[p53 mutations/p53 protein overexpression. Differential significance for the progression of head-neck carcinomas].
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Carcinoma, Squamous Cell↗
Biomedical subjects
C Conradt
Publications and source records attributed to C Conradt.
Prognostic impact of total tumor volume and hemoglobin concentration on the outcome of patients with advanced head and neck cancer after concomitant boost radiochemotherapy.
PURPOSE: To identify prognostic clinical and treatment related factors for local control, distant metastasis-free survival, and survival by means of a multivariate analysis in patients with advanced squamous cell carcinoma of the head and neck after concomitant boost radiochemotherapy. PATIENTS AND METHODS: From 1992 to 1995, 68 patients with squamous cell cancer of the head and neck (93% stage IV disease) were treated with a simultaneous radiochemotherapy with Carboplatin using a concomitant boost technique. The total tumor volume (TTV) was quantitatively determined based on computed tomography scans in 56 patients. A Cox proportional hazards regression analysis was performed for each of the above endpoints and statistical significance of the Cox models was verified using the likelihood ratio test and Bonferroni correction for multiple testing. RESULTS: The survival and locoregional control rates at three years were 35 and 32%. The multivariate analysis revealed a significant association between the TTV and survival (P = 0.0008) and between the pretreatment serum hemoglobin concentration and locoregional control (P = 0.01) and survival (P = 0.05). The locoregional control was significantly associated with the N-stage (P = 0.007) and there was a good correlation between the N-stage and TTV in this study population. CONCLUSION: Our data corroborate the prognostic relevance of the tumor volume and hemoglobin concentration. In studies comparing the survival of patients with advanced cancer of the head and neck, the use of the TTV as a covariable may improve the statistical power.
Adult↗
Acute and late toxicity, tumour control and intrinsic radiosensitivity of primary fibroblasts in vitro of patients with advanced head and neck cancer after concomitant boost radiochemotherapy.
BACKGROUND AND PURPOSE: The existence of hereditary factors influencing the cellular response to ionising radiation has led to the hypothesis that the inter-patient variability of clinical radiation reactions may, at least in part, be attributable to an individual, or intrinsic, radiosensitivity. Considerable effort has been spent in the development of test systems that would determine individual radiosensitivity before or early during radiotherapy to possibly predict treatment outcome, but the results are still conflicting. The present explorative study was therefore aimed at the detection of associations between acute and late radiation effects, tumour control and in vitro radiosensitivity of primary normal tissue fibroblasts. PATIENTS AND METHODS: Sixty-eight patients with squamous cell carcinoma of the head and neck (93% UICC stage IV) were treated with a simultaneous concomitant boost radiochemotherapy with Carboplatin as part of a prospective non-randomised multicenter study at the University of Heidelberg. Primary fibroblasts were obtained from skin biopsies prior to treatment from 25 unselected patients of this study and the SF2 was determined using the colony forming assay and high dose-rate irradiation. The median follow-up was 21 months (range 2.5-81 months). RESULTS: The locoregional control rate at three years was 32%. No significant association between acute (mucosa reaction grade 1 or 2 vs. grade 3 and 4), late radiation effects (subcutaneous fibrosis, osteonecrosis, larynx oedema), locoregional tumour control and SF2 of primary fibroblasts was found using Cox proportional hazards regression analysis, log-rank test and Mann-Whitney U-test. Although a steep dose-response relationship was observed for the radiation-induced severe larynx oedema, Cox proportional hazards regression analysis could not fully explain the occurrence of severe radiation-induced larynx oedema with the dose to the larynx (P = 0.09). In the subgroup of twenty-five patients, where the SF2 was determined, bivariate analysis revealed about the same non-significant influence of the dose to the larynx on the larynx oedema (P = 0.1) and no influence of the SF2 (P = 0.5). CONCLUSIONS: In our study of patients with advanced cancer of the head and neck, neither the normal fibroblast SF2 nor the severity of acute radiation effects were able to predict late radiation effects or locoregional tumour control.
Adult↗
Effectiveness of Harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a randomized, placebo-controlled, double-blind study.
