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Biomedical subjects

D Kotasek

Publications and source records attributed to D Kotasek.

At least 37 records · Page 2Linked to original sources
PubMed1991

A rare translocation (4;11)(q21;p14-15) in an acute lymphoblastic leukemia expressing T-cell and myeloid markers.

A 21-year-old male presented with a large mediastinal mass and a white cell count of 420 x 10(9)/L. A diagnosis of acute lymphoblastic leukemia (ALL) was made, with 90% of cells in the bone marrow (BM) and 99% in the peripheral blood (PB) being lymphoblasts (FAB L1). Cytogenetic analysis of these cells revealed a rare variant of the t(4;11) translocation involving chromosome arm 11p rather than 11q, namely t(4;11)(q21;p14-15). The standard form of the (4;11) translocation has been associated with leukemias with mixed-lineage phenotypes. Three cases of ALL with t(4q;11p) have previously been reported. One of these cases showed phenotypic heterogeneity involving myeloid and lymphoid lineages. The leukemia reported here also exhibits lymphoid/myeloid features. Immunophenotyping of the blasts showed that most of the cells were positive for CD2, CD5, CD7, CD10 (CALLA), CD34, and HLA-DR. A significant proportion of the cells expressed CD33. These results suggest a biphenotypic rather than a biclonal disease. Molecular analysis showed rearrangement of both immunoglobulin heavy-chain genes (JH) and of a single allele of the T-cell receptor (TCR) gamma 1 gene, while retaining germline TCR beta genes.

Adult↗
PubMed1991

Disposition of epirubicin and metabolites with repeated courses to cancer patients.

Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38-50 mg.m-2, mean 49.2 mg.m-2, administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4'-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.

Adult↗
PubMed1991

Mobilization of haemopoietic stem cells by cyclophosphamide into the peripheral blood of patients with haematological malignancies.

Thirty one peripheral blood stem cell mobilizations using cyclophosphamide, followed by leucapheresis, were performed in 25 patients with a variety of haematological malignancies. Cyclophosphamide at doses ranging from 0.25 g/M2/day x 4 days to 4 g/M2 on one day were given. Total doses of cyclophosphamide less than 4 g/M2 failed to induce a significant mobilization of stem cells into the peripheral blood. This compares to cyclophosphamide doses of 4 g/M2 given over one or two days where 70%-75% of patients yielded adequate stem cells for transplantation (greater than 20 x 10(4) CFU-GM/kg). Both the presence of tumour cells in the bone marrow and previous chemotherapy within 12 months of cyclophosphamide infusion significantly diminished the patients stem cell mobilizations. The rate of recovery of the patient's leucocyte count following cyclophosphamide was highly correlated to the peak level of PB CFU-GM and is a good indicator of the total stem cell yield. Fever in 50% of patients during the period of cytopaenia was the only complication seen in our patients and thus high dose cyclophosphamide is a suitable and safe agent for mobilizing haemopoietic stem cells.

Adult↗
PubMed1991

Choriogonadotropin-mediated thyrotoxicosis in a man.

A 38-year-old man with a metastatic gonadotropin-secreting tumor of unknown primary origin presented with both clinical and biochemical findings of hyperthyroidism in association with markedly increased concentrations of human choriogonadotropin (hCG) in plasma. After chemotherapy, the concentrations of both hCG and free thyroxin decreased and the patient became euthyroid. We discuss the rare occurrence of this presumably hCG-driven hyperthyroidism in men and compare it with the relatively more common eumetabolic hyperthyroidism associated with choriocarcinoma in women.

Adult↗
PubMed1990

Herpes simplex virus-infected cells disarm killer lymphocytes.

Human endothelial cells or human foreskin fibroblasts infected with herpes simplex viruses (HSVs) potently inhibit the lytic activity of natural killer cells and interleukin 2-activated killer cells. The inhibition occurs after as little as 8 hr of viral infection and requires contact between effector cells and HSV-infected targets. Inhibition evidently stems from direct blockade of killer cell function because killer cells placed atop HSV-infected targets rapidly become incapable of lysing subsequently added HL-60 or K-562 cells. The impairment of killer cell function is prevented when protein glycosylation in HSV-infected cells is blocked with tunicamycin. These studies may be relevant for understanding the persistence of herpes simplex virus infections and, further, suggest a mechanism for failed immune surveillance.

Adenoviruses, Human↗
PubMed1989

Alteration in doxorubicin and doxorubicinol plasma concentrations with repeated courses to patients.

