The potential of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.)-apheresis for patients with severe acute or chronic COVID-19.

Patients with long COVID and acute COVID should benefit from treatment with H.E.L.P. apheresis, which is in clinical use for 37 years. COVID-19 can cause a severe acute multi-organ illness and, subsequently, in many patients the chronic illness long-COVID/PASC. The alveolar tissue and adjacent capillaries show inflammatory and procoagulatory activation with cell necrosis, thrombi, and massive fibrinoid deposits, namely, unsolvable microthrombi, which results in an obstructed gas exchange. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis solves these problems by helping the entire macro- and microcirculation extracorporeally. It uses unfractionated heparin, which binds the spike protein and thereby should remove the virus (debris). It dissolves the forming microthrombi without bleeding risk. It removes large amounts of fibrinogen (coagulation protein), which immediately improves the oxygen supply in the capillaries. In addition, it removes the precursors of both the procoagulatory and the fibrinolytic cascade, thus de-escalating the entire hemostaseological system. It increases myocardial, cerebral, and pulmonary blood flow rates, and coronary flow reserve, facilitating oxygen exchange in the capillaries, without bleeding risks. Another factor in COVID is the "cytokine storm" harming microcirculation in the lungs and other organs. Intervention by H.E.L.P. apheresis could prevent uncontrollable coagulation and inflammatory activity by removing cytokines such as interleukin (IL)-6, IL-8, and TNF-α, and reduces C-reactive protein, and eliminating endo- and ecto-toxins, without touching protective IgM/IgG antibodies, leukocyte, or platelet function. The therapy can be used safely in combination with antiviral drugs, antibiotics, anticoagulants, or antihypertensive drugs. Long-term clinical experience with H.E.L.P. apheresis shows it cannot inflict harm upon patients with COVID-19.

The complex isotopologue space of glucose as a framework for the study of human intermediary metabolism.

The positional distributions of stable isotopes in metabolites provide specific fingerprints of the pathways and fluxes that have occurred in the organisms under study. In particular, modern nuclear magnetic resonance (NMR) spectroscopy enables the detailed assignment of isotope patterns in natural products, for example, in metabolites obtained from labelling experiments using (13)C-enriched precursors, such as glucose, acetate or CO2. In this study, the transient (13)C-isotopologue composition of blood glucose from an adult human volunteer after intravenous supply of [U-(13)C6]glucose was determined by high-resolution (13)C NMR spectroscopy. The non-linear progression curves displaying the relative amounts of eight (13)C-glucose isotopologues reflected the contributions of glucose metabolism by glycolytic cycling, the pentose phosphate pathway and anaplerotic reactions involving the citric acid cycle. The pilot study suggests that the experimental setting can be useful in analysing under non-invasive conditions the impact of physiological and pharmacological constraints on glucose turnover in humans.

Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.

BACKGROUND: We investigated in a longitudinal, multicenter, cohort study whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of lipoprotein(a) (Lp[a]) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone. METHODS: Eligible patients had coronary artery disease and Lp(a) levels > or =2.14 micromol/l (95th percentile). All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipid apheresis and lipid-lowering medication. The rates of the primary outcome, MACE, were recorded for both periods. RESULTS: A total of 120 patients were included. The mean duration of lipid-lowering therapy alone was 5.6+/-5.8 years, and that of apheresis was 5.0+/-3.6 years. Median Lp(a) concentration was reduced from 4.00 micromol/l to 1.07 micromol/l with apheresis treatment (P<0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P<0.0001). CONCLUSIONS: Lowering of Lp(a) levels by apheresis was efficacious and safe, and we recommend this therapy for patients in whom maximally tolerated doses of medication alone have failed to control coronary artery disease-associated events.

Clinical relevance of circulating nucleosomes in cancer.

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.

Preoperative CYFRA 21-1 and CEA as prognostic factors in patients with stage I non-small cell lung cancer: external validation of a prognostic score.