Two daily doses of oral Harpagophytum extract WS 1531 (600 and 1200, respectively, containing 50 and 100 mg of the marker harpagoside) were compared with placebo over 4 weeks in a randomized, double-blind study in 197 patients with chronic susceptibility to back pain and current exacerbations that were producing pain worse than 5 on a 0-10 visual analogue scale. The principal outcome measure, based on pilot studies, was the number of patients who were pain free without the permitted rescue medication (tramadol) for 5 days out of the last week. The treatment and placebo groups were well matched in physical characteristics, in the severity of pain, duration, nature and accompaniments of their pain, the Arhus low back pain index and in laboratory indices of organ system function. A total of 183 patients completed the study. The numbers of pain-free patients were three, six and 10 in the placebo group (P), the Harpagophytum 600 group (H600) and the Harpagophytum 1200 group (H1200) respectively (P = 0.027, one-tailed Cochrane-Armitage test). The majority of responders' were patients who had suffered less than 42 days of pain, and subgroup analyses suggested that the effect was confined to patients with more severe and radiating pain accompanied by neurological deficit. However, subsidiary analyses, concentrating on the current pain component of the Arhus index, painted a slightly different picture, with the benefits seeming, if anything, to be greatest in the H600 group and in patients without more severe pain, radiation or neurological deficit. Patients with more pain tended to use more tramadol, but even severe and unbearable pain would not guarantee that tramadol would be used at all, and certainly not to the maximum permitted dose. There was no evidence for Harpagophytum-related side-effects, except possibly for mild and infrequent gastrointestinal symptoms.
Analgesics, Opioid↗
Rise of oxygenation in cervical lymph node metastasis during the initial course of radiochemotherapy.
It has been hypothesized that during radiation treatment a reoxygenation of hypoxic tumor tissue takes place. To test this hypothesis, we have investigated whether reoxygenation in lymph node metastases could be determined by invasive PO (2) measurements. Through a hypodermic needle inserted transcutaneously into tumor-positive lymph nodes, polarographic oxygen determinations were made in 18 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx. These measurements were performed before therapy and a week after the onset of radiotherapy or radiochemotherapy, respectively. Low PO (2) values before treatment (mean value of the patient's median was 12.6 mm Hg PO (2)) and a mean hypoxic fraction (PO (2) < 5 mm Hg) of 39.6% indicated manifest tumor hypoxia. After 1 week of treatment, a significant increase in the median PO (2) (mean value of shift: 7.3 mm Hg) and a reduction in the hypoxic fraction (mean value of shift: 13.4% PO (2) < 5 mm Hg, P < 0.03) were observed after both radiotherapy and radiochemotherapy. Thus invasive PO (2) histography fulfills the requirements for a method to confirm tumor hypoxia in head and neck tumors. The results obtained indicate that reoxygenation occurs during the initial phases of radiotherapy and radiochemotherapy, and they will form the basis for future comparative investigations on the possible influence of hypoxic parameters on tumor responsiveness toward radiation and radiochemotherapy.
Adult↗
TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer.
Recent studies have suggested that different mutation types within the core domain of the tumour suppressor protein p53, i.e. DNA contact mutations and structural mutations, confer different biological properties. We have analysed in 86 head and neck squamous cell carcinomas (HNSCC), whether these p53 mutation types have a differential clinical impact. Thirty-seven missense mutations were identified. Thirteen of these (36%) were DNA contact mutations, occurring in the L3 loop, in the H2 loop sheet helix motif, in the S10 beta strand and in Zinc binding residues. Microsatellite marker analysis revealed a selective association between these mutations and the loss of wild-type alleles (100% LOH vs 50% LOH in tumours with structural mutations; P=0.0034, Fisher's exact, 2-tailed). In comparison to structural mutations or to the absence of mutations in the core domain, DNA contact mutations were associated with higher tumour stages (84.6% vs 62%), a higher incidence of lymph node metastasis (91.7% vs 56%; P=0.014, Fisher's exact, 2-tailed), a shortened recurrence-free survival (8.1 months vs 23.7 months, P=0.047, log rank test) and overall survival (11 months vs 29.2 months; P=0.003, log rank test). The latter was also the case when only stage IV tumours were analysed (P=0.0055, log rank test). These data indicate that in HNSCC, TP53 DNA contact mutations confer a strong selection pressure to eliminate wild-type alleles, and that they result in an accelerated tumour progression and reduced therapeutic responsiveness.
