Recombinant human erythropoietin in combined treatment with granulocyte- or granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes.

PURPOSE: Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopoietic progenitor cell disorders, and patients with MDS regularly develop anemia and frequently become transfusion-dependent. Treatment with erythropoietin (EPO) has been tried to correct anemia with only limited success with response rates ranging from 16% to 25%. However, it is becoming evident that the generally rather low response rate of EPO in patients with MDS will be improved by the combination of EPO with either G-CSF or GM-CSF. METHOD: Here, we analyzed the results from the literature (six papers and one abstract using EPO plus G-CSF, and seven papers using EPO plus GM-CSF). RESULTS: Among all trials the cytokine dose and schedule varied, and the response criteria were not uniform. The average response rate for improving anemia was 41% in 207 patients treated with EPO and G-CSF, and 26% in 154 patients treated with EPO and GM-CSF. There were higher response rates for refractory anemia (RA) (45%), ringed sideroblasts (RARS) (47%), and excess of blasts (RAEB) (38%) compared with blasts in transformation (RAEBT) (17%) for the treatment with EPO plus G-CSF. The corresponding response rates for treatment with EPO plus GM-CSF were 30% (RA), 29% (RARS), 16% (RAEB), and 0% (RAEBT), respectively. Prolonged administration even showed a higher increment in the response rates. CONCLUSION: In conclusion, the combination of EPO with G-CSF is probably superior to EPO plus GM-CSF. There seems to be a positive correlation between the duration of cytokine treatment and response rates, and higher response rates in early MDS stages compared to advanced entities. However, controlled studies are mandatory to evaluate the role of the combined cytokine treatment in patients with MDS.

[Genetically engineered drugs and their application with the example of erythropoietin]. / Gentechnische Herstellung von Arzneimitteln und ihre Anwendung am Beispiel des Erythropoetins.

Over the past two decades, many genetically engineered drugs have been developed and approved for the treatment of patients. Typically, these drugs are characterized by a high and specific activity in the presence of optimal safety. They include hormones, enzymes, growth and coagulation factors, antibodies as well as vaccines. All these proteins are generated using recombinant DNA technology. An expression vector with the gene encoding for the protein of interest is introduced into an appropriate microorganism or cell line. The biochemical machinery of the host cell then translates the genetic information into the corresponding protein. Large scale production of the recombinant drugs uses biotechnological processes. The genetically modified organisms are grown in bioreactors from which the desired protein is finally isolated and purified. This review focuses on the production and clinical application of recombinant erythropoietin in the areas of nephrology, hemato-oncology and elective surgery.

[Patient role in changing conditions: yesterday--today--tomorrow]. / Die Patientenrolle im Wandel der Rahmenbedingungen: Gestern--heute--morgen.

Changing conditions within the German healthcare system and new trends of information management will decisively change the patient's role. Increase in morbidity caused by the ageing population aggravates the economic pressure within the social healthcare system. Due to the ongoing medical progress, this will inevitably lead to the restriction of medical services trough budgeting. Whereas the patient's role in the past was rather passive, his position will change in future. This is not only caused by an increase in patient education and social status, but also by the availability of information provided by the worldwide web. The number of educated patients who are gathering information via the worldwide web and discussing their diseases with fellow patients via e-mail will rapidly grow. The traditional doctor-patient relationship will be less exclusive in future and will be embedded in the network of reimbursement facilities, patients' groups and information management.

[Cardiopathia fantastica: case report and literature review]. / Cardiopathia fantastica--Fallbericht und Literaturübersicht.

