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Patrick Schöffski

Publications and source records attributed to Patrick Schöffski.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection.

A reversed phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the simultaneous determination of imatinib (Gleevec, Glivec, STI571) and AMN107 in cultured tumour cells, using clozapine as an internal standard. The compounds of interest were extracted by liquid-liquid extraction using TOXI-TUBES((R)) A extraction tubes. Chromatographic separation was performed on a Phenomenex Gemini C18 reversed phase column (150 mm x 2.0 mm, 5 microm particle size), using a mixture of 65% CH(3)OH (methanol) and 35% NH(4)Ac (Ammonium acetate) buffer (20mM, pH 10). Separation was achieved under isocratic conditions at a flow rate of 0.5 ml/min. Imatinib, clozapine and AMN107 are detected by UV detection at 260 nm. Calibration curves were linear from 50 to 7500 ng/ml with correlation coefficients (r(2)) better than 0.998. The limit of quantitation (LOD) was 50 ng/ml. The method has been successfully applied to a cellular kinetics study.

Antineoplastic Agents↗
PubMed2006

Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.

Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out. Thirty-seven patients were included at 14 different dose-levels (10 to 6400 ng/kg). The complete clinical results are presented elsewhere. A 2-step CRM design enables one to speed-up the study and most importantly to obtain an accurate estimate of the maximum tolerated dose (MTD). Different management issues related to a multicenter study are illustrated and we show how the method can go wrong when severe toxicity, or dose limiting toxicity (DLT), is not considered by the clinician as being sufficient to limit dose escalation (here a grade 3 asthenia related to the drug). This would have affected any dose finding methods. We believe that CRM is a good alternative to the standard method from both a statistical and a practical point of view but further methodological research is necessary to address the issues related to the composite nature of the endpoint.

Adolescent↗
PubMed2006

Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate.

PURPOSE: The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA. We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants. EXPERIMENTAL DESIGN: Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays. Three patients with the KIT-V654A mutation were treated with SU11248. RESULTS: Based on ex vivo assays, SU11248 potently inhibits KIT kinase activity of V654A and T670I mutants and suppresses proliferation of the cells expressing these mutations. Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants. In contrast, SU11248 did not potently inhibit the PDGFRA-D842V mutant. In agreement with these results, two of the three imatinib-resistant patients with the KIT-V654A mutation responded to SU11248 treatment. CONCLUSIONS: These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant. Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842.

Animals↗
PubMed2006

Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.

BACKGROUND & AIMS: Intestinal neurofibromatosis (Online Mendelian inheritance in Man database number 162220) is an alternate form of neurofibromatosis. Patients present with neurofibromas limited to the intestine in the absence of any other typical features of NF1 and NF2. At present, the molecular basis of intestinal neurofibromatosis remains elusive. The aim of the present study was to find the gene responsible for intestinal neurofibromatosis and to characterize functionally the mutation. METHODS: Three candidate genes (NF1, KIT, and PDGFRA) were screened for mutations in 3 sisters diagnosed with intestinal neurofibromatosis. Five tumors were available for pathologic examination. Activation (phosphorylation) of PDGFRalpha was subsequently tested by Western blot analysis on a transfected 293T and Ba/F3 cell line. RESULTS: We found an inherited mutation (Y555C) in the juxtamembrane domain of PDGFRA in the affected individuals. The Y555C mutation leads to autophosphorylation and thus activation of PDGFRalpha. These observations confirm that PDGFRalpha(Y555C) is an oncogenic kinase. The clinical phenotype in the reported family resembles the syndrome of familial gastrointestinal stromal tumors (familial GIST). Somatic activating mutations in KIT and PDGFRA are frequent in sporadic GISTs, and mutations in both genes have also been described in familial GISTs. The tumors in the reported family are morphologically identical to intestinal neurofibromas, but, immunohistochemically, they do not express S100 or any of the known GIST markers. CONCLUSIONS: The inherited PDGFRA mutation in the reported family shows that intestinal neurofibromatosis is allelic to familial GIST caused by PDGRA mutations. We therefore propose that these tumors be classified as familial KIT-negative gastrointestinal stromal tumors.

