Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zürich, Switzerland, between 1990 and 1996.

BACKGROUND: Acute cardiotoxicity due to anthracyclines is a rare, but life-threatening event. Interindividual sensitivity to anthracyclines is highly variable and cannot be predicted for the individual patient. PATIENTS AND METHODS: This is a retrospective study. Medical charts and autopsy reports of patients treated for acute leukemia between 1990 and 1996 at the University Hospital of Zürich, Switzerland were reviewed and searched for anthracycline-associated acute cardiotoxicity. Patients with pre-existing heart disease known to be associated with cardiotoxicity were excluded. RESULTS: Seven patients treated for leukemia with proven anthracycline-associated acute cardiotoxicity were included. In six patients the direct cause of death was acute cardiotoxicity due to the treatment. One patient recovered from cardiac failure but died a few months later from refractory leukemia. Clinical symptoms were those of a heart failure. Pathological findings were dilatative cardiac hypertrophy and pericardial effusion. Microscopically the typical findings of myocardial fibrosis and perinuclear vacuolisated myocytes were seen. CONCLUSIONS: The awareness of acute adverse effects on cardiac performance by anthracyclines faciliates early recognition and prevention of heart failure. Reliable tests are needed for the early diagnosis of subclinical myocardial damage in order to identify patients at risk.

Infection imaging using whole-body FDG-PET.

The purpose of this study was to evaluate fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for the detection of soft tissue and bone infections. Forty-five PET examinations in 39 patients (26 male, 13 female, age range 27-86 years) with suspected infectious foci were examined with whole- or partial-body PET scans using FDG. Twenty-seven scans were done in patients with soft tissue and 18 in patients with bone infections. Corrected and uncorrected transaxial PET images were acquired. Seven hundred and twelve body regions in these 45 PET scans were evaluated. Pathological findings were graded using a confidence scale from A to E (A, definitive infection; E, no infection). Disease status was defined in all patients by culture, biopsy or surgery and clinical follow-up. In 45 PET scans there were 40 true-positive, four false-positive and one false-negative findings. Twelve foci suspected to be infectious in nature on the basis of other imaging examinations were identified as negative by PET, thus representing true-negative findings. Sensitivities for the patients with soft tissue (STI) and bone infections (BI) and for the pooled data were 96%, 100% and 98%, respectively. As the calculation of specificity is not straightforward, it was calculated on a per lesion as well as on a per body region basis to permit estimation of an upper and a lower limit. On a per lesion basis, specificities were 70% (STI), 83% (BI) and 75% for the pooled data and on a per body region basis (dividing the body into 22 regions) they were 99% (STI), 99% (BI) and 99% for the pooled data. One false-negative result was found in a patient with cholangitis. It is concluded that PET appears to be a highly sensitive method to detect infectious foci. Specificity is more difficult to estimate, but is probably in the range from 70% to above 90%.

[Cost effectiveness in treatment of acute myeloid leukemia]. / Kosten und Nutzen in der Behandlung der akuten myeloischen Leukämie.

Although the rise in health costs is a widely debated issue, in Switzerland it was until recently taken for granted that patients are given the best available treatment regardless of cost. An example of a disease requiring costly treatment is acute myelogenous leukaemia (AML). To relate cost to benefit we calculated expenditure per life years gained. To assess costs we determined the real cost of treatment up to total remission, followed by consolidation or withdrawal of treatment or death. For survival time exceeding the 2-year observation period we used data from recent literature. The average cost of treatment ranges up to 107,592 Swiss francs (CHF). In 1997 we treated 23 leukaemia patients at Zurich University Hospital and gained a total of 210 life years. This represents an average cost of CHF 11,741 per life year gained. Chief cost items were therapy and personnel costs for nursing staff, followed by hotel business and personnel costs for doctors and diagnosis. Our results for AML treatment are far removed from the $61,500 ranging up to $166,000 discussed in the literature as the "critical" QALY (quality adjusted life years) value. This is the first time the actual costs of AML therapy have been shown for a Swiss cohort. Despite high initial treatment costs and success only in a limited number of patients, the expenditure per QALY is surprisingly low and shows clearly the effectiveness of apparently costly acute medicine.

Safety of liver donation after fatal intoxication with the tricyclic antidepressant trimipramine.

