Haematological modifications after acute exposure to high altitude: possible implications for detection of recombinant erythropoietin misuse.
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Altitude↗
Biomedical subjects
C Bernasconi
Publications and source records attributed to C Bernasconi.
Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.
BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events. DESIGN AND METHODS: From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit < 45% and platelets < 400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy. RESULTS: Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis. INTERPRETATION AND CONCLUSIONS: This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.
Administration, Oral↗
Treatment of early-stage Hodgkin's disease with four cycles of ABVD followed by adjuvant radio-therapy: analysis of efficacy and long-term toxicity.
BACKGROUND AND OBJECTIVES: The use of combined modality therapy in early-stage Hodgkin's disease can spare staging laparotomy and reduces the risk of relapse compared to radiation alone. This paper reports on the efficacy and long-term events of a combined modality approach consisting of a brief course of chemotherapy followed by adjuvant radiotherapy, without laparotomy, in early-stage Hodgkin's disease. DESIGN AND METHODS: This study included 78 patients with Hodgkin's disease (20 in stage I and 58 in stage II); 60% had mediastinal enlargement (12% had bulky disease) and 5% had subdiaphragmatic disease. Their median age was 33 years (range: 15-64) and median follow-up 60 months. The treatment program consisted of four cycles of ABVD followed by adjuvant radiation to involved sites (43 patients) or involved and contiguous sites of disease (35 patients); radiation doses ranged from 30 to 36 Gy to uninvolved and involved sites, respectively; bulky disease received up to 44 Gy. Gonadal function in women was assessed by hormonal tests and evaluation of menses; young men were given the opportunity to have their semen cryopreserved. RESULTS: The treatment program was completed in a median of 6.2 months (range: 5-10). The complete remission rate was 88% after 4 courses of ABVD and 98.7% after adjunctive RT. The 5-year relapse-free survival was 97% and overall survival 98%; three patients died, one of disease progression and two of small cell lung carcinoma. Long-term events included three cases of pulmonary fibrosis with symptomatic interstitial disease, one case of dilated cardiomyopathy with cardiac failure (all had received mediastinal radiation) and four cases of dysthyroidism. Fertility was preserved in young women, with three subsequent normal pregnancies. Second neoplasms included two small cell lung carcinomas and one breast carcinoma. INTERPRETATION AND CONCLUSIONS: In early-stage Hodgkin's disease, four cycles of ABVD followed by adjuvant radiotherapy produced a 5-year overall survival of 98%. Prolonged monitoring for therapy-related long term complications is mandatory in these potentially curable patients.
Adolescent↗
Translocation (8;16) in a patient with acute myelomonocytic leukemia, occurring after treatment with fludarabine for a low-grade non-Hodgkin's lymphoma.
We describe a 65-year old woman who developed a t(8;16)(p11;p13) positive acute myeloid leukemia (AML)-M4 without a prior myelodysplasia thirty-six months after a low-grade non-Hodgkin's lymphoma treated with alkylating agents (chlorambucil and cyclophosphamide) and fludarabine, a purine analog with a significant activity in lymphoproliferative disorders. The t(8;16)(p11;p13) is present in 0.4% of AML of M4-M5 cytotype. In the present case it was identified by conventional cytogenetics; involvement of the MOZ and CBP genes was demonstrated by fluorescence in situ hybridization, but not by reverse transcription polymerase chain reaction. The patient died of sepsis after the first course of induction chemotherapy. This is the first t(8;16) AML-M4 arising after fludarabine treatment of which the leukemogenic role in our case is very difficult to ascertain. Most t(8;16) t-AML cases had received anthracyclines with or without cyclophosphamide; none was ever administered chlorambucil. Our patient was never given anthracyclines and the cumulative doses of chlorambucil and cyclophosphamide employed were low.