Adult↗
PubMed2005

Does a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer?

The purpose of this study was to determine whether baseline patients' self reported health-related quality of life (HRQOL) parameters could predict survival beyond key biomedical prognostic factors in patients with metastatic colorectal cancer. The analysis was conducted on 299 patients. HRQOL baseline scores were assessed using the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core30 (EORTC QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. The final multivariate Cox regression model retained four variables as independent prognostic factors for survival: white blood cell (WBC) count with a hazard ratio (HR) of 1.961 (95% CI, 1.439-2.672; P<0.001), alkaline phosphatase with HR=1.509 (95% CI, 1.126-2.022; P=0.005), number of sites involved with HR=1.108 (95% CI, 1.024-1.198; P=0.01) and the patient's score on the social functioning scale with HR=0.991 (95% CI, 0.987-0.996; P<0.001) which translates into a 9% decrease in the patient's hazard of death for any 10 point increase. The independent prognostic importance of social functioning and the stability of the final Cox regression model were also confirmed by the additional bootstrap model averaging analysis, based on 1000 bootstrap-generated samples. The results suggest that social functioning, acts as a prognostic measure of survival beyond a number of previously known biomedical parameters.

Adult↗
PubMed2005

Phase I study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor in patients with refractory solid tumors.

PURPOSE: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy. DESIGN: OSI-7904L was given as a 30-minute i.v. infusion every 21 days to 31 patients at eight dose levels from 0.4 to 15.0 mg/m(2), using three patients per dose level, up to 10 patients at the recommended dose. Baseline plasma homocysteine and 2'-deoxyuridine and genotype polymorphism were measured as potential predictors of biological activity. RESULTS: Minimal toxicity was reported up to 9.6 mg/m(2), but dose-limiting toxicity was seen in both patients at 15 mg/m(2) including stomatitis, fatigue, tachyarrhythmia, rash and hand-foot syndrome, diarrhea, and fatal neutropenic sepsis. Other toxicity such as nausea and vomiting was mild or moderate. This resulted in the investigation of an intermediate dose level of 12 mg/m(2), identified as the recommended dose for phase II studies. Prolonged disease stabilization was reported in 11 of 31 heavily pretreated patients. Pharmacokinetic data indicate that this liposomal formulation alters the disposition properties of the parent drug resulting in a prolonged plasma residence time. CONCLUSIONS: OSI-7904L given as a 30-minute i.v. infusion every 21 days is feasible and well tolerated at the recommended phase II dose of 12 mg/m(2). The main toxicities are rash, pruritus, lethargy, stomatitis, and myelosuppression. Observed toxicities were predictable and characteristic for TSIs.

Adult↗
PubMed2005

Adaptation and performance of an immuno-PCR assay for the quantification of Aviscumine in patient plasma samples.

An immuno-polymerase chain reaction (IPCR) assay is used to evaluate the kinetic behaviour of the novel anti-cancer drug Aviscumine in plasma samples taken from 41 patients during a 3-year clinical trial. The ultrasensitive IPCR assay employed the amplification of a detection-antibody linked marker-DNA and an internal competitor DNA for standardization, thus enabling the detection of the antigen in concentrations far below the detection limit of conventional enzyme-linked immuno-sorbent assay (ELISA). The quantification of Aviscumine was carried out using external calibration curves obtained from individual patient plasma samples, collected previous to the administration of Aviscumine, which were spiked with known amounts of the reference substance Aviscumine. Additional controls were measured containing standardized human serum spiked with Aviscumine to assure the continuous general reproducibility of the assay as well as to estimate differences between individual patients. Average recovery was found to be 95+/-19% and the average deviation in precision of the assay was determined to be 9+/-5%. Data for the quantification of Aviscumine were obtained from all patient samples investigated with the exception of a single patient. The collected data provided the basis for the valid routine quantification of patient samples for the calculation of the pharmacokinetic behaviour of Aviscumine in patient plasma.