We report the case of a patient receiving long-term treatment with the tricyclic antidepressant trimipramine who died 10 days after a trimipramine overdose. A few hours before death, the serum trimipramine concentration had fallen to 80 microg/L. Similar values are reported for patients taking therapeutic trimipramine doses. At this serum concentration, the liver content of trimipramine and it's 2-hydroxy and N-desmethyl metabolites was 1750 microg/kg, 850 microg/kg, and 225 microg/kg, respectively. The liver was morphologically normal. Back calculations suggest that a liver transplant obtained from a donor dying from a trimipramine overdose should be safe, if the serum trimipramine concentration has fallen below 2000 microg/L. If higher serum trimipramine concentrations are present, harvesting should be delayed to avoid trimipramine toxicity in the recipient.

Septic pulmonary embolism due to periodontal disease in a patient with hereditary hemorrhagic telangiectasia.

A patient suffering from multiple episodes of fever and chills due to septic pulmonary emboli is reported. Hereditary hemorrhagic telangiectasia was involving the mucous membranes of his oral cavity and the stomach but not the pulmonary vascular bed. Since no other infectious embolic sources were found and the patient's pulmonary infection was not extirpated by a prolonged course of antibiotics but only cured after surgical treatment of multiple periodontal abscesses, we speculate that gingival arteriovenous malformations being involved by periodontitis were the source of small septic emboli.

[Recombinant activated Factor VII (Novoseven Novo Nordisk) for hemostasis in acquired Factor VIII-inhibitor hemophilia]. / Rekombinanter aktivierter Faktor VII (Novoseven Novo Nordisk) zur Blutstillung bei erworbener Hemmkörper-Hämophilie.

One life threatening mediastinal hemorrhage and two limb threatening hemorrhages, one in the retroperitoneal and thigh muscles and the other in the back of the hand requiring surgical evacuation, were treated with recombinant activated factor VII concentrate (rFVIIa; Novoseven Novó Nordisk) in a patient with a postpartum acquired inhibitor against factor VIII. High dose activated prothrombin complex concentrate (Feiba sTIM4 Immuno), repeatedly administered, had proven to be ineffective; porcine factor VIII concentrate (Hyate C Porton) had become ineffective due to a rise in inhibitor titers against human and porcine factor VIII as well. 90 micrograms rFVIIa per kg body weight was administered as an i.v. bolus injection every 2-3.5 hours. The treatment periods were 22.5 days in the mediastinal and 11 days in each of the two other hemorrhages. Hemostasis was promptly achieved and maintained. All manipulations (bone marrow biopsy, surgical evacuation of the hematoma, change of venous access, withdrawal of drains, change of dressings) were done immediately after rFVIIa administration, without bleeding complications. There were no side effects despite the high dose, frequent and long lasting treatment with a total of 234 x 4.8 and 46 x 3.6 mg rFVIIa. The concentrate was well tolerated, there were no signs of systemic activation of coagulation, either in the coagulation test results or clinically, in spite of patient's factor VII levels up to 60 U/mL and prothrombin times around 6 s. No inhibitors against patient's factor VII, induced by rFVIIa, were detected. Due to its extrinsic factor VIII bypass effect, rFVIIa led to excellent hemostasis even with inhibitor titers of 376 Bethesda units against human and 44 against porcine factor VIII. Nevertheless, immunosuppressive treatment with cyclophosphamide and prednisone was performed, with prompt decrease of the inhibitor titer.(ABSTRACT TRUNCATED AT 250 WORDS)

[Meningitis in adults]. / Die Meningitis beim Erwachsenen.

The clinical presentation of a 38-year-old female patient with acute onset of fever and decreased level of consciousness is described. The clinical reasoning concerning differential diagnosis, therapeutic options, workup of the patient and possible bacterial etiologies, which is usually part of the physician's initial encounter with the patient, is included in the case presentation. This summary of a workshop offers a concise review of clinical aspects of bacterial meningitis.

Atypical manifestations of pityriasis lichenoides chronica: development into paraneoplasia and non-Hodgkin lymphomas of the skin.

