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Biomedical subjects

M Freund

Publications and source records attributed to M Freund.

At least 37 records · Page 2Linked to original sources
PubMed2000

Multicenter phase II study of oral idarubicin in treated and untreated patients with B-chronic lymphocytic leukemia.

Idarubicin is the first anthracycline that can be administered orally facilitating antineoplastic chemotherapy at an improved quality of life. In different studies idarubicin has proved clinical effectiveness in patients with advanced low grade non Hodgkin's lymphoma. We performed a phase II study in 19 patients with untreated and pretreated B-CLL of Binet stage A-C. Idarubucin was administered orally at a dose of 15 mg/m2 over 3 days every 4 weeks. Of 19 evaluable patients (m:f, 16:3, median age 64 years, range 41-80 years) 7 were previously untreated while 12 patients had received prior therapy with fludarabine, chlorambucil or similar non-anthracycline containing regimens. 12 pts had Binet stage C, 5 Binet stage B and 2 Binet stage A. Five patients achieved a partial remission (26%), 5 patients had stable disease (26%) and 9 patients showed progressive disease (47%), resulting in an overall response of 26% (5/19). There was no correlation of response rate with Binet stages or previous treatment regimens. Treatment associated side effects consisted predominantly of mild nausea and vomiting (26%) as well as minor infections (21%) and diarrhoea (16%). These data demonstrate that oral idarubicin as a single agent is well tolerated but of limited effectiveness in B-CLL. Further studies are needed to assess different doses and schedules of oral idarubucin and to test it in combination with other chemotherapeutic agents.

Administration, Oral↗
PubMed2000

GPV is a marker of in vivo platelet activation--study in a rat thrombosis model.

Thrombin plays a central role in the genesis of thrombotic events and is the most potent known platelet agonist. This enzyme activates platelets by cleaving G-protein coupled protease activated receptors (PARs) and by binding to glycoprotein (GP) Ib. Thrombin also cleaves platelet GPV to liberate a soluble 69 kDa fragment (GPVf1), leaving a 20 kDa fragment (GPVf2) attached to the membrane. The aim of this study was to assess the value of GPV as an in vivo marker of the activation of platelets by thrombin. Newly developed monoclonal and polyclonal antibodies recognizing rat GPVf1 and GPVf2 respectively were used to detect soluble GPV by ELISA and the new NH2-terminus exposed by thrombin using flow cytometry. These assays were employed in a rat thrombosis model designed to trigger thrombin formation in vivo. When thromboplastin (4.8 ml/kg/h) was infused for 30 min, thrombin generation was reflected by a rapid increase in thrombin-antithrombin (TAT) complexes in plasma and by the appearance of GPVf2 at the surface of circulating platelets. Simultaneously, GPVf1 disappeared from the surface of platelets and accumulated as a soluble fragment in plasma, where it was detected by GPV ELISA. These effects were inhibited by pretreatment of the rats with hirudin. Levels of plasma PF4 also increased in this model, but unlike GPV levels which returned slowly (> 2 hours) to baseline, PF4 had a very short half-life. In conclusion, GPV is cleaved by thrombin in vivo, circulates and is a reliable in vivo marker of the activation of platelets by thrombin. Monitoring of GPV levels in rats should be useful to evaluate the effects of antithrombotic and antiplatelet drugs, while further studies will be required to confirm the potential interest of GPV as a marker of thrombotic states in humans.

Animals↗
PubMed2000

Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

Adult↗
PubMed1999

[Intestinal lymphoma. A long diagnostic path].

CASE REPORT: We describe the case of a 43-year-old patient with a Burkitt lymphoma in the small intestine, who initially presented with abdominal discomfort, weight loss, constipation and neurological symptoms. DIAGNOSIS: In terms of differential diagnosis other inflammatory and tumorous diseases had to be considered. Non-Hodgkin lymphomas are common malignant afflictions of the GI-tract. The total body tumor burden is the principal determinant of prognosis. Serum lactate dehydrogenase (LDH) level is one parameter that reflects the tumor burden. On the other hand abdominal mass, bone marrow and central nervous system involvement are negative prognostic factors. Lymphomas can invade in the CNS at any time during the course of disease. This is generally associated with a poor prognosis if not treated immediately. TREATMENT: High doses of cyclophosphamid and MTX have been shown successful in the treatment of Burkitt lymphoma. Almost all relapses occur on therapy or shortly after termination of treatment. Therefore, criteria are needed to select patients of higher and lesser risk to protect the latter from the further intensification of therapy.

