H. Sauer

Multiple brown tumors in a patient with nutritional secondary hyperparathyroidism

SummaryFor years, brown tumors have been considered to be a characteristic of primary hyperparathyroidism. However, since 1963 several reports indicate the incidence of brown tumors in patients with renal secondary hyperparathyroidism to be 1.5%–1.7%. The appearance of multiple brown tumor lesions is rather uncommon in secondary hyperparathyroidism which is also true for malabsorption as its cause. We report on a 56-year-old man presenting with pain in the bones and multiple osteolyses. A bone biopsy specimen and the laboratory examinations were indicative of secondary hyperparathyroidism caused by malabsorption most likely due to Billroths II/I gastric resection. Thus, the patients osteolyses represent brown tumors which have been induced by nutritional secondary hyperparathyroidism.

Immunhämolytische Anämien mit Nierenversagen nach Nomifensineinnahme

SummaryTwo cases of immune haemolytic anaemia and acute renal failure induced by nomifensine are reported.The two female patients had been under continous nomifensin therapy because of reactive depressions. In both cases nomifensine had been discontinued and the clinical reactions — immune haemolytic anaemia and acute renal failure — started immediately after they had taken again a capsule of nomifensine.In one case the patients serum contained a potent antibody which agglutinated her red blood cells in presence of nomifensine in the antiglobulin test.ZusammenfassungWir berichten über zwei Fälle von immunhämolytischer Anämie und akutem Nierenversagen nach Nomifensineinnahme.Die beiden Patientinnen hatten wegen reaktiver Depressionen eine kontinuierliche Nomifensintherapie erhalten. In beiden Fällen war das Nomifensin zwischenzeitlich abgesetzt worden, und die klinischen Reaktionen — immunhämolytische Anämie und Nierenversagen — traten unmittelbar nach erneuter Einnahme einer Kapsel dieses Präparates auf.In einem Fall enthielt das Serum der Patientin einen potenten Antikörper, der in Gegenwart von Nomifensin ihre eigenen Erythrozyten im Antiglobulin-Test agglutinierte.

Methotrexate and methotrexate polyglutamates in human sarcoma metastases after high-dose methotrexate therapy

SummaryThe methotrexate concentrations in the lungs or cutaneous metastases of patients with osteogenic or soft-tissue sarcoma were determined at different times after a high-dose methotrexate therapy. The levels in the metastases were 0.964 to 2.96×10−7 molar six to nine days after the end of MTX infusion. They were thus 7.8 to 28 times higher than the corresponding serum levels. At the same time, an appreciable rise of dihydrofolate reductase activity was observed in the metastases. After chromatographic separation over Sephadex G15, MTX polyglutamates could be demonstrated in all tumor samples investigated so far; these amounted up to 68.3% of the total MTX. Taking into account the slower efflux of MTX polyglutamates compared to unchanged MTX, a new hypothesis for the principle of action of high-dose methotrexate therapy is discussed: the very high MTX doses lead to such high intracellular MTX concentrations even in transport-resistant tumor cells that at least part of the MTX is converted into MTX polyglutamates. Unchanged MTX flows relatively rapidly out of the cells, whereas the MTX polyglutamates only break down very slowly and thus can be cytostatically effective over a long period of time.

Knochenmarktransplantation im Erwachsenenalter bei akuter Leukämie, aplastischer Anämie und paroxysmaler nächtlicher Hämoglobinurie

SummaryEleven adults have been transplanted for various reasons between July 1979 and July 1982: 2 with aplastic anemia (AA), 1 with paroxysmal nocturnal hemoglobinuria (PNH), 8 with acute leukemia (AL). Four patients suffered from acute lymphocytic leukemia (ALL) and four from acute non-lymphocytic leukemia (ANLL). Two of them were transplanted in relapse, 1 in a partial remission, and 5 in complete remission. All patients were in their late stage of disease. The PNH-patient had an identical twin, 8 patients had an HLA- and MLC compatible sib, 1 an unrelated donor, and 1 was transplanted from his father. Four patients are alive, 2 more than 3 years: 1 with AA and 1 with ALL who was transplanted in relapse. Six patients died of infectious complications (4 of interstitial pneumonia, 1 of a candidasepsis, 1 of acute toxoplasmosis). Patients living more than 3 weeks had a take. Acute graft-versus-host (GvH) disease did not present a major problem. All patients received methotrexate for GvH-prophylaxis, in three instances the marrow was additionally pre-incubated with anti-T-cell globulin.Eleven adults have been transplanted for various reasons between July 1979 and July 1982: 2 with aplastic anemia (AA), 1 with paroxysmal nocturnal hemoglobinuria (PNH), 8 with acute leukemia (AL). Four patients suffered from acute lymphocytic leukemia (ALL) and four from acute non-lymphocytic leukemia (ANLL). Two of them were transplanted in relapse, 1 in a partial remission, and 5 in complete remission. All patients were in their late stage of disease. The PNH-patient had an identical twin, 8 patients had an HLA- and MLC compatible sib, 1 an unrelated donor, and 1 was transplanted from his father. Four patients are alive, 2 more than 3 years: 1 with AA and 1 with ALL who was transplanted in relapse. Six patients died of infectious complications (4 of interstitial pneumonia, 1 of a candida sepsis, 1 of acute toxoplasmosis). Patients living more than 3 weeks had a take. Acute graft-versus-host (GvH) disease did not present a major problem. All patients received methotrexate for GvH-prophylaxis, in three instances the marrow was additionally pre-incubated with anti-T-cell globulin.