OBJECTIVE: To validate the prognostic value of preoperative levels of CYFRA 21-1, CEA and the corresponding tumor marker index (TMI) in patients with stage I non-small cell lung cancer (NSCLC). METHODS: Two hundred forty stage I NSCLC patients (80 in pT1 and 160 in pT2; 100 squamous cell carcinomas, 91 adenocarcinomas, 32 large-cell carcinomas, 17 with other histologies; 171 males and 69 females) who had complete resection (R0) between 1986 and 2004 were included in the analysis. CYFRA 21-1 and CEA were measured using the Elecsys system (Roche) and AxSym-System (Abbott), respectively. Univariate analysis was performed using the Kaplan-Meier method to identify potential associations between survival and age, gender, CYFRA 21-1, CEA and TMI. RESULTS: Overall 3- and 5-year survival rates were 74 and 64%, respectively. Male gender (p = 0.0009) and age >70 years (p = 0.0041) were associated with a worse prognosis; there were no differences between pT1 and pT2 nor between histological subtypes. Three-year survival was 72% for CYFRA 21-1 levels >3.3 ng/ml versus 75% for levels 6.7 ng/ml versus 75% for CEA 0.05). Corresponding 5-year survival rates were near 64% both for patients with CYFRA 21-1 values above and below the cutoff (3.3 ng/ml), and 49 and 66% for patients with values above and below the CEA cutoff (6.7 ng/ml), respectively (both p values >0.05). Overall survival did not vary in the different TMI risk groups (p = 0.73). CONCLUSIONS: In this cohort of early-stage NSCLC patients, male gender and age >70 years were associated with a worse outcome, but elevated levels of CEA and CYFRA 21-1, and TMI risk were not.

Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit growth and to induce apoptosis in human hepatocellular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, which prompted us to test the efficacy of pravastatin in patients with advanced HCC. METHODS: We investigated prospectively a cohort of 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20-40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. RESULTS: During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5-26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3-13.7). CONCLUSION: Combined treatment of chemoembolization and pravastatin improves survival of patients with advanced HCC in comparison to patients receiving chemoembolization alone.

Nucleosomes as a new prognostic marker in early cerebral stroke.

BACKGROUND: The prognostic relevance of blood markers in cerebral stroke is still a matter of controversial debate. PATIENTS AND METHODS: In sera of 63 patients, nucleosomes, neuronspecific enolase (NSE), S100 protein, and C-reactive protein (CRP) were determined daily during the first week after cerebral stroke. Infarction volume was quantified by CT or MRI and the clinical status by Barthel Index (BI) at admission, discharge, and after 12 months (prognosis). All markers were evaluated by univariate and multivariate analysis on their prognostic relevance. RESULTS: During observation time (12 months), three patients died and 33 reached complete recovery. Infarction volume, nucleosomes, NSE, S100, and CRP correlated significantly with clinical status at admission. The same markers except CRP and initial BI correlated with recovery after 12 months. Almost all patients with initial BI double dagger 50 reached complete recovery. In patients with initially severe defects (BI < 50), nucleosomes and S100, both at day 3, were found to be prognostically relevant. At 100%-specificity for non-recovery, only nucleosomes maintained their prognostic power (sensitivity 52.6%; p = 0.014), whereas S100 did not (sensitivity 16.7%; p = 0.25). In multivariate analysis, nucleosomes and BI at admission showed independent prognostic relevance (p = 0.039). CONCLUSION: Circulating nucleosomes and clinical scores provide independent prognostic information concerning the later outcome in patients with initially severe defects after stroke.

Early and specific prediction of the therapeutic efficacy in non-small cell lung cancer patients by nucleosomal DNA and cytokeratin-19 fragments.

Facing an era of promising new antitumor therapies, predictors of therapy response are needed for the individual management of treatment. In sera collected prospectively from 311 patients with advanced non-small cell lung cancer receiving first-line chemotherapy, changes in nucleosomal DNA fragments, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. In univariate analysis, high levels, slower and incomplete decline in nucleosomal DNA, CYFRA 21-1, and CEA predicted poor outcome. DNA concentrations at day 8 of the first therapeutic cycle and CYFRA 21-1 before start of the second cycle were identified as best predictive variables. In multivariate analysis, they predicted progression with a specificity of 100% in 29% of the cases earlier than imaging techniques. Thus, nucleosomal DNA and CYFRA 21-1 specifically identify a subgroup of patients with insufficient therapy response at the early treatment phase and showed to be valuable for disease management.

Heparin-mediated extracorporeal low density lipoprotein precipitation as a possible therapeutic approach in preeclampsia.