Three patients with atypical courses and manifestations of pityriasis lichenoides chronica (PLC) are presented. The first patient is a 21-year-old white woman who showed a good response of her PLC lesions as well as her reactive oligoarthritis to repeated PUVA treatments combined with oral prednisone during 1 year. The effect of the treatment then decreased. The patient developed a low-grade malignant lymphoma of the lung. When the lymphoma of the lung improved after chemotherapy, the PLC eruptions improved, too. The second patient is a 41-year-old man, whose Hodgkin's disease stage IVa was successfully treated by chemotherapy and radiotherapy in 1984. In 1987 he showed PLC lesions which responded well to PUVA therapy, later also in combination with etretinate. Until 1988 repeated skin biopsies revealed a non-specific eczematous pattern. In 1989 the recalcitrant PLC eruptions finally revealed a pleomorphic non-Hodgkin lymphoma of the skin with medium-sized cells. The third patient had a PLC for about 9 years when Hodgkin's disease stage Ia was diagnosed. At the beginning the skin biopsy showed an eczematous pattern, but 2 years later, in 1990, skin infiltrations of a large-cell, anaplastic non-Hodgkin lymphoma were seen. These cases show that PLC in rare cases may either represent a paraneoplastic skin disease or may itself develop into cutaneous lymphomas.

[Health status and late complications following allogeneic bone marrow transplantation. A review]. / Gesundheitszustand und Spätkomplikationen nach allogener Knochenmarktransplantation. Eine Ubersicht.

Better results following bone marrow transplantation (BMT) have increased the number of patients in longterm follow-up. Health status and late effects are therefore of increasing interest. We discuss here the incidence and follow-up of late complications after allogenic BMT. Any conditioning regimen including TBI in postpubertal women introduces a postmenopausal status. In contrast, normal function is found after BMT without irradiation. In men, there is usually permanent azoospermia after TBI but not following chemotherapy alone. Thyroid dysfunction after BMT with TBI has been reported in about 40% of patients. In most of them compensated hypothyroidism with elevated TSH is found. BMT with TBI induces growth retardation in children. Decreased growth hormone levels are observed and substitution can induce normal height development. Interstitial pneumonitis (IP) is a major cause of death. It occurs on average three months after BMT but late onset IP's are increasingly reported. Cataracts are common after BMT. The risk of cataracts in patients given single dose TBI attains 80-100% after four years. Under treatment with cyclophosphamide alone, the risk of lens opacification is less than 20%. So far, patients treated with fractionated TBI have not developed more cataracts than those treated with chemotherapy alone. Impaired renal function is common early post-transplant. Risk factors include cyclosporine (CSA) nephrotoxic antibiotics and antifungal drugs. So far, few secondary malignancies have been reported in humans after BMT. However, actual observation time is still too short for final evaluation. Prevention or treatment is instituted for common complications. It is expected that other types of tissue damage will be recognized.(ABSTRACT TRUNCATED AT 250 WORDS)

[Aplastic anemia combined with an autoimmune disease (eosinophilic fasciitis or glomerulonephritis)]. / Aplastische Anämie kombiniert mit einer Autoimmunkrankheit (eosinophile Fasciitis beziehungsweise Glomerulonephritis).

We describe 3 patients with aplastic anemia and an autoimmune disease. Two had eosinophilic fasciitis and 1 glomerulonephritis. In all patients both diseases were successfully treated by immunosuppressive therapy. Pathophysiological aspects of this association are discussed.

Comparison of epidermal growth factor receptor expression in lung cancer by immunohistochemical staining of both frozen and formalin fixed specimens.

Two monoclonal antibodies used to investigate the expression of the epidermal growth factor receptor (EGF-R) in 45 lung cancers were compared. The R1 antibody recognises the extracellular domain portion of the receptor and the F4 is directed against the cytoplasmic portion. The reactivities of the two antibodies have been compared in fresh frozen tumour specimens. In addition the staining activity of the F4 antibody (the first to EGF-R which can be used in archival material) was compared using frozen and paraffin sections from the same series of tumours. Comparisons of the numbers of cells staining with the R1 and F4 antibody showed only slight discrepancy when fresh material was examined. The discrepancy that existed could be explained by the heterogeneity of the tumours. Very similar results were obtained using the F4 antibody on paraffin embedded and fresh non-small cell lung cancer material. We conclude that the expression EGF-R can be detected reliably by the F4 antibody in both the fresh frozen and formalin fixed, paraffin embedded material and could be useful in assessing the clinical importance of EGF-R in archival tumour material.

[Emergency therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF)]. / Notfalltherapie mit Granulozyten-Makrophagen-Kolonien stimulierendem Faktor (GM-CSF).