Adult↗
[Value of tumor-associated antigens CA 72-4 vs. CEA and CA 19-9 in the follow-up after stomach cancer].
OBJECTIVE: To compare the value of tumour markers CA-72-4 and CA 19-9 and the cardioembryonic antigen (CEA) in the follow-up of patients after potentially curative surgery of gastric carcinoma. PATIENTS AND METHODS: CA 72-4, CA 19-9 and CEA were measured prospectively in 279 patients 1-36 months after potentially curative primary surgery for histologically proven gastric carcinoma. Evaluation was by "receiver-operating-characteristics" (ROC) curves using "believe the positive" rules as well as by linear combinations. RESULTS: Recurrences were found in 54 patients. CA 72-4 (by radioimmunoassay) was the most sensitive single test (sensitivity 43%, specificity 95%). Radioimmunological and enzyme-immunological tests of CA 79-4 correlated well (r = 0.8). The various values, obtained by certain test kits, when newly calculated for the purpose of after-care, differed markedly from upper limits reported by the manufacturers. Measurement of both CA 72-4 and CA 19-9 increased the sensitivity to 54%. INTERPRETATION: Special levels of CA 72-4 and CA 19-9 have been identified which are of value in the follow-up of patients after operation for gastric carcinoma. Single measurements of CA 74-2 are as a rule preferable to those of CA 19-9 or of both CA 11-9 and CEA. In fact, CEA should be measured only in exceptional circumstances. But combined measurements of CA 72-4 and CA 19-9 increase sensitivity and prognostic value of the results.
Adenocarcinoma↗
Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control.
Two hundred eight primary squamous cell carcinomas of the head and neck have been analyzed with respect to the presence of the retinoblastoma tumor suppressor protein, pRb. Of these, 23 tumors (11%) that preferentially localized to the tonsils revealed complete absence or dramatic reduction in the amount of pRb. Other cell cycle components, cyclin D1 and p16INK4A, which are intimately related to pRb through an autoregulatory loop, were also dramatically decreased or overexpressed, respectively, in these pRb-defective tumors. On the other hand, the majority of the pRb-defective tumors contained the wild-type p53 gene. No evidence was found for genetic defects at the Rb locus in these tumors. Very significantly, in 11 of 12 pRb-defective tonsillar tumors, but in none of 9 pRb-positive tonsillar tumors (P < 10[-7]), DNA of oncogenic human papillomavirus types was identified, providing a strong indication for a human papillomavirus-associated etiology of these tumors and suggesting the functional inactivation of the pRb protein by the viral E7 gene product. In comparison to all head and neck squamous cell carcinomas studied, the pRb-defective tonsillar tumors were in general more poorly differentiated (P = 0.0059), and they were all metastatic at the time of resection. Of particular clinical interest, despite these adverse histopathological factors, the clinical outcome for these patients was relatively favorable, strongly implying that the pRb-defective tumors responded uniformly well toward postoperative radiation therapy.
Carcinoma, Squamous Cell↗
Smoking as a risk factor for end-stage renal failure in men with primary renal disease.
BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.
Adult↗
First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying.
BACKGROUND: Ethanol undergoes a first pass metabolism (FPM) in the stomach and liver. Gastric FPM of ethanol primarily depends on the activity of gastric alcohol dehydrogenase (ADH). In addition, the speed of gastric emptying (GE) may modulate both gastric and hepatic FPM of ethanol. AIMS: To study the effect of modulation of GE on FPM of ethanol in the stomach and liver. METHODS: Sixteen volunteers (eight men and eight women) received ethanol (0.225 g/kg body weight) orally and intravenously, and the areas under the ethanol concentration time curves were determined to calculate FPM of ethanol. In seven of these subjects, FPM of ethanol was measured after the intravenous administration of 10 mg metoclopramide (MCP) and 20 mg N-butylscopolamine (NBS) in separate experiments to either accelerate or delay GE. GE was monitored sonographically by integration of the antral area of the stomach every five minutes for 90 minutes after oral ethanol intake. In addition, gastric biopsy specimens were taken to determine ADH activity and phenotype, as well as to evaluate gastric histology. Blood was also drawn for ADH genotyping. RESULTS: GE time was significantly delayed by the administration of NBS as compared with controls (p<0.0001) and as compared with the administration of MCP (p<0.0001). This was associated with a significantly enhanced FPM of ethanol with NBS compared with MCP (p = 0.0004). A significant correlation was noted between GE time and FPM of ethanol (r = 0.43, p = 0.0407). Gastric ADH activity did not significantly correlate with FPM of ethanol. CONCLUSION: FPM of ethanol is strikingly modulated by the speed of GE. Delayed GE increases the time of exposure of ethanol to gastric ADH and may therefore increase gastric FPM of ethanol. In addition, hepatic FPM of ethanol may also be enhanced as the result of slower absorption of ethanol from the small intestine. Thus a knowledge of GE time is a major prerequisite for studying FPM of ethanol in humans.