Aged↗
N-acetylcysteine in the treatment of steroid-resistant acute graft-versus-host-disease: preliminary results. Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
BACKGROUND: Acute graft-versus-host disease (GVHD) results from reactivity of donor immunocompetent cells versus host tissues. Its pathogenesis involves co-stimulatory molecules, cytokines, free radicals, and oxidative stress products. N-Acetylcysteine (NAC) is an antioxidant that inhibits the B7-1/CD28 expression in vitro, and it may contrabalance the effects of free radicals and oxidative stress; it has been tested in eight patients with steroid-resistant acute GVHD. METHODS: NAC was given at the dose of 150 mg/kg bolus intravenously, followed by 50 mg/kg intravenous continuous infusion over 3 weeks or less up, to clinical GVHD resolution. In four patients, flow cytometric analysis of co-stimulatory molecules was performed on peripheral mononuclear cells before and after NAC therapy. RESULTS: We achieved prompt response in six patients: four had complete response, two partial response. Two patients died of acute GVHD, and four of intercurrent disease. We noticed significant decrease in CD80, CD25, and CD8+ cells after NAC therapy. CONCLUSION: NAC therapy is feasible; it may give response in steroid-resistant acute GVHD. More extensive studies are needed to confirm these data.
Acetylcysteine↗
Complex response to periodic inhibition in simple and detailed neuronal models.
Constant current injection with superimposed periodic inhibition gives rise to phase locking as well as chaotic activity in rat neocortical neurons. Here we compare the behavior of a leaky integrate-and-fire neural model with that of a biophysically realistic model of the rat neuron to determine which membrane properties influence the response to such stimuli. We find that only the biophysical model with voltage-sensitive conductances can produce chaotic behavior.
Animals↗
Assessment of renal function in patients with multiple myeloma: the role of urinary proteins.
Renal failure (RF) in multiple myeloma (MM) is considered an ominous complication even though, when timely therapy is started in patients with minimal damage, a high percentage of cases can achieve a regression. The evaluation of renal involvement usually relies on serum creatinine or its clearance, but these parameters have proved to be inadequate to identify initial damage. The aim of this study was to assess the role of the following urinary proteins in diagnosing renal impairment at an early stage: high-molecular-mass proteins (transferrin, IgG, albumin) as markers of glomerular damage, and low-molecular-weight proteins and parenchymal enzymes [alpha(1)-acid glycoprotein (AGP), alpha(1)-microglobulin (alpha(1)M), retinol-binding protein (RBP), beta(2)-microglobulin (beta(2)M), lysozyme (LZ), and N-acetyl-beta-d-glucosaminidase (NAG)] as indicators of tubular disorder. Thirty MM patients (nine at disease onset and 21 previously treated) were included in the study. No correlation was found between the urinary proteins and the phase or the stage of the disease. By the Spearman test, Bence Jones proteinuria correlated significantly with the 24 h proteinuria (p=0. 01) and beta(2)M (p=0.02), and weakly with the alpha(1)M. Serum creatinine concentrations and urea correlated with most of the analytes evaluated: RBP correlated well with urea (p=0.004) and creatinine (p=0.004); IgG (p=0.006) albumin (p=0.009), AGP (p=0.04), and NAG (p=0.02) correlated with serum creatinine. Significant statistical correlation was found between all the analytes except LZ and the creatinine clearance. Twelve of the 30 MM patients (40%) showed abnormal values of urinary proteins. Four of these patients showed overt renal failure with significant modification of the serum parameters and of creatinine clearance, three showed an isolated decrease of creatinine clearance, and five did not present any alteration of serum or urinary parameters. This testifies to the utility of urinary proteins in highlighting renal damage even in cases where the customary serum indicators of renal disorder are normal. In conclusion, our results demonstrate that AGP, RBP, NAG, transferrin, and IgG are good indicators of renal damage. They do not correlate with the severity of the disease, but they seem to be helpful in identifying a subset of patients with initial renal dysfunction.
Adult↗
On the directionality of cortical interactions studied by structural analysis of electrophysiological recordings.
To investigate the directionality of neural interactions as assessed by electrophysiology, we adapted methods of structural analysis from the field of econometrics. In particular, within the framework of autoregressive modelling of the data, we considered quantitative measures of linear relationship between multiple time series adopting the Wiener-Granger concept of causality. The techniques were evaluated with local field potential measurements from the cat visual system. Here, several issues had to be addressed. First, out of several statistical tests of the stationarity of local field potentials considered, those based on the Kolmogorov-Smirnov and on the reverse arrangement statistics proved to be most powerful. The application of those tests to the experimental data showed that the large part of the local field potentials can be considered stationary on a time scale of 1 s. Second, out of the several investigated methods for the determination of an optimal order of the autoregressive model, the Akaike Information Criterion had the most suitable properties. The identified order of the model, across different repetitions of the trials, was consistently 5-8. Third, although the individual segments of field potentials used for the analysis were relatively short, the methods of structural analysis applied produced reliable results, confirming findings of simulations of data with similar properties. Furthermore the features of the estimated models were consistent among trials, so that the analysis of average measures of interaction appears to be a viable approach to investigate the relationship between the recording sites. In summary, the statistical methods considered have proved to be suitable for the study of the directionality of neuronal interactions.