Preeclampsia is a pregnancy-related hypertensive disease resulting in substantial maternal and neonatal morbidity and mortality. Until today there is no satisfactory treatment to stop disease progression except immediate delivery of the fetus. Heparin-mediated extracorporeal low density lipoprotein (LDL) precipitation (H.E.L.P.) apheresis removes simultaneously circulating LDL, lipoprotein(a) [Lp(a)], fibrinogen, C-reactive protein (CRP) and various proinflammatory and procoagulatory factors. This study was to test the feasibility of H.E.L.P. apheresis in preeclamptic patients and its potential effects on blood and placental markers of preeclampsia. We applied H.E.L.P. apheresis to nine preeclamptic patients and it was well tolerated. Their gestational ages could be continued by 17.7 (3-49) more days. Eight of the nine neonates did well during their neonatal stage. One infant died of late-onset sepsis. H.E.L.P. apheresis reduced significantly circulating levels of triglycerides, total and LDL-cholesterol, Lp(a), fibrinogen, hs-CRP, TNFalpha, sVCAM-1, E-selectin, lipopolysaccharide binding protein (LBP), homocysteine and plasma viscosity. We conclude that H.E.L.P. apheresis reduced maternal circulating levels of proinflammatory and coagulatory markers and plasma viscosity without overt maternal or neonatal clinical side effects.

Nucleosomes in colorectal cancer patients during radiochemotherapy.

Apoptotic markers and tumor-associated antigens might be suitable to indicate the response to radiochemotherapy early. We analyzed the courses of nucleosomes, CEA, CA 19-9 and CYFRA 21-1 in 25 colorectal cancer patients during radiochemotherapy (4 postoperative, 13 preoperative, 8 local relapse therapy). Blood was taken before therapy, daily during the first week, once weekly during the following weeks, and at the end of the radiochemotherapy. After a temporary decline 6 h after the first irradiation, nucleosomes rose in most patients rapidly reaching a maximum during the first days which was followed by a subsequent decrease. In patients receiving postoperative therapy after complete resection of tumor, nucleosome levels generally were lower than in patients with preoperative or relapse therapy. Correspondingly, CEA, CA 19-9 and CYFRA 21-1 levels of postoperatively treated patients were the lowest whereas those with tumor relapse had the highest ones. During preoperative therapy, lower nucleosome concentrations were found in patients with response to therapy resulting in a smaller area under the curve of days 1-3 (AUC) than in those with progressive disease (p = 0.028). The other parameters did not indicate the response to therapy at the initial treatment phase. In conclusion, the course of nucleosomes (AUC) might be valuable for the early prediction of therapy response in preoperatively treated colorectal cancer patients.

Early prediction of therapy response in patients with acute myeloid leukemia by nucleosomal DNA fragments.

BACKGROUND: Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases. METHODS: We investigated the course of nucleosomal DNA, thymidine kinase, lactate dehydrogenase and leukocytes in sera of 25 patients with acute myeloid leukemia during the first cycle of induction chemotherapy and tested their power to distinguish between patients with complete remission and those with no remission. RESULTS: Almost all patients showed strongly decreasing levels of nucleosomal DNA during the first week, in some cases after initial peaks. In overall analysis of variance, DNA levels could clearly distinguish between patients with complete remission, who had higher DNA values, and those with insufficient response (p = 0.017). The area under the curve of DNA values of days 2-4 after start of therapy (AUC 2-4) discriminated between both groups with a sensitivity of 56% at a specificity of 100%. Further, pretherapeutic levels and AUC 2-4 of nucleosomal DNA correlated significantly with blast reduction after 16 days. A tendency to higher levels in patients with complete response was also found for thymidine kinase, lactate dehydrogenase and leukocytes, however the difference did not reach the level of significance (p = 0.542, p = 0.260, and p = 0.144, respectively). CONCLUSION: Our results indicate that nucleosomal DNA fragments are valuable markers for the early prediction of therapeutic efficacy in patients with acute myeloid leukemia.

Prognostic value of interleukin 6, procalcitonin, and C-reactive protein levels in intensive care unit patients during first increase of fever.