Adult↗
PubMed1999

Detection of residual aneuploid leukemic cells by "continuous gating".

BACKGROUND: A new method for the detection of residual aneuploid leukemic cells in bone marrow by flow cytometry is described. This method is based on the analysis of FCM derived list-mode-datasets with a new software called "Continuous Gating". The program is able to decrease the detection level of aneuploid tumor cells by analyzing groups of cells with comparable antigen density and scatter properties. METHODS: Aneuploid acute lymphocytic leukemia cells with a known CD34 expression were diluted with diploid bone marrow cells to a concentration of 10, 1, 0.1, 0.05, and 0.01%. Each sample was measured in a FACScan flow cytometer, after staining with CD34 Moab and propidium iodide. Listmode-data were analyzed with the new "Windows"-based "Continuous Gating" software. A gate was set in the DNA parameter, defining the channels in which the aneuploid G0/G1-peak of possible residual tumor-cells should be found. Ten thousand overlapping gates of size 200 x 200 channels (out of 1,023 x 1,023 channels) were set automatically by the program into the side-scatter (SSC)/CD34 dot-plot, calculating the percentage of aneuploid G0/G1-phase cells for every specific gate. RESULTS: The results are plotted in a contour-plot. In dot-plot gates with less than 20 cells, the calculation of the percentage of aneuploid cells was declared invalid and the area in the contour-plot was marked. Detection of residual aneuploid cells, based on a defined expression of CD34 and granularity (SSC), was possible down to a contamination of 0.1%. CONCLUSIONS: The new "Continuous Gating" software can be used for the automated detection of aneuploid leukemic cells, if the density of a certain surface-marker is slightly different from normal cells.

Adult↗
PubMed1999

[Treatment of adult acute lymphoblastic leukemia].

In patients with adult ALL, substantial progress has been made in the past 20 years. At present a cure rate of 30-40% can be achieved and varies in defined subgroups between 10-51%. ALL does not represent an uniform disease but is formed by biologic subentities, which differ in their natural history, clinical presentation and prognosis. A comprehensive diagnostic examination, including morphology, cytochemistry, immunology, cytogenetic and molecular genetic analysis is a precondition for prognostic assessment and therapeutic stratification. The basic principle of ALL treatment is a combination chemotherapy with sequential administration of induction, consolidation and maintenance therapy. Bone marrow transplantation has become an important part of the treatment strategy and is performed in patients with high risk. In the subgroup of T-ALL a significant progress has been made in the last years with survival rates of 40-50%. In B-ALL the results have been greatly improved to 48-51% by introduction of a specific treatment strategy. However, the results (about 30%) stagnate for the total group of B-lineage-ALL (common ALL, pre-B-ALL, pro-B-ALL). Patients with B-lineage-ALL can be subdivided in a high and low risk group according to the presence of risk factors (age, white blood cell count, time to achieve a complete remission, pro-B-ALL and the translocations t[4;11], t[9;22]). The outcome of the subgroup of adult pro-B-ALL has been substantially improved (50%). An increase of treatment results (20%) appears in outlines for patients above 50 years. The Ph/bcr-abl positive ALL has in spite of improved complete remission rates (60-70%) consistently unfavourable survival rates (10%).

Adult↗
PubMed1999

Antithrombotic effects of (n-3) polyunsaturated fatty acids in rat models of arterial and venous thrombosis.

The antithrombotic effects of dietary lipids were investigated in rat models of arterial and venous thrombosis. In the arterial model, thrombus formation was evaluated by determination of the occlusion time and the deposition of 111In-labeled platelets and 125I-labeled fibrinogen in a collagen-coated glass capillary inserted into an arterio-arterial shunt. Venous thrombosis was evaluated by measurement of the thrombus weight after administration of thromboplastin as a source of tissue factor and establishment of stasis in the vena cava. Diets were supplemented with saturated (SAT group) or (n-3) fatty acids, the latter being added either as MaxEPA oil (MaxEPA group), or as docosahexaenoic (DHA group) or eicosapentaenoic (EPA group) ethyl ester. Only the MaxEPA group displayed a prolonged occlusion time as compared with all other groups. Platelet accumulation, similar in the MaxEPA, EPA and DHA groups (13.3, 16.7 and 17.7 x 10(6) platelets/shunt, respectively), was significantly higher in the SAT group (25.3 x 10(6) platelets/shunt), while accumulation of fibrinogen-fibrin was similar whatever the group. There was a trend towards a lower venous thrombus weight in MaxEPA fed rats relative to those fed other diets. Our data indicate that the MaxEPA diet had antithrombotic effects in arterial and to a lesser extent venous thrombosis models, best attributed to its multiple targeting of platelets and coagulation.