Ferrokinetics after high-dose methotrexate therapy

SummaryAfter high-dose methotrexate with doses ranging from 2–10 g/m2, ferrokinetics were performed in 11 patients with different tumors. Iron-III-citrate-59Fe was injected at methotrexate serum concentrations ranging between 2.7×10−7−1.3×10−8 M. With MTX levels ≧4.2×10−8 M the plasma iron clearance was always retarded, and the plasma iron turnover was diminished in 5 of 6 patients with levels of 3.1−8.9×10−8 M at the time of the injection. In all cases with MTX concentrations ≧5×10−8 M the59Fe-utilization as the measure of effective erythropoiesis was reduced pathologically below normal range. These results show that the erythropoiesis resumes its normal extent even in case of normal methotrexate clearance only when the methotrexate serum concentrations have fallen down below 5×10−8 and that erythropoiesis is more sensitive against methotrexate toxicity than the granulocytopoiesis.ZusammenfassungNach einer hochdosierten Methotrexat-Therapie mit Dosen von 2–10 g/m2 wurde bei 11 Patienten mit verschiedenen Tumor-Erkrankungen eine Ferrokinetik durchgeführt. Eisen-III-zitrat-59Fe wurde bei Methotrexat-Serum-Konzentrationen zwischen 2,7×10−7 und 1,3×10−8 M injiziert. Bei Methotrexat-Spiegeln ≧4,2×10−8 M war die Plasma-Eisen-Clearance in allen Fällen verlangsamt. Der Plasma-Eisen-Umsatz war bei 5 von 6 Patienten mit MTX-Spiegeln von 3,1–8,9×10−8 M zum Zeitpunkt der Eisen-Injektion vermindert. In allen Fällen mit MTX-Spiegeln über 5×10−8 M war die59Fe-Utilisation als Maß der effektiven Erythropoese pathologisch erniedrigt. Diese Ergebnisse zeigen, daß die Erythropoese erst dann wieder ihr normales Ausmaß annimmt, wenn die MTX-Serum-Konzentrationen unter 5 × 10−8 M abgefallen sind. Damit reagiert die Erythropoese empfindlicher auf Methotrexat als die Granulopoese.

Zum gegenwärtigen Stand der internistischen Therapie des Mammacarcinoms

A renewal of interest in endocrine therapy of breast cancer is resulting from the demonstration of steroid hormone receptors in tumor cells sensitive to antiestrogens and the possibility for predicting endocrine responsiveness. Therefore new therapeutical concepts have been developed and some of the established endocrine regimens have been reduced to historical interest. It is more than doubtful that the present schematization in selecting the proper kind of endocrine treatment has any future as methodical difficulties in demonstrating hormone receptors will be overcome and the understanding of their biological function will increase.SummaryA renewal of interest in endocrine therapy of breast cancer is resulting from the demonstration of steroid hormone receptors in tumor cells sensitive to antiestrogens and the possibility for predicting endocrine responsiveness. Therefore new therapeutical concepts have been developed and some of the established endocrine regimens have been reduced to historical interest. It is more than doubtful that the present schematization in selecting the proper kind of endocrine treatment has any future as methodical difficulties in demonstrating hormone receptors will be overcome and the understanding of their biological function will increase.ZusammenfassungDie Hormontherapie des Mamma-Ca hat in jüngster Zeit durch den Nachweis von Hormonrezeptoren an den Tumorzellen und die gezielte Beeinflussung des Tumorwachstums durch kompetitive Hemmung der Rezeptoren mit Antiöstrogenen große Wandlungen erfahren. Einige der herkömmlichen hormonellen Maßnahmen haben nur noch historische Bedeutung, andere werden in Zukunft nicht mehr zur Anwendung gelangen. Ob mit einem methodisch verbessertem Nachweis und somit vertieftem Verständnis der Steroidhormonrezeptoren auf das Tumorwachstum das derzeit noch stark schematisierte Vorgehen bei der Auswahl der verschiedenen Therapieschritte zukünftig Bestand haben wird, ist fraglich.