We describe the case of a 71-year old medical technician, who was treated for instable angina pectoris in 29 different hospitals 38 times over 9 years. Dramatically presented retrosternal pain regularly started in crowded places, such as bus or railway stations or directly in front of the hospital. Ultrasound and ECG gave evidence of an old inferior myocardial infarction. Invasive diagnostic procedures were rejected by the patient because of an alleged allergy for contrast media. The single, retired patient never admitted former cardiac hospitalizations and restrained the physicians from contacting his local doctor. The patient mostly left the hospital against medical advice and achieved hospitalization in another clinic sometimes the same day. Because of his personality structure, the dramatic presentation of his complaints and the numerous hospitalizations in various hospitals with self-discharge, we made the diagnosis of a cardiac Munchausen syndrome, a so-called cardiopathia fantastica, in the presence of an accompanying coronary heart disease. In the literature we found 52 cases of cardiopathia fantastica since the first description of this phenomenon in the year 1953. Interestingly enough, mostly men were identified. Angina pectoris is by far the most frequent symptom of cardiopathia fantastica. In 8 of 53 patients (15%) an additional cardiac manifestation was present in addition to cardiopathia fantastica. Cardiopathia fantastica on the one hand is an important differential diagnosis of coronary heart disease; on the other hand it may develop in the presence of an underlying cardiac disease.

[Exhaustion and fatigue--a neglected problem in hematologic oncology]. / Erschöpfung und Müdigkeit--ein vernachlässigtes Problem in der Hämatoonkologie.

Exhaustion and tiredness are frequent symptoms in cancer patients. They are caused by the tumour itself and by application of chemotherapy, surgery, radiation or cytokine treatment. Exhaustion and tiredness are not a consequence of lacking sleep or exaggerated physical or mental labour, but are due to several other factors: Anemia, tumour cachexia, toxicity of chemo- and radiation treatment probably are the most decisive factors for the development of exhaustion and tiredness. As both were taken as inevitable side-effects of cancer and cancer treatment in the past, only little attention has been paid to exhaustion and tiredness and limited research has been done. Among several validated questionnaires measuring quality of life in tumour patients the FACT-An (Functional Assessment of Cancer Treatment--Anemia) and EORTC QLQ-C30 questionnaire are the most well-known for identifying exhaustion and tiredness. Nevertheless, until today there is no mere exhaustion scale exclusively dealing with the problem of exhaustion and tiredness. According to the 10th revision of the International Classification of Diseases (ICD) exhaustion and tiredness are subsumed under the diagnosis of tumour fatigue. In contrast to tumour fatigue, which comprises physical, mental and emotional dimensions, exhaustion and tiredness primarily refer to physical symptoms: Lacking resilience for activities of daily life, day sleepiness and nocturnal insomnia as well as restricted power of concentration are the mainstays of exhaustion and tiredness. However, regarding lacking interests, diminished energy and reduced mental capacity, exhaustion and fatigue partly overlap. From a therapeutic point of view behavioural interventions and drug therapy have successfully been tried. Beside physical exercise and psychostimulants application of Erythropoietin represents an innovative treatment of exhaustion and tiredness.

[Fatigue and exhaustion in tumor patients. Etiology, diagnosis and treatment possibilities]. / Fatigue und Erschöpfung bei Tumorpatienten. Ursachen, Diagnostik und Behandlungsmöglichkeiten.

Fatigue is a frequent symptom in tumor patients. Although the phenomenon is well known, there is no homogeneous definition. Decreased quality of life, exhaustion, fatiguability, tiredness, malaise and asthenia are synonymous or overlapping terms used for this syndrome. Validated fatigue questionnaires show that fatigue and exhaustion are present in at least 75% of all tumor patients. Fatigue and exhaustion are enhanced by chemo-, radiation- and immunotherapy as well as surgery. Fatigue in tumor patients has many reasons and comprises physical, mental and emotional facets. The expression exhaustion should be applied for physical fatigue in order to differentiate this form from mental or emotional fatigue. Tumor anemia, atrophy of the skeleton muscles and tumor cachexia are the decisive factors for exhaustion. Treatment of fatigue improves quality of life in tumor patients and enhances their compliance. This paper gives an overview about the different types of fatigue and demonstrates various forms of treatment.

Negative regulation of alpha2-adrenergic receptor-mediated Gi signalling by a novel pathway.