Algorithms↗
PubMed2005

Role of postchemotherapy surgery in the management of patients with liver metastases from germ cell tumors.

OBJECTIVE: To evaluate the role of postchemotherapy adjunctive surgery in patients with liver metastases from germ cell cancer (GCT). PATIENTS AND METHODS: Forty-three male patients with nonseminoma were treated in different multicenter treatment protocols between 1990 and 1999, and they underwent hepatic surgery. The results of postchemotherapy surgical resection, histologic findings found during postchemotherapy surgery, and prognostic factors for survival were assessed. RESULTS: Thirty-five of 43 patients (81%) were initially diagnosed with liver metastases and advanced GCT, and 8 patients (19%) presented with metachronous liver metastases after a median interval of 16 months (range, 6-103 months). Twelve patients (28%) had isolated liver metastases after completion of chemotherapy, while 31 patients (72%) had additional residual extrahepatic tumor masses. Liver surgery included tumor excision or segmentectomy in 32 patients (74%) and hepatectomy (right/left) or resection of multiple segments in 11 patients (26%). Histologic analysis of postchemotherapy resected residua yielded necrosis in 67%, teratoma in 12%, and viable cancer in 21%. Additional resections at other sites have been performed in 31 patients revealing necrosis in 61% (n = 19), teratoma in 29% (n = 9), and vital carcinoma in 10% (n = 3). In 39% of patients, histologic findings differed among liver and other resection sites. Refractoriness to chemotherapy was associated with a shorter survival after surgery, and a trend was seen in patients with elevation of AFP. CONCLUSION: The high rate of viable cancer and teratoma found in liver specimens, differing histologic results at residual tumor locations, and the high survival rate achieved support a multidisciplinary approach including resection of liver masses since no accurate selection of patients can narrow the use of surgery.

Adolescent↗
PubMed2005

Acral necrosis after inadequate excessive administration of bleomycin in a testicular cancer patient.

BACKGROUND: Testicular cancer has a favorable prognosis in the majority of patients due to the excellent susceptibility to chemotherapy with cisplatin, etoposide and bleomycin (BEP), which is commonly administered over 3-4 cycles of treatment. CASE REPORT: A 22-year-old male failed to achieve complete response after unconventional treatment with 6 courses of BEP for intermediate-risk metastasized testicular cancer. The patient developed chemotherapy-induced digital necrosis and substantial loss of digital function after this excessive treatment. This condition resolved with infusional alprostadil combined with oral clonidin and pentoxifyllin. RESULT: Infusional alprostadil adds substantial clinical benefit to combined vasoactive therapy in chemotherapy-induced vascular toxicity, even after the onset of digital necrosis.

Adult↗
PubMed2004

A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors.

