Biomedical subjects
P Kyrle
Publications and source records attributed to P Kyrle.
Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia--a randomized phase-III study.
Because of the recommendation to avoid the concomitant administration of growth factors and chemotherapy, there is only limited information on colony-stimulating factor (CSF) therapy in acute lymphoblastic leukemia (ALL) induction protocols, in which cytotoxic drugs are administered in divided doses over a prolonged period of time, thus requiring a simultaneous administration of growth factors and chemotherapy. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF; filgrastim) as an adjunct to phase I of induction chemotherapy for adult ALL. Patients (n = 53) were randomized to receive no growth factor or G-CSF (5 microg/kg/d subcutaneously) starting on day 2 of chemotherapy consisting of daunorubicin (45 mg/m2) and vincristine (1.5 mg/m2) on days 1, 8, 15, and 22; L-asparaginase (2500 U/m2) on days 1 through 14; and prednisone (60 mg/m2) on days 1 through 28. A total of 25 patients in the G-CSF group and 26 patients in the control arm fulfilled the inclusion criteria of the study. G-CSF markedly ameliorated neutropenia because the median proportion of days with neutropenia less than 1,000/microL was 29% in the G-CSF group as compared with 84% in the control arm (P < .00005). The median time to reach absolute neutrophil counts (ANC) > or = 1,000/microL was 16 days in G-CSF patients and 26 days in controls (P < .001). More importantly, G-CSF significantly reduced the incidence of febrile neutropenia (12% v 42% in controls, P < .05) and documented infections (40% v 77%, P < .05). No significant differences were found with regard to requirements for red blood cell transfusions and platelet concentrates. A total of 24 of 25 (96%) patients in the G-CSF group and 20 of 25 (80%) evaluable control patients had complete remission after phase I of induction therapy. We conclude that G-CSF can be safely administered as an adjunct to induction therapy of ALL and is clinically beneficial by ameliorating neutropenia and reducing infectious complications.
Plasma exchange for treatment of thrombotic thrombocytopenic purpura in critically ill patients.
OBJECTIVE: Description of diagnostic procedures, treatment modalities and intensive care management of patients with thrombotic thrombocytopenic purpura (TTP). DESIGN: Descriptive study. SETTING: Internal medicine Intensive Care Unit (University Hospital of Vienna). PATIENTS: Six patients (two after allogeneic bone marrow transplantation), treated for 12 episodes of TTP. INTERVENTIONS: Treatment with plasma exchange (fresh frozen plasma, 50-80 ml/kg per day), prednisone (0.75 mg/kg b.i.d.) and, in some cases, vincristine. Supportive therapy as needed. MEASUREMENTS AND RESULTS: Patients were admitted to the ICU because of neurological symptoms with acute onset (42% mild, 58% severe), hemolysis and thrombocytopenia. Additional symptoms were fever (50%), bleeding tendency (50%), acute renal failure (42%) and metabolic derangement (8%). Initial laboratory values showed thrombocytopenia (median 17 G/l), hemolysis (median hemoglobin 10.0 g/dl, lactate dehydrogenase 635 U/l, reticulocyte count 175 G/l) with red cell fragmentation. Coagulation tests were normal. Respiratory assist was needed in six episodes (severe seizures, cardiopulmonary resuscitation). In patients without preexisting hematological abnormality the platelet counts exceeded 100 G/l after 3-8 cycles of plasma exchange. In patients after bone marrow transplantation, the platelet counts never exceeded 40 G/l, but the lactate dehydrogenase levels dropped significantly. The neurological symptoms disappeared in all patients and renal function normalized. One patient died before the initiation of therapy. Three patients relapsed 1-3 times between 2 weeks and 5 months after the last episode. The relapses were associated with symptoms similar to the first episode and responded promptly to plasma therapy. CONCLUSIONS: TTP is a rare, but life-threatening disorder. It needs immediate diagnosis and has a good prognosis after adequate treatment with plasma exchange.
Recurrent, isolated factor X deficiency in myeloma: repeated normalization of factor X levels after cytostatic chemotherapy followed by late treatment failure associated with the development of systemic amyloidosis.
