involvement, age, sex, histology, laparotomy, erythrocyte sedimentation rate (ESR), leukocytes, lymphocytes, and alkaline phosphatase (AP). These data suggest that the inclusion criteria have selected a fairly homogeneous group of patients with respect to prognosis. In a separate trial (HD3 protocol) patients in stages IIIB/IV received induction chemotherapy with 3x (COPP + ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or further chemotherapy (COPP + ABVD). Patients not in CR received salvage therapy (40Gy in the case of persisting nodal disease, or else 4x CEVD chemotherapy). By October 1987, 137 patients had finished therapy and were evaluable for response. Of these 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. After 3 years FFTF is 56% (+/- 10%, 95% confidence interval) and SV 84% (+/- 8%, 95% confidence interval). Univariate and multivariate prognostic risk factor analyses were performed using FFTF as endpoint. Sex, age, stage, splenectomy, bone marrow, and liver and bone involvement had no prognostic impact. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml each appeared as significant prognostic factors (P less than 0.01; relative risk, 2.3). The two parameters can be combined to separate two groups (A: ESR and AP both low; B: ESR and/or AP high) which differ significantly for FFTF (P less than 0.001) and survival (P less than 0.04). The decision for risk-adapted treatment requires identification of groups of patients in the frame of specified diagnostic and therapeutic strategies.(ABSTRACT TRUNCATED AT 400 WORDS)
Untreated patients with Hodgkin's lymphoma in stages I-IIIA with risk factors (large mediastinal mass, massive splenic involvement, extranodal disease) were entered into the HD1 protocol and received a combined chemo-radiotherapy [2 X (COPP + ABVD) + 40 Gy extended field irradiation (EF) vs 2 X (COPP + ABVD) + 20 Gy EF]. Patients in stages IIIB/IV (HD3 protocol) received induction chemotherapy [3 X (COPP + ABVD)] and were randomized into consolidation by radiotherapy [20 Gy involved field irradiation (IF)] vs chemotherapy [1 X (COPP + ABVD)]. Seventy-three of 89 evaluable patients (82%) treated according to the HD1 protocol achieved a complete remission. Freedom from progression and survival of patients in stages I-IIIA with risk factors treated according to HD1 were no worse than those of patients in stages I and II without risk factors who received only radiotherapy. Eighty-six of 137 patients (63%) treated according to the HD3 protocol achieved complete remission after induction chemotherapy with COPP + ABVD. This is significantly better than the 31% complete remission rate observed in a previous pilot study with COPP alone (P less than 0.01). Including salvage therapy (radiotherapy in case of persisting nodal disease; chemotherapy with 4 X CEVD in case of persisting disseminated disease), a total of 76% complete remissions in stages IIIB/IVAB were achieved. A high erythrocyte sedimentation rate (greater than 80 mm h-1) was the most significant risk factor for achieving freedom from progression.
In a national multicentre trial in the FRG patients with Hodgkin's lymphoma in stages CS/PS III B/IV were entered into the HD 3 protocol and received induction chemotherapy with 3 x (COPP + ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or chemotherapy (COPP + ABVD). Patients not in CR received salvage therapy (40 Gy in case of persisting nodal disease, else 4 x CEVD chemotherapy). Between July 1983 and May 1987 230 untreated patients aged 15 to 60 qualified for this HD 3 protocol. This analysis is based on the first 137 patients evaluable for response. Of these, 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. Univariate and multivariate prognostic risk factor analyses were performed using freedom from treatment failure (FFTF) as endpoint. Sex, age, splenectomy, bone marrow, liver and bone involvement had no prognostic impact nor had stage according to the Ann Arbor classification. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml appeared as significant risk factors (p less than 0.01, relative risk 2.3). The two parameters were not independent. Comparing a group A (ESR less than or equal to 80 and AP less than or equal to 230) versus a pooled group B (ESR greater than 80 and/or AP greater than 230) increased the difference (p less than 0.001, relative risk of 2.8) which was also significant for survival (p less than 0.04).
Between July 1983 and May 1987 143 untreated patients with Hodgkin's lymphoma in stages I-IIIA with risk factors qualified for the HD1 protocol, and 230 patients in stages IIIB/IV qualified for HD3. Patients in HD1 received a combined chemo-radiotherapy (2 x COPP + ABVD + 20 Gy EF vs. 40 Gy EF). Patients in HD3 received induction chemotherapy (3 x COPP + ABVD) and were randomized into consolidation by radiotherapy (20 Gy IF) vs. chemotherapy (1 x COPP + ABVD). In HD1, 73 of 89 evaluable patients (82%) achieved a complete remission. The survival of patients in stages I-IIIA with risk factors treated according to HD1 is as good as the survival of patients in stages I and II without risk factors. In HD3, 86 of 137 patients (63%) achieved complete remission after induction chemotherapy with 3 x COPP + ABVD. This is significantly better than the 31% complete remission rate observed in a pilot study with COPP alone (p less than 0.01). Including salvage therapy (radiotherapy in case of persisting nodal disease; chemotherapy with 4 x CEVD in case of persisting disseminated disease), a total of 76% complete remissions in stages IIIB/IVAB were achieved. An ESR greater than 80 mm/h was the most significant single risk factor in stages IIIB/IV for induction of CR and freedom from progression.