Knochenmarktransplantation bei aplastischer Anämie

SummaryFrom March 1975 until May 1980 twelve patients with severe aplastic anemia were grafted with bone marrow from HLA-identical siblings by the Munich Cooperative Group for Bone Marrow Transplantation. Six patients are alive between 10 months and more than 5 years after grafting with normal blood values and marrow. One patient is treated as an out patient for chronic localized graft-versus-host disease (GvHD), five patients are well and without treatment. Six patients have died, one patient with a cerebral hemorrhage the day before transplantation, three patients following rejection of grafts 32, 40 and 55 days after grafting, one patient with severe GvHD 85 days after grafting and one patient, probably with interstitial pneumonia, following cerebral hemorrhage. Three of 6 patients who were conditioned with Cyclophosphamide (CY) only died following rejection of the graft. Two adults who were conditioned with CY and “total lymphoid irradiation” and three children, who were given unirradiated leukocyte concentrates from the marrow donor after grafting, did not reject their grafts. The results of the Munich-Cooperative Group for Bone Marrow Transplantation are comparable to those of large, specialized centers for bone marrow transplantation, they indicate possibilities of cure of severe aplastic anemia by marrow grafts from HLA-identical siblings. They confirm that better results are obtained with earlier transplantation in the course of the disease.ZusammenfassungIm Rahmen der Arbeitsgemeinschaft Knochenmarktransplantation — München (AG-KMT) wurden vom März 1975 bis Mai 1980 insgesamt 12 Patienten wegen schwerer, aplastischer Anämie mit Knochenmarktransplantation (KMT) behandelt. Sechs Patienten überleben derzeit mit normalem Blutbild und Knochenmark zwischen 10 Monaten und mehr als 5 Jahren nach KMT von HLA-identischen Geschwistern, eine Patientin steht noch in ambulanter Behandlung wegen lokalisierter, chronischer Graft-versus-Host Krankheit (GvHK), fünf Patienten sind klinisch gesund. Sechs Patienten starben, ein Patient starb am Tag vor KMT mit Hirnblutung, drei Patienten 32, 40 und 55 Tage nach KMT an den Folgen der Transplantatabstoßung, einer an schwerer GvHK 85 Tage nach KMT und einer 87 Tage nach KMT vermutlich an interstitieller Pneumonie nach Hirnblutung. Drei von 6 Patienten, die nur mit Cyclophosphamid (CY) vorbehandelt waren, starben infolge Abstoßung des Transplantates. Zwei erwachsene Patienten, die mit CY und „total lymphoid irradiation“ vorbehandelt waren, und drei Kinder, die nach KMT unbestrahlte Leukocytenkonzentrate von Knochenmarkspender erhalten hatten, stießen das Transplantat nicht ab.Die Ergebnisse der AG-KMT sind vergleichbar denen großer, spezialisierter Zentren für KMT und zeigen die Möglichkeiten einer Heilung schwerer aplastischer Anämien durch KMT von HLA-identischen Geschwistern. Die Erfolge sind besser bei frühzeitiger KMT.

[Current status in the treatment of breast cancer. II. Adjuvant chemotherapy, palliative polychemotherapy, chemoimmunotherapy--rating and results (author's transl)].

There is no well defined group of patients with primary breast cancer which benefits from combination chemotherapy as an adjuvant treatment, since, at present, the effect of this therapy in respect to the duration of disease-free interval, survival, and possible long-term side effects remain unknown. Therefore, controlled studies need to be initiated. Similarly, there seems to be no beneficial effect from unspecific immunotherapy. As far as combination chemotherapy in advanced breast cancer is concerned, we review on four different protocols which proved to be quite successful in our hands: adriamycine/cyclophosphamide (AC), cyclophosphamide/methotrexate/5-fluorouracil (CMF), CMF/vincristine/prednisone (CMFVP), and adriamycine/vincristine plus CMF plus Tamoxifen.SummaryThere is no well defined group of patients with primary breast cancer which benefits from combination chemotherapy as an adjuvant treatment, since, at present, the effect of this therapy in respect to the duration of disease-free interval, survival, and possible long-term side effects remain unknown. Therefore, controlled studies need to be initiated. Similarly, there seems to be no beneficial effect from unspecific immunotherapy.As far as combination chemotherapy in advanced breast cancer is concerned, we review on four different protocols which proved to be quite successful in our hands: adriamycine/cyclophosphamide (AC), cyclophosphamide/methotrexate/5-fluorouracil (CMF), CMF/vincristine/prednisone (CMFVP), and adriamycine/vincristine plus CMF plus Tamoxifen.ZusammenfassungFür die postoperative adjuvante Chemotherapie gibt es bisher keine genau definierte Risikogruppe, bei der die Rezidiv- oder Metastasierungsrate sicher vermindert werden kann. Weitere kontrollierte Studien müssen die Indikation für diese Therapie erst noch detaillierter herausarbeiten. Von einer generellen, unkontrollierten Anwendung der adjuvanten Chemotherapie wird abgeraten. Ähnliches gilt für die unspezifische Immunstimulation, die auch keinen gesicherten positiven Effekt hat.Für die palliative Polychemotherapie, eventuell in Kombination mit einer Antiöstrogentherapie, werden 4 verschiedene Therapie-Protokolle, die sich in unseren Händen gut bewährt haben, mit ihren Indikationen vorgestellt: Adriamycin/Cyclophosphamid (AC), Cyclophosphamid/Methotrexat/5-Fluorouracil (CMF), CMF/Vincristin/Prednison (CMFVP) und die Kombination von Adriamycin/Vincristin (AV) mit CMF auf der Basis einer Dauertherapie mit Tamoxifen.