Action Potentials↗
Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma.
PURPOSE: Fludarabine phosphate is effective as a single agent in low-grade non-Hodgkin's lymphoma (NHL). Combined with other antineoplastic agents it enhances the antitumor effect. Our aim was to define the therapeutic efficacy and toxicity of a combination of fludarabine, cyclophosphamide and dexamethasone (FluCyD) in patients with advanced low-grade lymphoma. PATIENTS AND METHODS: Twenty-five adults with pretreated advanced-stage low-grade NHL were treated with three-day courses of fludarabine 25 mg/m2/day, cyclophosphamide 350 mg/m2/day, and dexamethasone 20 mg/day, every four weeks for a maximum of six courses. RESULTS: Of the 25 patients, 18 (72%) responded, 8 (32%) achieving CR and 10 (40%) PR. Seven were failures. The median follow-up was 21 months (5-26). Eight CR patients remain in CR after 5-21 months. Of 10 PR patients, 3 are in continuous PR without further treatment after 12, 17 and 18 months. Myelosuppression was the most prevalent toxic effect. Although severe granulocytopenia (granulocyte count nadir < 500/microliter) and thrombocytopenia (platelet count nadir < 50,000/microliter) occurred in only 10% and 16% of courses, respectively, slow granulocyte or platelet count recovery caused delay of 40% of the courses. Nine patients (36%) required discontinuation of therapy because of persistent granulocytopenia and/or thrombocytopenia: three after one course, three after 2-4 courses, and three after five courses. Thirteen infectious episodes in 11 patients complicated 11% of courses. Two of 10 patients monitored for the circulating EBV load showed increased viral load. One of these developed aggressive lymphoma. CD4+ lymphocytes declined from a pre-therapy median value of 425/microliter to 141/microliter post-treatment (P = 0.001). Non-hematologic toxicities were rare and mild. CONCLUSIONS: The combination of fludarabine with cyclophosphamide and dexamethasone is effective in pretreated advanced-stage low-grade NHL. It may broaden the range of therapeutic options in the salvage treatment of these patients. The main toxicity of this combination is prolonged myelosuppression that may cause treatment delay or withdrawal. The benefit of adding granulocyte colony-stimulating factor, particularly in patients with poor marrow reserve, needs to be investigated.
Adult↗
Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases.
Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P<0.001). Bradyarrhythmia was noticed in two of 75 PBPC patients and in 14 of 51 BM patients (P<0.001). In the former group one patient had heart block; he died of renal failure 10 days later. Bradycardia and hemoglobinuria were more common in patients receiving BM where a higher concentration of red cells was present (P<0.001). Since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed BM. The strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content.
Adolescent↗
Chemotherapy and donor peripheral blood progenitor cells for acute leukemia in early relapse after allogeneic bone marrow transplantation.
Ten patients with acute leukemia (AL) in early relapse after allo-BMT were treated with a modified MEC (mitoxantrone, etoposide and Ara-C) regimen followed by donor PBPC collected after mobilization with G-CSF. Seven patients achieved CR or had normal hemopoietic reconstitution: two had an early relapse at days +53 and +48, two patients died from acute GVHD at days +31 and +96, one died of interstitial pneumonia at day +55, and two patients experienced long-term survival. One patient with refractory disease and nodal involvement who did not respond to the first BMT had overt expansion of the leukemia at day +36; one patient with Ph+ ALL and one with ANLL evolving from MDS, both with skin involvement, had blast cells in peripheral blood at day +27 and +26, respectively. Transient cytopenia occurred in all patients; a normal granulocyte and platelet count was achieved within 3 weeks in all patients but one; acute GVHD occurred in six patients, and four had chronic GVHD. This approach is feasible in patients in early relapse after allo-BMT. It assists prompt re-establishment of normal donor hematopoiesis avoiding the prolonged cytopenia observed after donor lymphocyte infusion in AL patients relapsed after allo-BMT.