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been tested for tolerability and efficacy on a compassionate need case basis in 17 patients (5 females, 12 males aged 4-72 years, median 35 years). GM-CSF was given at the rate of 3.5-32 micrograms/kg for 2-64 days as a continuous infusion for the following indications: impending rejection following bone marrow transplantation (5 patients), severe neutropenia secondary to chemotherapy in tumor patients (5), severe aplastic anemia (3), immune granulocytopenia (2) and accidental overdose with cytostatic agents (2 patients). Tolerance of GM-CSF was good in regard to doses of up to 16 micrograms/kg. Fever, myalgia and eosinophilia were the most frequent side effects. The patient treated with 32 micrograms/kg developed thrombosis of the vena cava. Efficacy is more difficult to assess in this heterogenous population, but 11 of 17 patients showed increased granulocyte counts and 3 patients clearly recovered from severe neutropenia. The role of GM-CSF in this recovery, however, cannot be proven. The results further indicate that GM-CSF cannot reverse ongoing rejection following allogenic BMT and cannot correct immune neutropenia. The value of GM-CSF therapy in patients with severe aplastic anemia and in the context of chemotherapy still needs to be defined. It is certainly indicated in patients with an accidental overdose of chemotherapeutic agents.

[Immunoglobulin deficiency after repeated plasmapheresis]. / Immunglobulinmangel nach wiederholter Plasmapherese.

In 10 patients with Guillain-Barré syndrome the level of globulins and immunoglobulins before and after plasmapheresis was investigated. As a plasma substitute either PPL (in 8 patients) or a plasma substitute solution rich in immunoglobulins (in 2 patients) was used. When plasma was substituted with PPL, the globulins and immunoglobulins dropped to a mean of 40% of the initial value (range 30-60%) after the first plasmapheresis. With daily or alternate day plasmapheresis, the globulins only partially recovered. Before the second plasmapheresis they were still reduced to a mean of 50% (range 20-50%), and dropped further with ongoing exchanges to a mean of 33% (range 20-50%) as measured before the third plasmapheresis. Accordingly, there was a loss of immunoglobulins of similar magnitude. With the use of a plasma substitute solution rich in immunoglobulins (IRP), globulins could be maintained at normal levels. The lowest immunoglobulin values measured after plasmapheresis were 6 g/l (normal range 8-17 g/l). One patient developed gram-negative septicaemia after plasmapheresis with PPL, possibly due to a low immunoglobulin concentration. We conclude that a plasma substitute solution rich in immunoglobulins should be used for therapeutic plasmapheresis in order to maintain physiological immunoglobulin concentrations.

High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study.

In a dose escalation study we tested the feasibility and tolerance of high-dose recombinant human erythropoietin (r-HuEPO) therapy in four patients with ineffective erythropoiesis due to myelodysplastic syndromes (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Recombinant human EPO was administered i.v. with an initial dose of 50 U/kg body weight (BW) three times per week. The dose was increased by steps of 25 or 50 U/kg bW with intervals of 1-4 weeks up to a maximum dose of 500 U/kg BW three times per week. All patients were treated as outpatients. Pre-study treatment with cyclosporin A and/or Danazol was continued in three patients. In one patient r-HuEPO was discontinued after 20 weeks because of relapse of severe aplastic anemia. No major side effects were observed even at the maximum dose. One patient with PNH showed an increase of hemoglobin from 89 to 139 g/liter that permitted monthly phlebotomies to reduce his iron overload. In one patient with MDS the reticulocyte count increased from 2.5 to 50 x 10(9)/liter, and the transfusion requirement decreased to 2 U every 3-4 weeks instead of every 2 weeks. Two patients did not complete the whole treatment period and showed no rise in reticulocyte count. We conclude that high dose r-HuEPO therapy is feasible in patients with anemia due to MDS or PNH. High-dose r-HuEPO appears to have some effect on anemia due to ineffective erythropoiesis in a subgroup of patients. Further studies are needed to identify potential responders and to define the optimal administration of r-HuEPO.

DNA analysis by flow cytometry in malignant pleural mesothelioma: relationship to histology and survival.

In a retrospective study of 70 patients with malignant pleural mesothelioma, 168 formalin-fixed, paraffin-embedded tumour specimens were examined for DNA content by flow cytometry. In 20 patients where two or more blocks of the same tumour were available, there was considerable agreement between ploidy status and S-phase percentage in the different specimens. There were no significant differences for survival for patients who had been exposed to asbestos and those in whom no exposure could be elicited, nor for aneuploid and diploid tumours. The S-phase content was examined for different areas of the same tumour and the percentages were largely in agreement. However, those patients who had tumours with an S-phase percentage greater than the median (6 per cent) had a significantly shorter survival than those with tumours of lower S-phase percentage. Differences in DNA content and other cell cycle parameters were not associated with the histological subtypes.

Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody.

The expression of epidermal growth factor receptor (EGF-R) in 34 formalin fixed paraffin embedded specimens of malignant mesothelioma was examined using the F4 antibody. Eight samples of reactive pleura showed homogenous cytoplasmic staining with the antibody. EGF-R positive cells (greater than or equal to 5%) were found in 68% of the mesotheliomas examined. EGF-R positivity was more commonly seen in the epithelial histological subtype than in the sarcomatous or mixed subtypes. Patients with less than 5% of mesothelioma cells staining positive for EGF-R had a significantly shorter survival (median 299 days) compared with patients whose tumours had a greater number of cells positive for EGF-R (median 446 days) (P = 0.04). However, when the histological subgroup was also taken into consideration (epithelial type had a significantly longer survival than the sarcomatous or mixed) the survival difference in relation to EGF-R positivity was no longer significant (P = 0.08). EGF-R could not be used to distinguish between malignant and benign mesothelial tissue and was not an independent prognostic factor for survival.

DNA analysis by flow cytometry in nonsmall cell lung cancer: relationship to epidermal growth factor receptor, histology, tumour stage and survival.

In a retrospective study, surgical specimens of 136 patients with nonsmall cell lung cancer, were investigated for DNA content by flow cytometry. Seventy per cent of all tumours were aneuploid. Aneuploidy was a statistically significant factor for shorter survival and was independent of tumour size, histology, grade of differentiation, regional lymph node involvement, age and sex (P less than 0.02). A high proliferation index (greater than 7.5%) was also a prognostically unfavourable factor and was observed significantly more often in tumours where the majority of cells expressed epidermal growth factor receptor.

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: a phase II study.

Recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) were used to treat 34 patients with progressing metastatic melanoma. Five patients had solely non-visceral disease and the median number of organ sites involved was two. Five doses of rIL-2 were given, the first dose intrasplenically via a femoral artery catheter with a further dose 4 h later i.v. and the other doses i.v. on alternate days. The rIL-2 dose was 11 x 10(6) Cetus units m-2; the day before rIL-2, FAA (4.8 G m-2) was given as a 6 h i.v. infusion, in order to enhance further killer cell activity. A total of three courses at 21-day intervals was planned and 74 courses in all were given. Despite the high dose of rIL-2 and the potential overlapping toxicity affecting blood pressure with the addition of FAA, side-effects were generally mild. There were only five episodes of grade 4 toxicity: one of ventricular tachycardia and four other episodes of transient biochemical or haematological disturbance. Grade 3 hypotension or hypertension occurred on 22 courses but again was transient. No patient required intensive care facilities. Five patients had tumour response, one being complete. Responses occurred in pulmonary and hepatic metastases, but mainly in non-visceral sites. Eleven patients remain alive at 6-17 months and in five there is no relapse or progression of disease. Despite the impressive results in animal tumour models, the addition of FAA to rIL-2 in the present study has not markedly improved results over rIL-2 alone.

Recombinant interleukin-2 (rIL-2) given intrasplenically and intravenously for advanced malignant melanoma. A phase I and II study.

Recombinant interleukin-2 (rIL-2) was used to treat 31 patients with progressing metastatic malignant melanoma. Only three patients had disease confined to non-visceral sites; the median number of organ sites involved was four. The first dose of rIL-2 was given intrasplenically (to stimulate cytotoxic cells in high concentration) via a femoral artery catheter, and four further i.v. doses were given over 6 days. A total of three courses at 21-day intervals was planned. Doses were escalated in 15 patients from 1 x 10(6) to 16.4 x 10(4) Cetus units m-2. The maximum tolerated dose (11.0 x 10(6) U m-2) was used in the other 16 patients. Of the 71 courses, severe but transient toxicity requiring interruption of rIL-2 or additional care occurred on three courses (dyspnoea) and 15 from hypotension, but the patients' performance status improved. Four patients had partial tumour responses although in only one patient did response occur in all sites of disease. However, responses occurred in visceral sites and six patients are alive at 9-16 months. IL-2 is of use in advanced melanoma and does not need complicated ICU facilities.