Animals↗
PubMed1999

Optimized preoperative planning of calcaneal fractures using spiral computed tomography.

The aim of this study was the evaluation of spiral-CT examinations in preoperative planning of calcaneal fractures supported by 3D reconstructions after electronic disarticulation. We examined 45 patients with 47 calcaneal fractures with diagnostic spiral-CT examinations in a prospective study. In addition to the conventional axial slices and sagittal reconstructions, 3D reconstructions prior to and after electronic disarticulation were performed and rated by orthopaedic surgeons and radiologists. The following diagnostic criteria were rated: involvement of articular facets, number of fragments and hindfoot deformities. Axial slices were considered to be the gold standard, because not all patients underwent surgical treatment. Axial slices showed involvement of 90 articular facets (100 %). Three-dimensional reformations after electronic disarticulation depicted 82 fractures (82 of 90, 91 %), sagittal reconstructions 63 fractures (63 of 90, 70 %). Three-dimensional reconstructions without electronic disarticulation showed five fractures (5 of 90, 5.5 %). The number of fragments was demonstrated best on sagittal reconstructions (two, three or four fragments); five fragments were diagnosed best on axial slices, and 3D reconstruction without electronic disarticulation showed only a very small number of fragments, due to overlaying bones. Hindfoot deformities (lateralisation, varus deformation, shortening) were demonstrated best on axial slices, except in terms of showing height reduction, which was demonstrated better on sagittal and 3D reconstructions. Three-dimensional reconstructions after electronic disarticulation support a clear understanding of the 3D position of the fragments and of their displacement in comparison with 3D reconstruction without electronic disarticulation, which is essential for an effective surgical reduction. Due to the potential manipulation of surface-oriented 3D reconstructions, regardless of whether electronic disarticulation is used, this imaging technique should not be considered in an isolated framework. Three-dimensional images without electronic disarticulation are superfluous in any case.

Calcaneus↗
PubMed1999

Complete paraplegia due to multiple intracerebral and spinal cavernomas.

We report on a 29-year-old male patient with multiple intracerebral and spinal cavernomas. Bleeding in the thoracic cord at admission and additional bleeding which occurred 12 days later in the cervical cord resulted in complete paraplegia below thoracic level 4 (Th4). Four years earlier multiple cerebral cavernomas had been diagnosed by magnetic resonance imaging (MRI). Based upon reported cases in the literature multiple intracerebral and spinal cavernomas are exceptional. Additionally, the clinical presentation in our case is uncommon.

Adult↗
PubMed1999

Ascending myelopathy in the early stage of spinal cord injury.

A 30-year-old healthy woman was involved in a road traffic accident. She sustained a fracture dislocation of T11/12 with a complete Frankel A paraplegia below T11. She had no associated injuries. High Dose Methylprednisolone was administered according to the NASCIS III protocol (48 h) together with low molecular weight Heparin and gastroprotected medication. Complete transection of the spinal cord and an anterior haematoma from T11 to T12 were confirmed on X rays, CT's and MRI scans. Posterior surgical stabilisation was performed using Isola instrumentation, starting 8 h post injury. Her post surgical period was uneventful except for some episodes of low blood pressure (85/60 mmHg) from which she had no symptoms. On the 12th post operative day, while in the physiotherapy department, she complained of right scapular pain. This occurred every time she was sat up and was associated with paraesthesia of both upper limbs. Two days later she deteriorated neurologically and her level ascended initially to T8 and then to T3. MRI of the spine with and without gadolinium showed spinal cord oedema between C3 and T1. There was no evidence of haemorrhage or syringomyelia. The authors discussed this case making different hypotheses. They are mainly the following: (1) Gradually ascending ischaemia due to a vascular disorder; (2) Double spinal trauma; (3) Ischaemia related to repeated hypotensive episodes; (4) Low grade intramedullary tumour; and (5) Thrombus of the Radicularis Magna artery. The case has been recognised as being very rare and interesting. In the conclusions, the presenting author stresses the importance of adopting MRI-compatible instrumentation for the surgical stabilisation of the spine, and careful monitoring of blood pressure during the acute phase of spinal cord injury. Dr Aito agrees with Mr El Masry about the opportunity of forming a group of clinicians in order to discuss protocols to cope with this devastating complication.