We describe the case of a 64-year-old woman with isolated severe factor X deficiency associated with kappa light chain myeloma. At the time of diagnosis there was no evidence for amyloidosis. Complete remission (CR) of myeloma as well as normalization of factor X levels were achieved after cytostatic chemotherapy. Subsequently, factor X deficiency recurred twice without any evidence for relapse of myeloma. The first time factor X normalized again following cytostatic treatment, the second time, however, factor X deficiency was refractory to chemotherapy. Finally, relapse of myeloma became evident associated with rapidly progressing, systemic amyloidosis, which was fatal within a few months. Initially, factor X infusion studies showed a normal recovery, but when amyloidosis became overt the recovery decreased to 0%. We assume that factor X deficiency was due to a binding of factor X to kappa light chains associated with the proliferation of the malignant myeloma cell clone.
Effect of interleukin-3 on responsiveness to granulocyte-colony-stimulating factor in severe aplastic anemia.
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In vivo synergism of recombinant human interleukin-3 and recombinant human interleukin-6 on thrombopoiesis in primates.
Using a primate model, we examined the effect of recombinant human interleukin-3 (rhIL-3) and rhIL-6 on thrombopoiesis in vivo. Administration of 33 micrograms/kg/d of rhIL-3 for 11 to 14 days increased levels of circulating colony-forming units megakaryocyte (CFU-Mk) by approximately 15-fold in five rhesus monkeys without raising their platelet counts. In contrast, administration of 30 micrograms/kg/d of rhIL-6 for 10 days in four animals did not increase CFU-Mk levels but significantly raised platelet counts from a mean pretreatment value of 460 x 10(3)/microL (range 360 to 610) to a mean maximum of 746 x 10(3)/microL (665 to 790) on day 8. If monkeys were pretreated with rhIL-3 (33 or 100 micrograms/kg/d for 11 days) to expand their CFU-Mk compartment, the thrombopoietic effect of rhIL-6 was synergistically enhanced leading to platelet counts above 1,000 x 10(3)/microL (mean maximum value 1,247) in all three primates studied. The sequential administration of rhIL-3 and rhIL-6 might represent a powerful strategy to stimulate thrombopoiesis in vivo.
[Obstetrical management of dysfibrinogenemia with increased thrombophilia].
Dysfibrinogenaemias are characterised by qualitatively abnormal fibrinogen, causing functional defects. In pregnant women, the incidence of recurrent abortions and placental abruption as well as haemostatic complications is high. In this case report, we report on a 22 year old woman with dysfibrinogenaemia complicated by thrombotic episodes. After two stillbirths under dramatic circumstances (placental abruption, eclampsia) and after an early abortion (7th gestational week), the patient was treated by subcutaneously administered heparin. Pregnancy ended successfully by delivery in the 39th gestational week.
[Problems of long-term therapy with anticoagulants].
Oral anticoagulants are highly effective for the prevention of recurrence of venous thromboembolism and of thromboembolic complications in rheumatic and non-rheumatic atrial fibrillation, dilated cardiomyopathy and in patients with prosthetic heart valves, but less effective for prevention of arterial thrombosis. Bleeding is the main side effect, the risk of fatal bleeding is 0.2 to 0.4% per year, depending on the intensity of treatment. The problem of the standardization of the prothrombin time determination has been solved by the introduction of the international normalized ratio. Recent studies have shown that a lesser degree of anticoagulation (INR 2.0 to 3.0) is sufficient to prevent venous thromboembolism and cardiac emboli. The measurement of activation markers of coagulation will probably allow a more rational monitoring in the near future.
1-Deamino-8-D-arginine vasopressin in the treatment of non-haemophilic patients with acquired factor VIII inhibitor.