Between July 1983 and September 1986 358 untreated patients with Hodgkin's lymphoma qualified for the protocols HD1 (stages I to IIIA with risk factors), HD2 (stage IIIA), and HD3 (stages IIIB and IVAB). Patients in HD1 received a combined chemo-radiotherapy (2 X COPP/ABVD + 40 Gy EF vs. 2 X COPP/ABVD + 20 Gy EF). Patients in HD2 were randomized into radiotherapy (TNI 40 Gy) vs. combined chemo-radiotherapy (2 X COPP/ABVD + 20 Gy IF). Patients in HD3 received induction chemotherapy (3 X COPP/ABVD) and were randomized into consolidation by radiotherapy (20 Gy IF) vs. chemotherapy (1 X COPP/ABVD). In HD1, 51 out of 65 evaluable patients (78%) achieved a complete remission. The survival of HD1 patients is as good as the survival of patients in stages I and II without risk factors. In HD3, 58 out of 93 patients (62%) achieved complete remission after induction chemotherapy with COPP/ABVD. This is significantly better than the 31% complete remission rate observed in a pilot study with COPP alone (p less than 0.01). Including salvage therapy (radiotherapy in case of persisting nodal disease; chemotherapy with 4 X CEVD in case of persisting disseminated disease), a total of 71% complete remissions in stages IIIB/IVAB were achieved. The progression-free survival of HD3 patients who received consolidation therapy is significantly longer than of patients who refused consolidation therapy.
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The substructure of the tubulin molecule was studied by limited proteolysis and high affinity polyclonal antibodies specific for alpha or beta-tubulin. Brief enzymatic cleavage separates the tubulin monomer into two domains of unequal size. Trypsin splits alpha-tubulin into components with Mr values of 36 X 10(3) and 14 X 10(3), chymotrypsin splits beta-tubulin into 31 X 10(3) Mr and 20 X 10(3) Mr fragments. The cleavage occurs at Arg339 (alpha) and Tyr281 (beta), as determined by sequencing several N-terminal residues of the small domains, i.e. the small domains are the C-terminal parts of the molecules, the large ones are the N-terminal parts. There is a second cleavage site of chymotrypsin within Mr 10(3) to 2 X 10(3) of the C terminus of beta-tubulin. The fragments can be separated only under denaturing conditions. They copolymerize into microtubules and incomplete microtubule walls joined by a wall junction, forming S-shapes and hooks in cross-section. The antibodies were raised against electrophoretically purified tubulin monomers. Those produced with alpha-tubulin are directed predominantly against the large domains; they are either specific for alpha-tubulin or cross-react with the large domain of beta-tubulin. Conversely, antibodies raised against beta-tubulin are directed predominantly against the small domains (beta-specific and beta-cross-reacting fractions). Thus the antibodies discriminate not only between the tubulin chains but also between the domains generated by the proteases. The complementary antigenicity correlates well with the stability of the domains. Potential sites of antigenic determinants are located within the polypeptide chains by comparing theoretical predictions with the pattern of immunoblots. Two epitopes of the alpha-cross-reacting antibodies have been located approximately. One is very close to the C terminus (within about 20 residues), the other is close to the N terminus (within about Mr 8 X 10(3) ). The epitope of the beta-cross-reacting antibody is also located within Mr 12 X 10(3) of the C terminus. The antibodies prevent microtubule assembly and cause disassembly of preformed microtubules. A variety of breakdown products are observed by electron microscopy. They include fibres of about 10 nm width, sheets with undefined substructure, thick tapered fibrous bundles and wispy filaments.(ABSTRACT TRUNCATED AT 400 WORDS)
Yoshida sarcoma cells, which have the same growth characteristics as ascites cells in the mouse and in cell suspension, were partially synchronized in vitro by means of excess thymidine (0.1 mM thymidine for 18 h). The growth of non-synchronized cultures was inhibited by irradiation, the degree depending on the dose of radiation. At the same time, a 50% inhibition in vivo (380 rad) and in vitro (480 rad) was determined. The incorporation of 3H-thymidine into the DNA is inhibited by 10-32%, depending on the radiation dose. The mitotic index decreases 2 h after irradiation by a dose-dependent amount. A mitotic maximum develops later; the delay is dose-dependent. Partially synchronized cells were irradiated in the G1/S-, G2-, and G1-phase. As compared to the 3H-thymidine incorporation and the mitotic index there were no significant differences between the cultures which were irradiated in the individual phases of the non-synchronized control cultures. The cultures which were irradiated in the G2-phase, however, showed a significantly reduced growth in vivo after 48 h. If the cells were cultured for more than 72 h after irradiation, the differences between the cultures irradiated in the G2-phase and the other phases were reduced.