Chinese hamster ovary (CHO) cells stably expressing alpha(2) adrenergic receptor (alpha(2)AR) were pretreated with cholera toxin (CTX) and then treated with or without PMA. The alpha(2A)AR-mediated inhibition of forskolin-stimulated cAMP accumulation was completely ablated by CTX pretreatment only after additional treatment with PMA. Although the addition of cycloheximide (protein synthesis inhibitor) and H-89 (cAMP dependent protein kinase inhibitor) did not completely counteract the negative regulation, the elevation of cAMP was a primary factor for negative regulation by treatment with CTX and PMA. In contrast with the cAMP response, the inhibition of membrane adenylate cyclase activity and the agonist competition curve were not influenced by treatment with CTX or PMA, suggesting that a cytosolic factor was involved in this negative regulation. The m2-muscarinic-acetylcholine-receptor-mediated inhibition of the forskolin-stimulated accumulation of cAMP was also attenuated by treatment with CTX and PMA. The ablation of alpha(2A)AR-mediated inhibition was not observed when alpha(2A)AR was expressed in Rat2 fibroblast cells, suggesting that this negative regulation is not dependent on the receptor type but is instead a phenomenon common to G(i)-coupled receptors in CHO cells. Reverse-transcriptase-mediated PCR and Northern blot analysis showed that the expression of GOS8/RGS2 mRNA, which is a member of the regulator of G-protein signalling (RGS) group of proteins, was considerably increased by pretreatment with CTX. These results indicate a novel regulatory pathway, whereby a cytosolic factor induced by the elevation of cellular cAMP levels negatively regulates G(i) signalling in a protein-kinase-C-dependent manner.

RGS3 and RGS4 are GTPase activating proteins in the heart.

RGS family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes when tested in vitro and in vivo. Although the function of RGS proteins in cardiac physiology is unknown, their ability to deactivate Galpha subunits suggests that they may inhibit the action of muscarinic, alpha-adrenergic, endothelin, and other agonists. To evaluate the role of RGS family members in the regulation of cardiac physiology, we investigated the expression pattern of two RGS genes in normal and diseased rat heart tissue. RGS3 and RGS4 mRNAs and proteins were detected in adult myocardium. RGS3 and RGS4 gene expression was markedly enhanced in two model systems of cardiac hypertrophy: growth factor-stimulated cultured neonatal rat cardiomyocytes and pulmonary artery-banded (PAB) mice. RGS3 and RGS4 mRNA levels were reduced in failing myocardium obtained from SHHF/Mcc-fa(cp) (SHHF) rats. These findings support the hypothesis that RGS gene expression is highly regulated in myocardium and imply that RGS family members play an important role in the regulation of cardiac function.

Aip3p/Bud6p, a yeast actin-interacting protein that is involved in morphogenesis and the selection of bipolar budding sites.

A search for Saccharomyces cerevisiae proteins that interact with actin in the two-hybrid system and a screen for mutants that affect the bipolar budding pattern identified the same gene, AIP3/BUD6. This gene is not essential for mitotic growth but is necessary for normal morphogenesis. MATa/alpha daughter cells lacking Aip3p place their first buds normally at their distal poles but choose random sites for budding in subsequent cell cycles. This suggests that actin and associated proteins are involved in placing the bipolar positional marker at the division site but not at the distal tip of the daughter cell. In addition, although aip3 mutant cells are not obviously defective in the initial polarization of the cytoskeleton at the time of bud emergence, they appear to lose cytoskeletal polarity as the bud enlarges, resulting in the formation of cells that are larger and rounder than normal. aip3 mutant cells also show inefficient nuclear migration and nuclear division, defects in the organization of the secretory system, and abnormal septation, all defects that presumably reflect the involvement of Aip3p in the organization and/or function of the actin cytoskeleton. The sequence of Aip3p is novel but contains a predicted coiled-coil domain near its C terminus that may mediate the observed homo-oligomerization of the protein. Aip3p shows a distinctive localization pattern that correlates well with its likely sites of action: it appears at the presumptive bud site prior to bud emergence, remains near the tips of small bund, and forms a ring (or pair of rings) in the mother-bud neck that is detectable early in the cell cycle but becomes more prominent prior to cytokinesis. Surprisingly, the localization of Aip3p does not appear to require either polarized actin or the septin proteins of the neck filaments.