BACKGROUND: Matrix metalloproteinases play a role in the process of tissue invasion and metastasis by degrading the extracellular matrix. Inhibitors of matrix metalloproteinases are therefore of interest as anticancer drugs. CP-471,358 is a matrix metalloproteinase inhibitor that in vitro demonstrates strong inhibition of matrix metalloproteinases 2 and 9. The drug can be administered orally without food restriction. STUDY DESIGN: An open-label phase I study was performed in patients with advanced solid tumors to assess the safety, tolerability, maximal tolerated dose (MTD) and pharmacokinetics of CP-471,358. The CP-471,358 doses studied were 50, 100 and 200 mg three times daily (TID) continuously, 50, 100 and 200 mg TID for 21 days followed by a 1-week treatment-free interval and 75 mg and 150 mg twice daily (BID) continuously. RESULTS: A total of 38 patients were treated in the study. The median number of cycles administered was two (range one to five). Myalgia and arthralgia were the most frequently observed adverse events (in 27 of 38 patients) and were observed at all dose levels and with all schedules except for the 150 mg BID continuous dosing level. In six patients National Cancer Institute (NCI) Common Toxicity Criteria (CTC) grade 3 myalgia/arthralgia was observed and this adverse event was considered to be the dose-limiting toxicity (DLT). Introduction of a 1-week treatment-free interval between cycles had no effect on the occurrence of myalgia/arthralgia. After cessation of treatment, arthralgia/myalgia was reversible in all patients. Other adverse events observed were fatigue and an increase of liver enzymes but these rarely exceeded CTC grade 2. Pharmacokinetic analysis showed that target efficacious concentrations were achieved throughout the morning dosing interval with 150 mg BID and 200 mg TID. CONCLUSION: The DLT of CP-471,358 was myalgia and arthralgia, an adverse event observed during treatment with most matrix metalloproteinase inhibitors. A drug-free interval of 1 week was unable to prevent the occurrence of these adverse effects. Clearly this represents a limitation for potential long-term use of this compound.

Adult↗
PubMed2004

XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer.

PURPOSE: Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen. PATIENTS AND METHODS: The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning). RESULTS: A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for >/= 3 months following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen, except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%. CONCLUSION: XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination with oxaliplatin for MCRC.

Adult↗
PubMed2004

The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors.

The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile as compared to the classical i.v. bolus administration, prolonged infusions can be inconvenient for the patients and catheter-related problems are common complications. An oral 5-FU formulation would allow for sustained 5-FU plasma concentrations, mimicking the pharmacokinetics (PK) of a continuous infusion with the addition of convenience of administration. The oral administration of 5-FU itself is not feasible due to the high activity of dihydropyrimidine dehydrogenase in the gut wall, which causes rapid metabolism of the drug, and results in decreased and erratic absorption of 5-FU and non-linear PK. To bypass this problem, oral fluoropyrimidine derivatives were developed either in the form of 5-FU prodrugs (i.e. tegafur, doxifluridine or capecitabine), or as enzyme inhibitors (i.e. eniluracil) administered with 5-FU, or as both prodrugs and enzyme inhibitors (i.e. S-1, UFT or BOF-A2). This review will focus on the oral fluoropyrimidine S-1, which consists of the 5-FU prodrug tegafur (ftorafur, FT) and two enzyme inhibitors, i.e. CDHP (5-chloro-2,4-dihydroxypyridine) and OXO (potassium oxonate), in a molar ratio of 1(FT):0.4 (CDHP):1(OXO). Phase II trials have demonstrated that S-1, as a single agent, is active for the treatment of gastric, colorectal, head and neck, breast, non-small cell lung, and pancreatic cancers. Phase III trials are currently underway in gastric cancer and these results are awaited to confirm the phase II findings. Furthermore, the combination of S-1 with cisplatin (CDDP), irinotecan or docetaxel for the treatment of gastric cancer and with CDDP for non-small cell and pancreatic cancer is feasible and active. The activity observed with S-1 in the phase II studies is at least equivalent, if not better, than continuous i.v. and bolus 5-FU and the other oral fluoropyrimidines. Thus, we may finally be seeing the realization of oral treatments for the management of various solid tumors and could be on the brink of a new approach to treatment strategies.

Administration, Oral↗
PubMed2003

Ghrelin in chronic liver disease.