1-Deamino-8-D-arginine vasopressin (DDAVP) was administered to 3 patients with spontaneous factor VIII inhibitors. In 2 patients with baseline factor VIII levels above 1%, a marked increase of factor VIII activity after DDAVP infusion could be observed. No rise of factor VIII activity after DDAVP was seen in the 3rd patient with a baseline factor VIII level of less than 1%. Daily infusion of DDAVP resulted in a reduction of the efficacy, but the full effect could be retained when DDAVP was given at 48-hour intervals. The effect of DDAVP infusion on factor VIII levels in the 2 responding patients was superior to the treatment with 30 U/kg factor VIII concentrate and approximately equivalent to infusion of 45 U/kg factor VIII concentrate. DDAVP may be a useful and less expensive treatment for patients with acquired factor VIII inhibitors and a baseline factor VIII level of more than 1%.
Decreased serum osteocalcin levels in phenprocoumon-treated patients.
Osteocalcin (OC) is a noncollagenous bone matrix protein containing gamma-carboxyglutamic acid, the synthesis of which is vitamin K dependent. Serum OC levels are generally believed to reflect the de novo synthesis of OC by osteoblasts and thus reflect bone formation. We measured serum OC levels by RIA in 48 patients receiving phenprocoumon anticoagulant treatment, which inhibits the posttranscriptional synthesis of gamma-carboxyglutamic acid, and in 22 matched normal subjects. The median serum OC level in the patients receiving phenprocoumon therapy was significantly lower than that in the normal subjects (P less than 0.0001). In 27 patients receiving anticoagulant therapy and in 21 normal subjects the proportion of noncarboxylated OC to total OC also was determined. The proportion of OC that was noncarboxylated was significantly higher in the patients receiving phenprocoumon therapy than in the normal subjects (P less than 0.0001). We conclude that OC carboxylation is impaired in patients receiving oral anticoagulant therapy. The decreased total OC levels in patients receiving phenprocoumon treatment might result from decreased bone formation, although these patients do not have symptoms of bone disease.
[Oral anticoagulant therapy--renaissance of an old therapy?].
Although the antithrombotic potential of oral anticoagulants is undisputed, bleeding complications constitute a serious problem. One of the main causes for these complications has been a lack of standardization of the prothrombin time. The introduction of the International Normalized Ratio (INR) has led to a better standardization of prothrombin time. Thus, the same level of anticoagulation can be reached using different reagents and therefore over- and undercoagulation can be avoided. Furthermore, the benefit/risk ratio can be improved by adapting the intensity of anticoagulation to the indication. The following clinical conditions are established indications for treatment with oral anticoagulants: Prevention of cardiac emboli in acute anterior myocardial infarction with atrial thrombus, in patients with atrial fibrillation with or without mitral valve disease, in patients with prosthetic heart valves and in patients with dilated cardiomyopathy. Furthermore, oral anticoagulants should be given to patients after femoropopliteal bypass. A relatively mild oral anticoagulant treatment (INR 2-3) is sufficient to prevent recurrences of venous thrombosis and pulmonary emboli. The duration of treatment in patients with venous thromboembolism depends on some clinical features and the results of clotting tests which indicate an increased tendency to thrombosis.
Activation of protein kinase C inhibits sodium fluoride-induced elevation of human platelet cytosolic free calcium and thromboxane B2 generation.
Addition of NaF to washed platelets produces a dose-dependent and transient elevation of the intracellular free calcium concentration ([Ca++]i), thromboxane B2 (TxB2) generation and dense granule release, all of which are significantly inhibited when the extracellular calcium concentration ([Ca++]e) is reduced with EGTA. Inhibition of platelet cyclo-oxygenase by acetylsalicylic acid (ASA) does not affect NaF-induced elevation of [Ca++]i and dense granule release in the presence of 1 mM [Ca++]e. Pre-incubation of the platelets with the phorbol ester TPA produces a marked inhibition of NaF-induced elevation of [Ca++]i and TxB2 generation without affecting dense granule release. Thus, NaF may have more than one site of action. Pretreatment of the platelets with the selective protein kinase C inhibitor H7 prevents TPA induced inhibition of NaF mediated rise in [Ca++]i and TxB2 generation. Thus we propose that NaF induced calcium mobilisation is analogous to receptor-operated calcium mobilisation in platelets, as it is readily inhibited by protein kinase C activation or by the reduction of [Ca++]e and is independent of platelet cyclo-oxygenase activity.