[Radiologic diagnosis of primary extranodal lymphoma manifestations]. / Radiologische Diagnostik primärer extranodaler Lymphommanifestationen.

Primary extranodal lymphoma manifestation in the narrow sense is the term used to define the primary organ manifestation of a malignant lymphoma, excluding the thymus, spleen, Waldeyer's tonsillar ring, the appendix and Peyer's patches. However, in the clinical routine the term is also used for the secondary organ manifestation of underlying lymphoproliferative disease. Primary extranodal lymphomas are mainly non-Hodgkin lymphomas; there is primary extranodal manifestation of Hodgkin's disease in only about 1% of the cases. Among the extranodal NHL, the highly malignant forms predominate. A major exception is MALT lymphomas, which mainly show low slow growth. In the past, they were considered to be pseudolymphomas because of their slow and localized tumor growth. They were included as an entity of their own for the first time in the Revised European American Lymphoma (REAL) classification of 1994. The incidence data vary between < 10% and 25% for primary extranodal manifestation. The major reason for this is the difference in extranodal regions because of classification. Secondary organ involvement of an NHL occurs in up to 40% of the cases in the long-term course of the disease in primary nodal lymphomas. Secondary organ involvement is frequently diagnosed in AIDS patients who develop an AIDS-related lymphoma (85% of cases). The following contribution reports on the radiological imaging of extranodal lymphoma manifestation in the thoracoabdominal region.

[Glomerulonephritis and malignant lymphoma. Mostly men with low-grade lymphoma with various forms of glomerulonephritis]. / Glomerulonephritis und malignes Lymphom. Uberwiegend Männer mit niedrigmalignem Lymphom mit unterschiedlichen Glomerulonephritisformen.

BACKGROUND: The association of non-Hodgkin's lymphoma with different types of glomerulonephritis is well-known for many years. Whereas in Hodgkin's disease, minimal change glomerulonephritis is mainly observed, in non-Hodgkin's lymphoma various forms of glomerulonephritis are found. PATIENTS AND RESULTS: We describe 3 cases of non-Hodgkin's lymphoma, which were associated with glomerulonephritis. Two cases of glomerulonephritis showed nephrotic syndromes, which improved by medicinal treatment. In 2 cases glomerulonephritis and non-Hodgkin's lymphoma developed simultaneously. In a third lymphoma was followed by glomerulonephritis after 3 years. CONCLUSION: Although the pathogenetic relationship between non-Hodgkin's lymphoma and glomerulonephritis is not fully understood, the high number of reported cases yield interdependence. Lymphoma associated glomerulonephritis is found more often in men than in women. Low-grade non-Hodgkin's lymphomas--especially chronic lymphatic leukemias--seem to develop glomerulonephritis more frequently than high-grade. The majority of non-Hodgkin's lymphoma do not show any predisposition to a special type of glomerulonephritis, only in cutaneous lymphoma IgA-nephropathy predominates.

Association of primary renal non-Hodgkin's lymphoma with mesangioproliferative glomerulonephritis.

A 27-year-old male developed nonoliguric renal failure. Renal biopsy of the left kidney showed infiltration by a diffuse large-cell non-Hodgkin's lymphoma (NHL). Laparoscopy, CT scans of the abdomen and thorax, and bone-marrow biopsy revealed no further manifestations of lymphoma. Primary renal NHL was diagnosed. The patient attained complete remission with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy and remained disease-free for 13 years. Eight years after his first presentation, the patient developed acute oliguric renal failure with nephrotic syndrome. Mesangioproliferative glomerulonephritis was diagnosed in a biopsy of the left kidney. Chronic hemodialysis was required until cadaver kidney transplantation was successfully performed 5 years later. Although the association of NHL and glomerulonephritis has been described several times before, to our knowledge this is the first report of glomerulonephritis in primary renal lymphoma.

