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Notes: Abstract Purpose: At present, treatment results for patients withadvanced-stage Hodgkin's disease remain unsatisfactory. Standard chemotherapyM(C)OPP (nitrogen mustard (cyclophosphamide), vincristine, procabazine, andprednisone), ABVD (adriamycine, bleomycine, vinblastine, and dacarbacine) orM(C)OPP/ABVD +/− radiotherapy fail to achieve long-term completeremission in 35% to 50% of these patients. The BEACOPP(bleomycin, etoposide, adriamycine, cyclophosphamide, vincristine,procarbazine, and prednisone) regimen was developed to improve treatmentresults by dose intensification achieved by reduced duration of treatment(time intensification) and addition of etoposide. Patients and methods: Thirty untreated patients with advancedHodgkin's disease stage IIB–IV according to the Ann Arbor classificationwere treated with the time intensified BEACOPP regimen. Each patient wasscheduled to receive eight cycles of chemotherapy with consolidatingradiotherapy to sites of initial bulk disease and to residual tumor remainingafter chemotherapy. Results: All patients were evaluable for assessment of toxicity,treatment response, freedom from treatment failure (FFTF) and survival (SV).Of 30 treated patients, 29 patients received the intended eight cycles ofBEACOPP. One patient, in clinical CR, terminated the chemotherapy at his ownrequest after six cycles and is at this time, 48 months after the end oftreatment, in complete remission. Toxicity was tolerable with WHO grade 3/4leucopenia in 28% of chemotherapy cycles and one severe (WHO grade 3)infection. No treatment-related death occurred. Cycles could generally begiven on schedule. Complete remission (CR) was achieved in all but twopatients (93%). At present, only one patient has relapsed. At a medianfollow-up of 40 months, FFTF-rate is 89% (lower confidence limit:80%). One patient died due to progressive disease. Conclusion: The BEACOPP regimen is feasible at moderate hematopoeitictoxicity. With a FFTF-rate of 89% at a median follow-up of 40 months,the treatment results are very encouraging. A prospective randomised trial hasbeen initiated to compare the BEACOPP regimen with the standard COPP/ABVDregimen in advanced-stage Hodgkin's disease.

Notes: Abstract.  We propose a phase-sensitive micromaser setup to demonstrate experimentally a violation of a Bell-type inequality. The interaction of atoms with the cavity field produces entanglement between the atoms and the cavity photons and therefore also between the atoms. We derive a Bell-type inequality for the atom–atom correlations and show that it can be violated not only in an idealized model but also under realistic circumstances when various sources of additional randomness are accounted for. Among them are the energy dissipation in the resonator and the Poissonian arrival statistics of the atoms.

Notes: Abstract We propose a phase-sensitive micromaser setup to demonstrate experimentally a violation of a Bell-type inequality. The interaction of atoms with the cavity field produces entanglement between the atoms and the cavity photons and therefore also between the atoms. We derive a Bell-type inequality for the atom-atom correlations and show that it can be violated not only in an idealized model but also under realistic circumstances when various sources of additional randomness are accounted for. Among them are the energy dissipation in the resonator and the Poissonian arrival statistics of the atoms.

Notes: [Auszug] Each five-membered ring in the target polymer la (Fig. 1) is joined to three six-membered rings as shown. The polymer should, therefore, have a planar, board-like structure. There is no doubt that the well known and often applied method to increase the solubility of conformationally rigid polymers ...

Notes: Abstract HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio] methoxy] methyl] -2,4-bis [(hydroxyimino) methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8°C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of thesyn/syn-isomer, less than 2% of thesyn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö 7 (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6. After i.v. injection: t1/2α = 5 min; t1/2ß = 46 min; VD = 0.24 1/kg; Clp1 = 3.7 ml x min−1 x kg−1; Clren= 3.2 ml x min−1 x kg−1; renal excretion of unchanged HLö 7 = 86%. After i. m. injection: t1/2abs = 14 min; t1/2ß = 48 min; Vd = 0.27 1/kg; Clp1= 3.9 ml x min−1 x kg−1; Clren= 2.7 ml x min−1 x kg−1; renal excretion of unchanged HLö 7 = 76%; bioavailability 〉95%. Plasma protein binding was 〈5%; HLö 7 did not permeate into red cells. A dose of 20 μmol/kg was well tolerated both after i.v. and i.m. administration. In anaesthetized dogs (chloralose) HLö 7 i.v. (20 (imol/kg) showed marginal hypotensive effects, whereas 50 μmol/kg resulted in decreased mean blood pressure (−15%) and blood flow (−30%) without reflex tachycardia. One out of four dogs developed a circulatory shock syndrome with anuria. Respiration varied only transiently. Blood gases and pH were not influenced. Similar cardiovascular effects were observed in anaesthetized (urethane) guinea-pigs. In isolated guinea-pig hearts (Langendorff) sinus and ventricular heart rate were not influenced by HLö 7 〈500 μM. HLö 7 antagonized both carbachol and nicotine effects. Red cell AChE was inhibited by HLö 7 by up to 50%; C50 about 100 μM. Previously, HLö 7 was shown to block ganglionic transmission (IC50= 500 μM), probably due to ion-channel blockade. These data indicate that HLö 7 combines ganglion blocking, anticholinergic and indirect cholinergic properties like other bispyridinium compounds. The results suggest that HLö 7 may be tolerated by man at a dose of 10 μmol/kg. Vital functions are not expected to be impaired. At such a dose (250–500 mg), which can be injected by an autoinjector, HLö 7 is expected to be superior to HI 6.