[Is the CO2 laser surgery advantageous? A morphological and experimental study (author's transl)].
The great advantages of CO2 laser surgery are the contact-less cutting and the haemostatic effect. An obliteration of blood- and lymph-vessels thus preventing tumour-cell mobilisation and metastatic spread is considered as most advantageous for tumour surgery. Basing on own morphological and experimental investigations, some of these advantages are critically discussed. The morphology of human skin incisions made by a CO2 laser is described, using light microscopy, and the wound healing process of laser incisions in the dorsal skin of rats is compared with incisions made by thermocautery and conventional scalpel. After contamination of laser and scalpel incisions with india-ink, the migration of these particles to the regional lymph-nodes was also investigated. Compared to the scalpel-incisions, the laser- and even more the thermocauter-incisions showed the well known delay in healing, due to the extensive tissue necrosis at the wound margins. This coagulation necrosis, however, was not obliterate the lymphatic drainage. It is concluded from these experiments that the use of the CO2 laser will not guarantee the prevention of metastatic spread and should mainly be recommended where the haemostatic effect is essential.
Ultrastructure of skeletal muscle after CO2-laser incision.
The immediate effect of CO2-laser incision to the dorsal skin and underlying muscular tissue of rats was studied by light and electron microscopical methods. In the subcutaneous layer of skeletal muscle cells an increased susceptibility was found, resulting in distinct zones of cellular changes which are attributed mainly to thermal effects of the laser beam. The importance of these findings for the surgical application of lasers is discussed.
[Application of laser rays in surgery (author's transl)].
Some years will have to pass, until there will be evidence, if the application of laser beam in surgery of breastcancer, melanomas or basaliomas will be justified and whether it will be possible or not to interrupt or reduce intraoperative tumor cellspread. As an increasing number of surgeons have started to use laser rays in these cases of illness, results of laser surgery and those of tradional methods could be compared in a couple of years. Possibly other indications for the use of laser than those we have worked out will be outlined in general surgery. Surgeons working with laser beam may discredit the method by putting the indication not rigorusly enough. Greatest care should be taken by everybody who starts working with laser rays. Collaboration with a technician is recommended.
[Application of laser rays in surgery (author's transl)].
Some years will have to pass, until there will be evidence, if application of leaser beam in surgery of Breastcancer, Melanomas or Basaliomas was justified and whether it is possible or not to interrupt or reduce intraoperative tumor cellspread. As an increasing number of surgeons have started to use laser rays in these illnesses, result of laser surgery and those of traditional methods could be compared in a couple of years. Possibly other indications will be outlined in general surgery for the use of laser beside those we have been working out. It may happen that surgeons working with laser beam might bring the method into discredit putting indication not rigorous enough. I should like to remind everybody who starts working with laser rays, to do so with greatest possible care. Collaboration with a technician is recommended. Periodic he should control the machine and handle arising technical problems.
[Myotomy: surgical treatment of diverticulitis (author's transl)].
Since 1973 myotomy has been performed in 36 patients with sigmoid diverticulosis or diverticulitis. The operation is most suitable for patients with moderate stenosis and clinically recurring symptoms no longer responding to conversative treatment. When widespread inflammation is present, the risk involved in the operation rises: the separation of the intestinal wall layers is difficult and the danger of a mucosal perforation followed by peritonitis will increase. In those cases an exteriorisation resection is less risky. On performing a myotomy operation an early carcinoma developing between the diverticula can remain undetected.
[Myotomy: a surgical treatment for diverticulitis (author's transl)].
Since 1973 myotomy after Reilly has been performed on 30 patients with sigmoid diverticulosis or diverticulitis. The operation is most suitable for patients with moderate stenosis and clinically recurring symptom that no longer respond to conservative treatment. When widespread inflammation is present the risk involved in the operation should not be underestimated: separation of the intestinal wall layers is more difficult and the danger of perforation is increased. The operation cannot be used successfully to remove an early carcinoma developing between the diverticula.