BACKGROUND/AIMS: Ghrelin is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor involved in energy metabolism, glucose homeostasis and food intake. We investigated the role of ghrelin and insulin-like growth factor-1 (IGF-1), the mediator of the GH axis, in patients with chronic liver diseases (CLD). METHODS: Ghrelin and IGF-1 serum levels were determined in 105 CLD patients and 97 healthy controls and correlated with clinical and biochemical parameters. RESULTS: Ghrelin was significantly elevated and IGF-1 reduced in CLD patients compared with healthy controls. IGF-1 serum levels inversely correlated with Child's classification. Ghrelin levels were significantly elevated in Child C cirrhosis patients independent of the aetiology of liver disease. Ghrelin levels did not correlate with liver function. In contrast, there was a correlation of ghrelin with clinical (gastrointestinal bleeding, ascites, encephalopathy) and biochemical (anaemia, inflammatory markers, hypoglycaemia, renal dysfunction) parameters. In a subgroup of patients with CLD and hepatocellular carcinoma (HCC), we observed a strong inverse correlation between alpha-fetoprotein (AFP) and ghrelin levels. CONCLUSIONS: Unlike IGF-1, ghrelin is not correlated with liver function, but increases in Child C cirrhosis and with complications of CLD. The inverse correlation with AFP in HCC patients requires further studies on the potential impact of ghrelin on the pathogenesis of anorexia-cachexia syndrome.

Adolescent↗
PubMed2003

Plasma P-selectin levels are elevated in patients with chronic liver disease.

P-selectin is a leukocyte receptor and platelet activation marker that has been shown to be involved in thrombogenesis as well as bleeding disorders and may represent a possible link between inflammation and thrombosis. In animal models, high plasma levels correlated with a procoagulant tendency. In acute liver damage models such as hepatic ischaemia-reperfusion-injury, P-selectin was found to be a key mediator of liver injury. In order to investigate the clinical and pathogenetic role of P-selectin in chronic liver diseases, plasma P-selectin levels were measured in 111 patients with chronic liver diseases. P-Selectin was significantly elevated in patients (median 56 ng/ml, range 0-180) compared with controls (n = 38, median 20 ng/ml, range 3.3-42, P < 0.001). Current clinical bleeding symptoms were common, whereas thrombotic events occurred rarely. P-selectin levels were not associated with haemorrhagic or thromboembolic complications. P-selectin correlated with platelet and white-blood-cell counts, but not with endothelial injury markers thrombomodulin and tissue factor or coagulation factors. Interestingly, P-selectin levels were not associated with Child's stage of cirrhosis or disease aetiology, but were generally elevated in chronic liver diseases. Severe hepatic leukocyte infiltration in liver histology was associated with a tendency towards higher P-selectin levels. In line with its role in acute liver damage, P-selectin elevation in chronic liver disease may suggest a possible pathogenetic role in the course of liver cirrhosis.

Adolescent↗
PubMed2002

Development of an optimal pharmacokinetic sampling schedule for rubitecan administered orally in a daily times five schedule.

PURPOSE: Our aim was to develop an optimal sampling strategy for the description of the pharmacokinetics of rubitecan and its active metabolite 9-aminocamptothecin (9-AC) for use in phase II/III studies with oral rubitecan administered in a daily times five schedule. METHODS: Concentration-time data of rubitecan and 9-AC were obtained from 14 patients who had received 1.5 mg/m(2) per day rubitecan orally. Population pharmacokinetic analysis of both the parent and the metabolite was performed using the nonlinear mixed effect modelling program (NONMEM). Optimal sampling points were selected on the basis of the assessed population pharmacokinetic parameters using a D-optimality algorithm. RESULTS: The pharmacokinetics of both rubitecan and 9-AC were adequately described with a one-compartment model. The absorption rate constant, apparent volume of distribution and apparent clearance of rubitecan were 0.81 h(-1), 50 l and 1.7 l/h, respectively. For 9-AC the corresponding values of the apparent volume of distribution and the elimination rate constant were 51 l and 0.102 h(-1). Interindividual variability of the pharmacokinetic parameters ranged from 38% to 49%. For the first dose, optimal sampling points were 1, 3, 5, 8 and 24 h after dosing. Monte Carlo simulations indicated that the sampling schedule produced parameter estimates which were unbiased and precise. CONCLUSIONS: An optimal sampling schedule was derived which allowed assessment of the pharmacokinetic parameters of both the parent compound and its metabolite 9-AC after oral administration of rubitecan.