Notes: Zum Thema Für die Mehrzahl der hierzulande tätigen Ärztinnen und Ärzte dürfte zutreffen, daß sie sich zwar an den Ergebnissen klinischer, insbesondere therapeutischer Studien orientieren und sie in ihre ärztliche Tätigkeit integrieren. Wie aber solche Studien geplant und durchgeführt werden, ist nur einer Minderheit bekannt: das Fachgebiet der Medizinischen Biometrie ist sicher für viele Neuland. In der vorliegenden Arbeit werden zunächst die verschiedenen Typen klinischer Studien und deren potentielle Ziele erläutert; sodann werden dazu Beispiele vorgestellt. Des weiteren werden Verzerrungsquellen diskutiert und die Bedeutung randomisierter Studien und statistischer Schlußfolgerungen sowie Probleme unterdimensionierter Studien dargestellt. Selbst kritikfähig zu bleiben und nicht alle Studienergebnisse kritiklos zu übernehmen, setzt sicher die Kenntnis methodischer Grundlagen der Biometrie voraus.

Notes: Zum Thema Die vorliegende Arbeit beschreibt die Entwicklung und Optimierung von Therapiestrategien für das Hodgkin-Lymphom innerhalb der Deutschen Hodgkin Lymphom Studiengruppe (DHSG) in den letzten 20 Jahren. Rekrutierte die DHSG im Jahr 1980 gerade 20 Patienten in 8 Behandlungszentren, so waren es im Jahr 1998 schon mehr als 700 Patienten in über 300 Zentren in Deutschland und im europäischen Ausland. Innerhalb dieser Zeit wurden Hodgkin-Patienten streng stadienadaptiert in 3 Studiengenerationen innerhalb prospektiv randomisierter Therapiestudien behandelt. Die 4. Studiengeneration wurde in diesem Jahr aktiviert. Der Schwerpunkt der Therapieoptimierung in den frühen und intermediären Stadien war die Reduktion der Toxizität der Strahlentherapie unter Beibehaltung der guten Therapieergebnisse. Das Bemühen in den fortgeschrittenen Stadien galt der Verbesserung der unbefriedigenden Therapieergebnisse. Durch die Entwicklung einer Zeit- und Dosis-intensivierten Therapie gelang hier in der 3. Studiengeneration erstmals ein therapeutischer Durchbruch für diese Patienten. Ein großes Anliegen der Studie war von Beginn an die Qualitätssicherung. Hierfür waren neben der Arbeit der Studienzentrale insbesondere die Einrichtung einer Referenzpathologie und einer Referenzstrahlentherapie entscheidend. Diese Gremien hatten entscheidenden Anteil daran, daß im Rahmen der bisherigen Studiengenerationen der DHSG die Qualität der Behandlung flächendeckend zwischen den einzelnen Zentren angeglichen werden konnte.

Notes: Abstract The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Notes: Abstract In this article we summarize the theoretical arguments which led us in the German Hodgkin's Disease Study Group to introduce the BEACOPP-regimen and to initiate a large randomised trial to investigate the role of moderate dose escalation in the treatment of advanced stage Hodgkin's disease. Although some indications for a role of dose were available in the early 1990s no prospective randomised trial had been undertaken. In order to obtain an impression of the shape of the essential dose response characteristic we developed a novel statistical model that could be used to analyse a set of data in which dose variations had occured. The model took tumour growth and chemotherapy effects into account. The model could be applied to clinical data on tumour control and treatment given in a patient population. The model was fitted to the data of 706 patients which had received COPP/ABVD-like regimens. It revealed considerable heterogeneity in chemosensitivity and a positive slope of the doseresponse relationship. The model was used to simulate the effect of various treatment strategies with dose escalation and schedule changes. On the basis of such simulations we predicted that shortening cycle intervals from 4 to 3 weeks should lead to small benefits (about 3% in five-year tumour control rates). In contrast, we predicted that a moderate average dose escalation by 30% of a standard chemotherapy would lead to a potential benefit in the order of 10%-15% in tumour control at five years. Subsequently we searched for a treatment scheme that would permit such a dose escalation. The BEACOPP-scheme was invented to allow the three major myelotoxic substances (cyclophsphamide, adriamycin and etoposide) to be given in the beginning of a cycle. These three substances were then subject to dose escalation in a dose finding trial. G-CSF was introduced to compensate for the myelotoxic effects. The dose level found feasible for a large multicentre setting turned out to be in the required magnitude. The HD9 trial of the GHSG was then initiated to examine whether the predicted dose response curve really exists.