Genetic analysis of the bipolar pattern of bud site selection in the yeast Saccharomyces cerevisiae.

Previous analysis of the bipolar budding pattern of Saccharomyces cerevisiae has suggested that it depends on persistent positional signals that mark the region of the division site and the tip of the distal pole on a newborn daughter cell, as well as each previous division site on a mother cell. In an attempt to identify genes encoding components of these signals or proteins involved in positioning or responding to them, we identified 11 mutants with defects in bipolar but not in axial budding. Five mutants displaying a bipolar budding-specific randomization of budding pattern had mutations in four previously known genes (BUD2, BUD5, SPA2, and BNI1) and one novel gene (BUD6), respectively. As Bud2p and Bud5p are known to be required for both the axial and bipolar budding patterns, the alleles identified here probably encode proteins that have lost their ability to interact with the bipolar positional signals but have retained their ability to interact with the distinct positional signal used in axial budding. The function of Spa2p is not known, but previous work has shown that its intracellular localization is similar to that postulated for the bipolar positional signals. BNI1 was originally identified on the basis of genetic interaction with CDC12, which encodes one of the neck-filament-associated septin proteins, suggesting that these proteins may be involved in positioning the bipolar signals. One mutant with a heterogeneous budding pattern defines a second novel gene (BUD7). Two mutants budding almost exclusively from the proximal pole carry mutations in a fourth novel gene (BUD9). A bud8 bud9 double mutant also buds almost exclusively from the proximal pole, suggesting that Bud9p is involved in positioning the proximal pole signal rather than being itself a component of this signal.

[Successful therapy of a postpartum lymphangioleiomyomatosis. Case report and literature review]. / Erfolgreiche Therapie einer postpartalen Lymphangio-leiomyomatose. Fallbericht und Literaturübersicht.

Immediately after delivery a 17-year-old Turkish primipara developed edema, supraclavicular lymphoma and pleural effusion. CT-scans showed massive abdominal and mediastinal lymphoma. Lymphangioleiomyomatosis (LAM) was diagnosed by supraclavicular and retroperitoneal biopsy and progesterone receptors were documented in the tumor. There was no evidence of pulmonary involvement. 5 months' treatment with the LHRH-analogue goserelin showed neither clinical improvement nor regression of LAM. Irradiation of the ovaries and the abdomen with 30.2 Gy was followed by amenorrhea without immediate tumor remission. A follow-up examination 1 year later revealed clinical improvement and CT scans showed 50% abdominal and mediastinal regression of LAM. 5 1/2 years after diagnosis the asymptomatic patient is still in partial remission. Successful treatment of LAM is rare. We describe a case in which a major tumour reduction was documented by CT scanning.

[Immunoproliferative small intestinal disease (IPSID): an unusual form of gastrointestinal lymphoma]. / Immunoproliferative Dünndarmerkrankung (IPSID): eine seltene Form gastrointestinaler Lymphome.

Worsening of long-lasting diarrhea, abdominal discomfort and weight loss were main symptoms in a 27-year-old Moroccan woman who had lived in Germany for 18 years. Pseudomonas, salmonella and lamblia cysts were found in stools. Histological examination of the gastrointestinal tract showed immunoproliferative small intestinal disease (IPSID), characterized by atrophy of the villi and lymphoplasmocytic infiltrates. alpha 1-heavy chains were found immunohistologically in the biopsy specimen, but not in serum, urine or jejunal juice. HLA-typing gave evidence of A9. Antibiotic treatment was successful for almost one year. Clinical, histological and immunological diagnosis of IPSID in an African woman living for nearly 20 years in Europe shows that, besides environmental factors, genetic disposition is an essential factor in the development of IPSID.

Results of conventional-dose cytosine arabinoside and idarubicin in elderly patients with acute myeloid leukemia.

Conventional-dose Ara-C (200 mg/m2 d 1-5) combined with idarubicin (12 mg/m2 d 1-3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60-75) with AML according to the FAB criteria (M1 n = 3, M2 n = 10, M4 n = 6, M5 n = 2, M6 n = 2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.