Administration, Oral↗
Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.
PURPOSE: In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS: Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS: Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION: Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.
Adult↗
Aberrant p21(CIP1/WAF1) protein accumulation in head-and-neck cancer.
p21(CIP1/WAF1) is an inhibitor of cyclin-dependent kinases and, in normal tissues including squamous epithelia, has been associated with cell-cycle exit and differentiation. As shown in this pilot study, however, the majority of head-and-neck squamous-cell carcinomas (HNSCC) display aberrant p21(CIP1/WAF1) expression: of 42 tumors analyzed by immunohistochemical staining, 28 (67%) over-expressed the p21(CIP1/WAF1) protein. Accumulation of p21(CIP1/WAF1) was independent of the histological grade of the tumors as well as the genetic status of the p53 gene. In many cases, most notably in poorly differentiated or undifferentiated HNSCC, p21(CIP1/WAF1)-positive cells were actively proliferating tumor cells, since they also expressed proliferating-cell nuclear antigen (PCNA) and Ki-67. Accumulation of p21(CIP1/WAF1) occurred through a post-transcriptional mechanism since, in contrast to immunohistochemical analysis of the p21(CIP1/WAF1) protein, in situ hybridization showed no increase of mRNA levels as compared with cells in normal mucosa (n = 25). Clinically, among the patients with p21(CIP1/WAF1)-over-expressing tumors, there was increased recurring disease (p = 0.03; chi2-test), shortened disease-free survival (p = 0.0019; log-rank test) and shortened overall survival (p = 0.0071; log-rank test). These in vivo data indicate that in many HNSCC, accumulated p21(CIP1/WAF1) is compatible with increased tumor-cell proliferation, and they provide preliminary evidence that p21(CIP1/WAF1) may be of prognostic and predictive significance.
Biopsy↗
In vitro radiosensitivity of primary human fibroblasts. Lack of correlation with acute radiation toxicity in patients with head and neck cancer.
BACKGROUND AND PURPOSE: There is a considerable hope among clinicians and radiobiologists to detect genetically radiosensitive patients prior to radiotherapy. A predictive assay would enable adjustment of the total irradiation dose to the individual at a constant risk of normal tissue complications. In this prospective study, the clonogenic survival assay for primary human fibroblasts to determine radiosensitivity in vitro was evaluated and then correlated with clinically observed acute radiation reactions. MATERIALS AND METHODS: One hundred twenty-five independent survival experiments with primary fibroblasts derived from 63 biopsies from 55 cancer and non-cancer patients were performed. RESULTS: A wide variation of cell survival between biopsies was detected. Statistical analysis revealed a highly significantly larger interindividual than intraindividual variation of SF2 values. However, a considerable scatter of SF2 values in repeated experiments was observed in individual cases. Age, gender, disease status (cancer patient, non-cancer patient) and origin of fibroblasts (skin, periodontal tissue) were demonstrated not to be statistically significant confounding factors on the intrinsic radiosensitivity in vitro. In a prospective study, no correlation of the SF2 and acute reactions in 25 patients with head and neck cancer treated with a primary accelerated radiochemotherapy was detected. CONCLUSION: Our data show that the clonogenic assay is able to distinguish between intrinsic radiosensitivities of primary human fibroblasts if a statistical approach is used but does not predict acute radiation toxicity.
Acute Disease↗
Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin.