To investigate the prognostic value of interleukin 6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) in critically ill patients during the first increase of fever, serum levels were measured in 38 patients admitted to intensive care unit of the Department of Medicine, Klinikum Grosshadern, University of Munich, immediately after increase of body temperature more than 38.3 degrees C. Ten healthy controls were also included for comparison. The onset of fever was accompanied by elevated circulating levels of all the 3 markers in comparison with healthy controls. However, only IL-6 levels were significantly higher (P < 0.05) in nonsurvivors (n = 21) compared with survivors. Sensitivity, specificity, positive, and negative predictive values calculated from median levels was higher for IL-6 compared with PCT and CRP. Areas under receiver characteristic operating curves revealed the highest area under the curve for IL-6 in contrast to PCT and CRP. These data suggest that IL-6 rather than PCT or CRP may be an early predictor of mortality in patients with onset of fever and identify patients, who need intensive monitoring to initiate appropriate therapy at an early stage.

Nucleosomes in serum of patients with early cerebral stroke.

BACKGROUND: Nucleosomes are cell death products that are elevated in serum of patients with diseases that are associated with massive cell destruction. We investigated the kinetics of circulating nucleosomes after cerebral stroke and their correlation with the clinical status. METHODS: In total, we analyzed nucleosomes by ELISA in sera of 63 patients with early stroke daily during the first week after onset. For correlation with the clinical pathology, patients were grouped into those with medium to slight functional impairment (Barthel Index BI >or=50) and those with severe functional impairment (BI<50). RESULTS: Patients with BI >or=50 showed a continuous increase in nucleosomes until day 5 (median: 523 arbitrary units, AU) followed by a slow decline. In contrast, patients with BI<50 showed a steeper initial increase reaching a maximum already on day 3 (869 AU). Both, days after stroke (p < 0.001) and BI (p < 0.001), had a significant influence on nucleosome concentrations, respectively. Consistently, patients with BI<50 had a significantly larger area under the curve (AUC/day) of nucleosome values during the first week after stroke (800 AU) than patients with BI >or=50 (497 AU; p=0.031). Concerning the infarction volume, nucleosomes showed significant correlations for the concentrations on day 3 (r=0.43; p=0.001) and for the area under the curve (r=0.34; p=0.016). CONCLUSION: Even if nucleosomes are nonspecific cell death markers, their release into serum after cerebral stroke correlates with the gross functional status as well as with the infarction volume and can be considered as biochemical correlative to the severity of stroke.

[Atherogenesis: interplay between cholesterol, inflammation and coagulation]. / Atherogenese: Wechselspiel zwischen Cholesterin, Inflammation und Koagulation.

It is now generally accepted that, in addition to hypercholesterolemia, pro-inflammatory and procoagulatory factors play a major role in atherogenesis. Risk factors such as smoking, hypertension, diabetes and renal diseases alter lipoprotein profile and composition thus rendering them susceptible to modification. Modified lipoproteins induce local inflammation possibly due to activation of nuclear factor (NF-)kappaB and subsequent expression of adhesion molecules, release of pro-inflammatory cytokines, growth factors and mitogens, which are mediators for cell growth, proliferation and lipid deposition. Furthermore, activation of collagenases and proteases in combination with prothrombotic processes attenuate clot formation, plaque rupture and occlusion of vessels. Clinical as well as experimental studies suggest that elevated levels of pro-inflammatory markers may have a diagnostic potential. Thus, a therapeutic approach which modulates circulating cholesterol levels and improves pro-inflammatory and procoagulatory situation may prove beneficial as adjuvant therapy in atherosclerotic disease.

Changes in myocardial vasoreactivity after drastic reduction of plasma fibrinogen and cholesterol: a clinical study in long-term heart transplant survivors using positron emission tomography.

BACKGROUND: Given the central importance of the microvasculature in heart transplant recipients, we investigated the possibility of increasing cardiac perfusion after reduction of low-density lipoprotein (LDL)-cholesterol, lipoprotein (a), C-reactive protein (CRP) and fibrinogen plasma levels after apheresis treatment in transplanted patients. METHODS: Ten long-term heart transplant recipients were examined with positron emission tomography (PET) to measure myocardial perfusion before and after a single heparin-mediated extracorporeal LDL/fibrinogen precipitation (HELP)-apheresis treatment. PET studies were performed the mornings before and after the apheresis treatment. Myocardial blood flow at rest and during adenosine-induced hyperemia was measured using (13)N-ammonia. RESULTS: HELP-apheresis reduced the plasma levels of LDL-cholesterol, lipoprotein (a) and C-reactive protein by 48% (p < 0.001), fibrinogen by 42% (p = 0.02), plasma viscosity by 14% (p = 0.004) and erythrocyte aggregation by 28% (p < 0.02). Osmolality (<1%) and hematocrit (<2%) remained stable. A single apheresis treatment increased median corrected rest flow by 17.5% (p = 0.007) and median hyperemic flow by 27% (p = 0.02). Median coronary flow reserve increased by 8.1% (p = 0.09). Hyperemic flow after adenosine infusion increased plasma vascular endothelial growth factor levels only before HELP-apheresis (+60%), indicating better ischemic tolerance after apheresis (p = 0.01). CONCLUSIONS: Myocardial perfusion in transplanted hearts increases significantly after single HELP-apheresis treatment. The present study is only a proof of concept, providing complementary evidence to clinical long-term studies showing that cholesterol reduction either with statins and/or apheresis improves heart transplant outcome.