The authors studied the survival rates of the P2 and P3 patients within a group of 287 patients suffering from carcinomas of the urinary bladder who had been treated by urologic operation and radiotherapy. A differentiation was made between the surgical methods transurethral resection (TUR), bladder wall resection and cystectomy. P2 patients presented significantly higher three-year survival rates after bladder wall resection or cystectomy (10/17) than after TUR (7/23). In stage P3, no differences were found with regard to the surgical method. The results are discussed and compared to those communicated in literature.
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Clinical data of 116 patients with chronic lymphocytic leukaemia (CLL) and of 114 patients with lymphoplasmacytic/lymphoplasmacytoid lymphoma (synonym: LP immunocytoma, IC) as diagnosed according to the Kiel classification were compared. This interim evaluation of a prospective multicenter study of the Kiel Lymphoma Study Group characterizes IC the less favorable lymphoma entity as evidenced by a more rapid lymph node enlargement, by a higher incidence of constitutional symptoms and of marked anaemia, and by a higher percentage of patients requiring early treatment. In addition, in IC autoimmune haemolytic anaemia was detected in 11.2% of investigated patients as compared to none of the patients with CLL, and monoclonal gammopathy was disclosed in 34.2% of investigated patients as compared to only three patients with CLL who could be, however, unrecognized cases of IC. Actuarial survival data after a follow-up period of 40 months are in favor of an overall better prognosis of patients with CLL than of patients with IC.
Clinical data of 48 patients with centrocytic, 83 patients with centroblastic/centrocytic and 64 patients with centroblastic lymphoma who had entered a prospective multicenter study of the Kiel Lymphoma Study Group since October 1975 were compared. Advanced (stage IV) disease at time of diagnosis, predominantly due to bone marrow infiltration, was most frequent in centrocytic (69% of patients) and in centroblastic/centrocytic (51% of patients) lymphomas as compared to only 28% of patients with centroblastic lymphoma. High survival probability of patients with localized centrocytic and centroblastic/centrocytic lymphomas after radiotherapy, contrasting with a worse prognosis of corresponding patients with centroblastic lymphoma, is compatible with the classification of these lymphoma entities as neoplasias of low-grade malignancy. However, as shown by this prospective and previous retrospective trials overall survival probability of patients with advanced centrocytic lymphoma was inferior to that observed in corresponding patients with centroblastic/centrocytic lymphoma. These findings suggest the possibility that patients with advanced centrocytic lymphoma occupy an intermediate position between typical low-grade and typical high-grade malignant non-Hodgkin lymphomas.
Comparison of clinical data of 64 patients with centroblastic lymphoma, 55 patients with immunoblastic lymphoma and 31 patients with lymphoblastic lymphoma not only confirmed the original assumption of high-grade malignancy as proposed by the concept of the Kiel classification but also demonstrated distinct clinical differences, particularly between lymphoblastic lymphoma and the two other entities. Rapid lymph node enlargement as well as steep fall of survival curves within the first year after diagnosis were common characteristics. Bimodal age distribution, predominance of males and early generalization of disease were typical features of lymphoblastic lymphoma; elderly patients and patients with the unclassified subtypes of lymphoblastic lymphoma exhibited the worst prognosis. Whereas patients with centroblastic and immunoblastic lymphomas showed similar distribution of age, sex and initial stage of disease, patients with immunoblastic lymphoma presented more frequently with a reduced performance status and showed a poorer response to radio- and chemotherapy resulting in a worse prognosis discernible after the first year of follow-up. Generalization during course of the disease was significantly more frequent in immunoblastic than in centroblastic lymphoma.
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Results of radiotherapy (42 MeV-Beta-tron) on 93 patients with esophageal cancer treated between 1969 and 1976 are reported and compared with those in the literature (on orthovoltage- and telecobalt-therapy). Complete remissions occured in 29%; the one -- and two-year-survival-rate for all 93 patients was 38% and 24% respectively, and for patients with complete remission 74% and 44% respectively. Although there was improvement in complete remission and short term survival compared to that reported in the literature, the five-year-survival-rate (only about 5% of patients) showed no significant improvement.