Acute Disease↗
A model for analysing the cost of autologous peripheral blood progenitor cell (PBPC) transplantation.
Data from autologous peripheral blood progenitor cell (PBPC) transplant recipients were used for cost analysis and modelling so as to link the main intervention procedures and clinical events to resource use and costs. This cohort consisted of 64 patients from 4 to 62 years old at transplantation (mean, 36.9 years) who underwent a first transplant between August 1994 and May 1997. The main indications for transplantation were non-Hodgkin's lymphomas (47%), multiple myeloma (30%) and Hodgkin's lymphomas (15%). The course of a patient during the whole transplant procedure was modelled using a Markov chain of six states of health: (1) mobilisation and recovery of PBPC; (2) post-mobilisation phase; (3) conditioning and transplant; (4) critical haematological reconstitution; (5) non-critical haematological reconstitution; (6) death. The probability of transition between the different health states, together with the estimated costs, were the input for the Markov model. The model also managed transition probabilities depending both on the current health state and on various demographic, clinical and procedure-related covariates unique to the patient. The expected time spent in each clinical state and the expected total cost were, therefore, estimated. This analysis gave an actual total cost per transplanted patient of $26,600 (95% range: $24,700 to $43,500) while mean duration was 197 days. The expenses for in-hospital stay accounted for 80% of the costs. Both the probability of staying in the different states, and the consequent cost were dependent on the number of CD34-positive cells collected, the phase and the type of the disease, the subset of patients (either children or adults), and the post-transplant G-CSF prophylaxis. The sensitivity of the estimates to alternative assumptions was studied, and the method of comparing alternative future scenarios by the model was explored.
Adolescent↗
A novel t(Y;11) translocation with MLL gene rearrangement in a case of acute myelomonocytic leukemia (AML-M4)
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Adult↗
The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders.
Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). A major side-effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein-Barr virus (EBV) reactivation and possibly favour transformation to high-grade malignancy. The aim of this study was to evaluate the immunosuppression-related effects of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3-27 months. The CD4+ lymphocyte counts decreased significantly during therapy from a median of 484/microliter pre-treatment (range 142-1865) to a median of 198/microliter (71-367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high-grade B-cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T-lymphocytopenia and has the potential to reactivate a latent EBV infection. T-cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.
Adult↗
Effects of ACTH-induced hypertension in the pregnant ewe.
Adrenocorticotropic hormone (ACTH; 5 microg/kg/ day) infused into 10 pregnant ewes (gestation age, 127-139 days) for 72 h caused an increase in arterial pressure within 1-2 h (p < 0.05), which was sustained for the rest of the experiment. Cardiac output was increased at 24 h (p < 0.05). Total peripheral resistance did not change. There were no changes in four pregnant ewes infused with 0.15 M saline at the same rate for 72 h. In ACTH-treated pregnant ewes, a relation between arterial pressure and plasma renin activity observed in nontreated pregnant ewes (r = 0.71; p = 0.0005) was no longer evident. Compared with nonsurgical pregnant ewes, total angiotensin II (Ang II)-receptor density in the uterine artery was decreased in ewes that had previously had surgery (p = 0.015) and further reduced in ACTH-treated ewes (p < 0.0005). This was due to a reduction in the AT2-receptor density, which was inversely related to plasma cortisol levels (r = 0.73; p < 0.03). AT1-receptor density and the affinities of the AT1 and AT2 receptors were unchanged. The correlation between plasma cortisol and AT2-receptor density in uterine blood vessels may partly explain why these receptors are downregulated after surgery.
Adrenocorticotropic Hormone↗
Steatapheresis: a new term for a new obesity surgery.
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Humans↗
Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women.
PURPOSE: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives. METHODS: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mg/day) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 microg ethinylestradiol (EE) and 250 microg levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle. RESULTS: Compared with placebo, areas under the plasma concentration curves (AUC(0-24h, geometric means) decreased by 47% for both EE (from 1,677 to 886 pg.h/ml; p < 0.01) and LN (from 137 to 73 ng.h/ml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < 0.01), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p < 0.01). CONCLUSIONS: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.
Adolescent↗
A successful combination of plasma exchange and intravenous cyclophosphamide in a patient with a refractory thrombotic thrombocytopenic purpura.
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Combined Modality Therapy↗