Administration, Oral↗
PubMed2002

Determination of 9-nitrocamptothecin and its metabolite 9-aminocamptothecin in human plasma using high-performance liquid chromatography with ultraviolet and fluorescence detection.

A high-performance liquid chromatography assay is described for the determination of the investigational anti-cancer drug 9-nitrocamptothecin (9-NC) and its metabolite 9-aminocamptothecin (9-AC) as the total of their lactone and carboxylate forms. The sample pre-treatment consisted of a deproteinisation step and a quantitative acid-catalyzed conversion of all 9-NC and 9-AC into their lactone forms and a subsequent solid-phase extraction. Redissolved extracts were analyzed on a Prodigy analytical column, using a mixture of methanol-phosphate buffer (pH 2.5). Detection was concomitantly performed with UV for 9-NC and fluorimetrically for 9-AC. The lower limit of quantifications were 10 ng/ml and 2.5 ng/ml for the determination of 9-NC and 9-AC, respectively, using 500 microl of plasma. The presented method was successfully applied to a clinical pharmacokinetic study.

Camptothecin↗
PubMed2002

Thrombopoietin serum levels are elevated in patients with hepatitis B/C infection compared to other causes of chronic liver disease.

BACKGROUND/AIMS: Thrombocytopenia in patients with advanced liver disease may stem from a deficient hepatic thrombopoietin production. METHODS: We determined the relationship between thrombopoietin, thrombocytopenia, aetiology and extent of liver damage by incorporating serum thrombopoietin measurements in the pretransplant evaluation of 111 patients with liver disease. RESULTS: The extent of thrombocytopenia was related to the underlying cause of disease. The platelet count directly correlated with factor V, II, fibrinogen, and PTT, and a negative correlation was found for splenic size and Child's stage. The thrombopoietin concentrations were age-dependent, and no significant difference resulted between the median thrombopoietin level of liver disease patients with age-matched healthy controls. Thrombopoietin concentrations and platelet counts were not correlated. Although noncirrhotic patients had higher platelet counts than those with Child's A-C cirrhosis (p < 0.001, U-test), no such difference was found in thrombopoietin levels. Patients with hepatitis B and/or C had lower platelet counts compared to patients with nonviral diseases (p < 0.001), and their median thrombopoietin concentrations were significantly higher (p < 0.001). CONCLUSION: We conclude that thrombocytopenia in patients with liver disease is unlikely to be explained only based on a deficient hepatic production of thrombopoietin. Patients with chronic viral hepatitis have significantly elevated thrombopoietin levels; the involved pathomechanisms require further study.

Adult↗
PubMed2002

Quantification of hepatic thrombopoietin mRNA transcripts in patients with chronic liver diseases shows maintained gene expression in different etiologies of liver cirrhosis.

BACKGROUND/AIMS: Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired hepatic TPO production. As we reported previously, TPO serum levels are not decreased in patients with liver diseases compared with healthy controls and do not depend on the stage of cirrhosis or platelet count, but are highly elevated in patients with chronic virus hepatitis. METHODS: To study possible mechanisms, we measured hepatic TPO mRNA levels in liver tissue samples from 31 liver cirrhosis patients by quantitative TaqMan real-time RT-PCR and corresponding serum TPO concentrations by ELISA. RESULTS: Median TPO serum levels were elevated in patients with viral hepatitis (n = 12) compared with patients with a biliary (n = 10), alcoholic (n = 6) or other (n = 3) disease etiology, while hepatic TPO mRNA levels did not differ. The TPO mRNA levels in patients with chronic liver diseases were not different from normal liver tissue sample. The TPO mRNA and TPO serum level did not correlate. CONCLUSIONS: We conclude that hepatic TPO gene expression appears to be maintained on a constitutive transcriptional level in patients with liver diseases and does not change dependent on disease etiology.

Adolescent↗