Knochenmarktransplantation bei rezidivierter, akuter Leukämie

SummarySeventeen patients with relapsed, acute leukemia were grafted with bone marrow from HLA-identical siblings by the ‘Munich Cooperative Group for Bone Marrow Transplantation’ during the period from August 1975 to June 1980. The antileukemic and immunosuppressive conditioning treatment consisted of high doses of Bischlorethyl nitrosourea, Cytosine-Arabinoside and Cyclophosphamide, as well as, total body irradiation of about 9 Gy (midline body dose) from dual60Cobalt sources. Methotrexate was given to all patients for prophylaxis of graft-versus-host disease (GvHD). Nine patients received marrow that was treated with anti-T-cell globulin (ATCG) “in vitro”. — Crossreacting antibodies against hemopoietic stem cells were removed by absorption. Two of 5 evaluable patients given untreated marrow developed chronic GvHD, while patients given ATCG-treated marrow did not show unequivocal symptoms of GvHD. Six patients are in complete remission one to 33 months following bone marrow transplantation (b.m.t.) Five patients died with relapses of leukemia between 3 1/2 and 24 months following b.m.t., 3 patients died with interstitial pneumonia within 3 months of b.m.t. and 3 patients died with insufficient graft function within 4 weeks of b.m.t. Four of thirteen patients that were grafted more than 6 months ago are presently alive and in continuous complete remission at 11, 14, 29 and 33 months following b.m.t. Our results confirm that longterm remissions can be obtained with b.m.t. in patients with acute leukemia in advanced stage.ZusammenfassungIm Rahmen der Arbeitsgemeinschaft Knochenmarktransplantation München wurden von August 1975 bis Juni 1980 insgesamt 17 Patienten mit rezidivierter, akuter Leukämie mit Knochenmark von HLA-identischen Geschwistern transplantiert. Die antileukämische und immunsuppressive Vorbehandlung bestand aus BCNU, Cytosin-Arabinosid, Cyclophosphamid in hoher Dosierung und Ganzkörperbestrahlung mit etwa 9 Gy Körpermitteldosis an einer60Co-Doppelbestrahlungsanlage. Die Prophylaxe einer Graft-versus-Host Krankheit (GvHK) wurde in allen Fällen mit Methotrexat durchgeführt, bei neun Patienten wurde als zusätzliche GvHK-Prophylaxe das Knochenmark mit Anti-T-Zell-Globulin inkubiert, von dem die Antikörper gegen hämopoetische Stammzellen absorbiert waren. Zwei von fünf auswertbaren Patienten, die unbehandeltes Knochenmark erhalten hatten, entwickelten chronische GvHK, während kein Patient nach ATCG-Inkubation des Knochenmarkes eindeutige GvH-Krankheit bekam. Sechs Patienten leben in Vollremission zwischen einem und 33 Monaten nach Knochenmarktransplantation (KMT). Fünf Patienten starben mit Rezidiven zwischen 3 1/2 und 24 Monaten nach KMT, drei Patienten mit interstitieller Pneumonie innerhalb von 3 Monaten nach KMT und drei Patienten innerhalb von 4 Wochen ohne ausreichende Knochenmarkfunktion. Vier von 13 Patienten, die vor mehr als 6 Monaten transplantiert wurden, überleben zur Zeit 11, 14, 19 und 33 Monate in Vollremission. Unsere Ergebnisse bestätigen, daß selbst in fortgeschrittenen Stadien akuter Leukämie durch KMT noch langfristige Remissionen erreichbar sind.