Adult↗
PubMed1999

[Posttraumatic syringomyelia].

The improvement of preclinical emergency medicine, better surgical and conservative therapies, and the development of intensive care units and specialized centers have improved the survival rate for patients with serious spinal cord injuries. Therefore, more sequelae of chronic spinal cord injuries such as post-traumatic spinal cord cavitations also occur. The first such case was described by Bastian in 1867. Generally, these cavitations were diagnosed from 2 months up to 32 years after the trauma. The overall prevalence of post-traumatic syringomyelia (PTS) is not known; however, with the increasing use of magnetic resonance imaging (MRI), its diagnosis has increased, ranging from 2.3% of paraplegic and tetraplegic patients in 1976 and 3.2% in 1985, to nearly 50% in a selected group of patients in 1991 and 1993. In 1995, a 4.45% incidence was reported. In our clinic we are currently treating 440 cases of syringomyelia, 140 of which are PTS. Several observations suggest more than one potential mechanism for the evolution of a post-traumatic cyst or PTS. Various factors, such as hemorrhage or, in particular, ischemia within the spinal cord, blockage of the cerebrospinal fluid (CSF) pathways around the cord or localized meningeal fibrosis either alone or in combination with other factors, may be involved. Clinically, sensory disturbances, loss of motor function, pain, and modification of the deep tendon reflexes are observed in most patients. On MRI, PTS is seen as a longitudinal, cystic cavity within the spinal cord, giving a hypointense signal on T1-weighted images and a hyperintense signal on T2-weighted images. For treatment planning it is mandatory to identify the lower and upper end of the PTS on the MRI.

Humans↗
PubMed1999

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice.

ADP is a key agonist in hemostasis and thrombosis. ADP-induced platelet activation involves the purinergic P2Y(1) receptor, which is responsible for shape change through intracellular calcium mobilization. This process also depends on an unidentified P2 receptor (P2cyc) that leads to adenylyl cyclase inhibition and promotes the completion and amplification of the platelet response. P2Y(1)-null mice were generated to define the role of the P2Y(1) receptor and to determine whether the unidentified P2cyc receptor is distinct from P2Y(1). These mice are viable with no apparent abnormalities affecting their development, survival, reproduction, or the morphology of their platelets, and the platelet count in these animals is identical to that of wild-type mice. However, platelets from P2Y(1)-deficient mice are unable to aggregate in response to usual concentrations of ADP and display impaired aggregation to other agonists, while high concentrations of ADP induce platelet aggregation without shape change. In addition, ADP-induced inhibition of adenylyl cyclase still occurs, demonstrating the existence of an ADP receptor distinct from P2Y(1). P2Y(1)-null mice have no spontaneous bleeding tendency but are resistant to thromboembolism induced by intravenous injection of ADP or collagen and adrenaline. Hence, the P2Y(1) receptor plays an essential role in thrombotic states and represents a potential target for antithrombotic drugs.

Adenosine Diphosphate↗
PubMed1998

Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study.

OBJECTIVE: To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients. DESIGN: Single centre stratified, randomised non-blinded phase II study. SETTING: University hospital providing tertiary clinical care. SUBJECTS: 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27). INTERVENTIONS: Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion. MAIN OUTCOME MEASURES: Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute). RESULTS: Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05). CONCLUSIONS: Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs.

Adolescent↗
PubMed1998

Radiologic and histopathologic findings in a rare case of complex occult spinal dysraphism with association of a lumbar fibrolipoma, neurenteric cyst and tethered cord syndrome.

We present the case of a 60-year-old farmer who reported non-specific back pains for the past 30 years. Increasing paralysis of the left leg led to hospitalization. A complex occult spinal dysraphism comprising a fibrolipoma of the conus medullaris, an neurenteric cyst, and a tethered cord syndrome was diagnosed and operated on. The radiological and histological findings are demonstrated.

Follow-Up Studies↗