Fifteen cancer patients were studied following repeated courses of doxorubicin (12-44 mg/m2) (together with other anticancer agents) to consider the possibility of enhanced metabolism as a cause of the previously reported reduction in doxorubicin plasma concentrations with repeated courses. Plasma doxorubicin and doxorubicinol concentrations were measured by a modified high-performance liquid chromatography/fluorescence method. The results presented confirmed the significant decline in doxorubicin plasma concentration-dose ratios measured 3 h after the 1-h infusion. Although the degree of this reduction varied markedly between patients, it was shown not to be associated with a rise in the plasma concentration-dose ratio of the major metabolite doxorubicinol or with altered renal and/or hepatic function, which may have influenced disposition. Alternative mechanisms that might explain the reduction in doxorubicin concentrations, such as increased doxorubicin clearance or volume of distribution, were not considered in the present study.

Adolescent↗
PubMed1988

Mechanism of cultured endothelial injury induced by lymphokine-activated killer cells.

A new form of therapy of experimental tumors, utilizing lymphokine-activated killer (LAK) cells and high doses of interleukin 2, has recently been applied in the treatment of human neoplasms. Severe side effects, suggestive of a diffuse vascular injury of unknown etiology, have prevented a more widespread application of this form of therapy. We have investigated the etiology of this clinical capillary leak syndrome, using an in vitro model of endothelial injury. LAK cells, but not interleukin 2 itself, are cytotoxic to cultured human endothelial cells, and this cytotoxicity is time and dose dependent. This human endothelial cell cytotoxicity can be inhibited by depletion of extracellular Ca2+, inhibition of the effector cell microtubular system, and inhibitors of serine proteases, but is not inhibited in the presence of toxic oxygen radical scavengers. LAK cell-mediated endothelial cytotoxicity is far more potent than that exhibited by maximally stimulated polymorphonucleocytes. LAK cell-mediated injury of human endothelium may possibly be responsible for the capillary leak syndrome observed in patients treated with high doses of interleukin 2 and LAK cells.

Calcium↗
PubMed1988

Renal clearance and protein binding of melphalan in patients with cancer.

The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.

Adult↗
PubMed1988

Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor.

Pentoxifylline has been claimed to work a beneficial effect in arterial insufficiency by improving erythrocyte deformability and thus improving blood flow. A number of observations, including the drug concentrations required to work the red cell effect, suggested that this was not likely to be a complete explanation. We therefore examined the effect of pentoxifylline on several granulocyte and platelet functions. Pentoxifylline inhibited platelet aggregation in response to 4 mumol/L adenosine diphosphate; although statistically significant inhibition was seen at 1 mumol/L pentoxifylline, over 200 mumol/L was required for 50% inhibition. The adherence of unstimulated platelets to cultured endothelial cells was not strongly inhibited by pentoxifylline; however, the additional increment in adherence seen in the presence of thrombin was strongly inhibited (50% attenuative dose [AD50] = 18 mumol/L). Granulocyte aggregation in response to C5a was modestly inhibited (AD30 approximately equal to 8 mumol/L; AD50 greater than 1 mmol/L), and the adherence of unstimulated polymorphonuclear neutrophils (PMNs) to endothelium was uninhibited. The C5a-mediated augmentation of PMN adherence to endothelium was mildly inhibited (AD50 = 240 mumol/L). Inhibition of PMN chemotaxis to N-Formyl-methionyl-leucyl-phenylalanine (FMLP) or C5a (AD50 = 12 mumol/L) and inhibition of superoxide production in response to FMLP-cytochalasin B (AD50 = 24 mumol/L) were seen at more clinically credible concentrations. Perhaps most important, pentoxifylline blocked the ability of platelet activation factor to prime neutrophils for enhanced response to subsequent stimuli (AD50 approximately equal to 8 mumol/L; AD60 = 10 mumol/L when production was the indicator system); in vivo, this could broaden the drug's effect to include functions that it does not inhibit potently in a primary fashion. Although pentoxifylline is known to be a phosphodiesterase inhibitor, and we found it to elevate intracellular cyclic adenosine monophosphate in stimulated PMNs, we found it to be only marginally more potent than theophylline in this regard; therefore, the failure of theophylline to inhibit PMN priming suggests that this enzyme inhibition is not a complete explanation of the pharmacologic action of pentoxifylline. We suggest that the effects of pentoxifylline on platelet and granulocyte function are likely to contribute to the drug's clinical efficacy.

Blood Platelets↗
PubMed1988

Excessive vulnerability of herpes-infected endothelium to lymphokine-activated lymphocytes: a possible role in lethal viral pneumonitis following bone marrow transplantation.