Secondary prevention of atherosclerosis, especially before the onset of symptoms, appears desirable and could be possible with a serum marker detecting atherosclerosis. Circulating, shedded forms of adhesion molecules may serve as such because their expression is upregulated in atherosclerotic plaques. In 52 patients with peripheral arterial vascular disease (Fontaine class IIa, 7 patients; class IIb, 29 patients; and class III, 16 patients), the extent of atherosclerosis was evaluated on the basis of angiograms of a large portion of the arterial system. The area diseased by atherosclerosis was determined by the percentage of vessel wall irregularities of the following calculated segments: aorta (distal from the kidney arteries), common iliac artery, external iliac artery, common femoral artery, lateral circumflex femoral artery, and popliteal artery. The maximal surface area that could exhibit atherosclerotic changes was 250 cm2. The serum concentration of circulating vascular cell adhesion molecule-1 (VCAM-1) correlated with the extent of atherosclerosis (r = .8, P < .001). In contrast, circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin (as markers for endothelial cell damage) did not correlate with the extent of atherosclerosis. Furthermore, circulating VCAM-1 could be used to indicate stages of atherosclerosis with a high degree of statistical significance. The potential bias of factors such as age, diabetes mellitus, hypercholesterolemia, arterial hypertension, renal failure, and history of myocardial infarction on the correlation of circulating VCAM-1 with the extent of atherosclerosis could be excluded by multivariate analysis. These findings suggest an important role of VCAM-1 in atherosclerosis and may serve as the basis for further evaluation of circulating VCAM-1 as a potential serum marker for atherosclerosis.
Adult↗
[Rehabilitation of patients with alcoholic liver cirrhosis after orthotopic liver transplantation: a 7-year follow-up].
Alcoholic liver cirrhosis is the main indication for orthotopic liver transplantation. Since 1988, 52 patients with alcoholic liver cirrhosis have been transplanted at the Department of Surgery of the University of Heidelberg. The survival rates are as follows: 73% of the patients survived for 1 year, 68% for 2 and 3 years, 64% for 4 years, and 57% survived for 5 years. After transplantation, recidivism occurred in 6 patients. Remarkable in this case was the fact that all 6 patients had a relatively short period of abstention prior to surgery (2 to 5 months). In 12 patients, a small carcinoma was found in the cirrhotic liver. This had neither been seen previously by ultrasound nor by computer tomography. In summary, orthotopic liver transplantation is an excellent mode of treatment in end-stage alcoholic liver cirrhosis. However, the patients have to be carefully selected in order to avoid recidivism following transplantation.
Adult↗
Distinct nonrandom patterns of chromosomal aberrations in the progression of squamous cell carcinomas of the head and neck.
Fifty-one randomly selected primary squamous cell carcinomas of the head and neck, derived from the larynx (n = 18) and pharynx (oropharynx, n = 18, and hypopharynx, n = 15) were analyzed with centromeric probes for chromosomes 1, 7, 9, 11, 17, and 18 to study numerical aberrations, chromosome imbalances, and aneuploidy by fluorescence in situ hybridization. The tumors were grouped into nonmetastasizing (N0) tumors (from patients clinically free of lymph node metastases for at least 18 months after surgery, n = 25) and metastasizing (N1-3) tumors (n = 26). We found a significant association between the tumor ploidy and the nodal status; in the N0 group, diploidy prevailed, and the most common aberration was loss to monosomy for chromosome 9 (44%), whereas in the N1-3 group, aneuploidy predominated (P = 0.002). Specifically, these genomic changes associated with progression to metastasis were: (a) tetrasomic or polysomic chromosomes were detected in 17 of 26 N1-3 tumors but in none of the 25 N0 tumors (P < 0.0001); (b) heterogeneous chromosomal copy numbers (i.e., extensive chromosomal imbalances) were also much more frequent in the N1-3 tumors (69.2% versus 24.0% in the N0 group; P = 0.018); and (c) loss of chromosome 9 (73%) and gains of chromosomes 7 (35%) and 17 (31%) persisted, but in addition, loss of chromosome 18 occurred in 31%. Overexpression of the p53 protein correlated with an increased incidence of chromosomal imbalances and aneuploidy (P < 0.001) and, hence, constituted an additional risk factor. The lower metastatic potential of larynx tumors as compared with tumors from the pharynx was reflected by a lower incidence of these genomic changes. These specific patterns of chromosomal aberrations can characterize and distinguish different stages of tumor progression of squamous cell carcinomas of the head and neck and should be valuable diagnostic and prognostic markers.