1. Lymphokine-activated killer cells are cytotoxic to human umbilical vein endothelial cells in vitro. 2. Cytotoxic efficiency of LAK cells correlates with serine esterase activity. 3. LAK cells generated from bone marrow transplant patients, as compared to normal volunteers, are significantly more cytotoxic for cultured endothelium, which correlates with their elevated serine esterase content and phenotypic NK-cell proportion. 4. Endothelium infected with herpes simplex virus for very brief periods (4 hr) becomes even more vulnerable to LAK cell-mediated injury. 5. Thus, bone marrow transplant patients harbor "primed" lymphocytes, highly liable to become lymphokine-activated killer cells. These cells have an NK phenotype, readily generate cytotoxic serine esterase activity, and manifest a proclivity to damage vascular endothelium--especially virally infected endothelium. We suggest this proclivity may underlie the severe endotheliitis and lethal pulmonary hemorrhage suffered by bone marrow transplant patients infected with herpesviruses.

Bone Marrow Transplantation↗
PubMed1987

Effect of L-leucine on oral melphalan kinetics in patients.

Melphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5 +/- 0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4 +/- 3.7 micrograms/ml fasting and 35.4 +/- 5.2 micrograms/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.

Administration, Oral↗
PubMed1987

Lymphokine activated killer (LAK) cell-mediated endothelial injury: a mechanism for capillary leak syndrome in patients treated with LAK cells and interleukin-2.

We have investigated the possible etiology of a severe clinical syndrome seen in cancer patients treated with a new form of cancer-specific therapy, referred to as adoptive immunotherapy. This syndrome, apparently characterized by diffuse capillary injury, results in the leakage of intravascular fluid into interstitial tissues, with consequent organ dysfunction that limits the applicability of this form of therapy. We have demonstrated, using an in vitro model of cultured human endothelial cell injury, that LAK cells--lymphocytes stimulated in vitro by IL-2--appear to be potent mediators of endothelial injury. This LAK cell-mediated endothelial cytotoxicity is both time and dose dependent and is not manifested by freshly isolated human lymphocytes or lymphocytes cultured for up to 7 days in the absence of IL-2. In contrast, significant LAK cell-mediated damage to human endothelial cells is observed in lymphocytes cultured for as little as 24 hr in media containing IL-2 and is still found in 14-day-old LAK cells. LAK cells appear to be far more potent than maximally stimulated PMNs in their cytolytic activity against endothelium. In contrast, no damage to cultured endothelial cells is provoked by very large doses of IL-2 alone. Levels of IL-2 that are 3-5 times greater than peak blood IL-2 levels, transiently present in patients following bolus IL-2 injections, fail completely to produce HEC cytotoxicity even during prolonged incubation. The mechanism by which LAK cells kill their targets appears to be analogous to that previously described for related cytolytic T lymphocytes and NK cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Capillaries↗
PubMed1986

A five-year experience with central nervous system lymphoma.

The experience with central nervous system (CNS) non-Hodgkin's lymphoma at a 700-bed teaching hospital over five years (1979-1983) is reported. During this period 222 patients with non-Hodgkin's lymphoma were seen. Ten new cases (eight patients with secondary and two patients with primary CNS lymphoma) were diagnosed during this period, representing an overall incidence of 4.5%. The clinical, pathological and neuroradiological findings of this group are described with special emphasis on the varied appearances that were found on computer-assisted tomographic scans.

Adult↗
PubMed1986

The effect of food on oral melphalan absorption.

Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95-336) ng X h X ml-1, and when taken with food, 122 (47-227) ng X h X ml-1, the median reduction being 39% (P less than 0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38-71) was no different from its oral half-life [55 (27-104) min fasting; 55 (30-72) min with food] (P greater than 0.1). In these patients bioavailability was 85% (26-96)% when the drug was taken fasting and 58% (7-99)% when taken with food (P less than 0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104-694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs = 0.915, P less than 0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.

Absorption↗
PubMed1986

Aleukaemic leukostasis in a case of large cell non-Hodgkin's lymphoma: report of a case with a distinctive central nervous system involvement.

A 52-year-old man with large cell non-Hodgkin's lymphoma developed a unique pattern of central nervous system involvement by lymphoma while in apparent systemic remission. Despite intermittent neurological episodes suggestive of CNS involvement by lymphoma no evidence of CNS lymphoma was found on repeated cerebrospinal fluid and brain CT scan examinations. At necropsy widespread occlusion of cerebral blood vessels by malignant lymphoid cells was observed with extensive tissue necrosis and haemorrhages. Leukaemic involvement of peripheral blood was not detected on repeated blood film examinations during life.

Brain↗
PubMed1983

The hypereosinophilic syndrome.

The hypereosinophilic syndrome groups together patients with idiopathic eosinophilia and diffuse organ infiltration with eosinophils. It appears to be a continuum of disease from the asymptomatic patient with skin and heart disease at one end to eosinophilic leukaemia at the other. A case is described of a young woman who presented with asthma, mononeuropathy multiplex and eosinophilia and subsequently developed eosinophilic gastroenteritis, vasculitis and probable myocarditis. The response to prednisolone has been pleasing.

Adult↗