Carcinoma, Squamous Cell↗
Peripheral blood progenitor cell (PBPC) counts during steady-state hematopoiesis allow to estimate the yield of mobilized PBPC after filgrastim (R-metHuG-CSF)-supported cytotoxic chemotherapy.
Peripheral blood progenitor cells (PBPC) can be mobilized using cytotoxic chemotherapy and cytokines. There is a substantial variability in the yield of hematopoietic progenitor cells between patients. We were looking for predictive parameters indicating a patient's response to a given mobilization regimen. Multiparameter flow-cytometry analysis and clonogenic assays were used to examine the hematopoietic progenitor cells in bone marrow (BM) and peripheral blood (PB) before filgrastim (R-metHuG-CSF; Amgen, Thousand Oaks, CA)-supported chemotherapy and in PB and leukapheresis products (LPs) in the recovery phase. Fifteen patients (four with high-grade non-Hodgkin's lymphoma [NHL], two with low-grade NHL, two with Hodgkin's disease, two with multiple myeloma, three with breast cancer, one with ovarian cancer, and one with germ cell tumor) were included in this study. The comparison of immunofluorescence plots showed a homogenous population of strongly CD34+ cells in steady-state and mobilized PB whereas in steady-state BM, the CD34+ cells ranged from strongly positive with continuous transition to the CD34- population. Consistent with the similarity in CD34 antigen expression, a correlation analysis showed steady-state PB CD34+ cells (r = .81, P < .001) and colony-forming cells (CFCs; r = .69, P < .01) to be a measure of a patient's mobilizable CD34+ cell pool. Individual estimates of progenitor cell yields could be calculated. With a probability of 95%, eg, 0.4 steady-state PB CD34+ cells x 10(6)/L allowed to collect in six LPs 2.5 x 10(6) CD34+ cells/kg, the reported threshold-dose of progenitor cells required for rapid and sustained engraftment after high-dose therapy. For the total steady-state BM CD34+ cell population, a weak correlation (r = .57, P < .05) with the mobilized CD34+ cells only became apparent when an outlier was removed from the analysis. Neither the CD34+ immunologic subgroups defined by the coexpression of the myeloid lineage-associated antigens CD33 or CD45-RA or the phenotypically primitive CD34+/HLA-DR- subset nor the BM CFC count had a predictive value for the mobilization outcome. This may be caused by the additional presence of maturing progenitor cells in BM, which express lower levels of the CD34 antigen and do not circulate. Our results permit us to recognize patients who are at risk to collect low numbers of progenitor cells and those who are likely to achieve sufficient or high progenitor cell yields even before mobilization chemotherapy is administered.
Adult↗
Increased messenger RNA levels for low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat liver after long-term ethanol ingestion.
Because long-term alcohol intake leads to severe alterations of cholesterol metabolism resulting in both elevated serum cholesterol levels and increased hepatic concentrations of cholesterol esters, we investigated the effect of long-term ethanol consumption on the hepatic messenger RNA (mRNA) content of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and low-density lipoprotein receptor, two major regulatory factors in cholesterol metabolism, and of apoprotein E. Twenty-four male Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories as either ethanol or isocaloric carbohydrates for 3 wk. In addition, the lipid content of the diets was varied, resulting in 35%, 17.5%, and 8.8% of total calories corresponding to a daily intake of cholesterol of between 1.2 and 6.3 mg/kg body wt. Although increasing dietary cholesterol intake resulted in a significant decrease of hepatic mRNA for low-density lipoprotein receptor and HMG-CoA reductase (p < 0.05), long-term ethanol consumption led to a significant increase of the mRNA for both proteins (p < 0.01), and this increase was predominantly obvious in animals fed a low-cholesterol diet. In contrast, mRNA content of apoprotein E was found to be significantly lower in livers from rats fed ethanol for a prolonged period of time as compared with controls (p < 0.01), and this effect was found to be still present, although less pronounced, after low cholesterol intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