Pharmacokinetics of repinotan in healthy and brain injured animals.

Repinotan hydrochloride (repinotan) is a highly potent and selective 5-HT(1A) full receptor agonist. The ability of repinotan to cross the blood-brain barrier (BBB) and penetrate into rat brain tissue was investigated, because rapid penetration into brain tissue is thought to be essential for neuroprotective efficacy. Intravenous (i.v.) repinotan was rapidly distributed into brain, and the distribution equilibrium between blood and brain was reached immediately after the start of infusion. Free concentrations of repinotan were identical in brain and plasma, indicating that repinotan crosses the BBB freely in both directions with diffusion as a driving force. The brain concentration of repinotan was determined by the free plasma concentration. Thus, the total plasma concentration of repinotan (sum of bound and unbound compound) is only indicative for the brain concentration as long as the unbound fraction remains constant. Metabolites of repinotan do not penetrate the BBB and are retained in the perfusing blood due to their increased polarity. The penetration of [14C] repinotan into ischemic areas of the brain was dependent on time. In studies using injured animals (pMCAO), high levels of [14C] repinotan could be detected in ischemic areas when the compound was administered up to 5 h post injury. [14C] repinotan radioactivity could no longer be detected in ischemic areas when administered 18 h after pMCA-O. After the end of infusion, repinotan was rapidly and completely eliminated from rat brains. Elimination occurred in parallel from plasma and brain with half-lives of about 1 h. In conclusion, repinotan rapidly and to a considerable extent penetrates into brain tissue of healthy and injured animals.

Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study.

Despite the advances in therapeutic approaches in the management of inflammatory conditions, the incidence of sepsis is on increase in the intensive care units (ICU). In a pilot study, we investigated whether the use of an apheresis system based on DEAE-cellulose is capable of reducing the plasma concentration of endotoxin in patients with severe sepsis. We enrolled 15 intensive care patients with severe sepsis and plasma endotoxin concentrations >0.3 EU/mL. In addition to standard ICU therapy, a total of 83 apheresis treatments were performed. About 1.7 volumes of plasma (6000 mL) were treated at each apheresis session. A significant reduction in plasma endotoxin levels from a median of 0.61 to 0.39 EU/mL (-35%) could be achieved (P < 0.001). Long-term comparison of the initial and post-treatment levels after a series of five to six individual apheresis treatments also showed a statistically significant decline in circulating endotoxin, interleukin (IL)-6, C-reactive protein (CRP), fibrinogen, and an increase in cholesterol levels. Except for a transient and reversible increase of prothrombin time, no adverse events were observed in patients undergoing this new adsorption apheresis treatment. Our data show that reduction of endotoxin by extracorporeal DEAE-cellulose-based plasma treatment may prove a promising therapeutic tool for patients suffering from bacterial sepsis and proven endotoxemia.

Nucleosomes in pancreatic cancer patients during radiochemotherapy.

Nucleosomes appear spontaneously in elevated concentrations in the serum of patients with malignant diseases as well as during chemo- and radiotherapy. We analyzed whether their kinetics show typical characteristics during radiochemotherapy and enable an early estimation of therapy efficacy. We used the Cell Death Detection Elisa plus (Roche Diagnostics) and investigated the course of nucleosomes in the serum of 32 patients with a local stage of pancreatic cancer who were treated with radiochemotherapy for several weeks. Ten of them received postsurgical therapy, 21 received primary therapy and 1 received therapy for local relapse. Blood was taken before the beginning of therapy, daily during the first week, once weekly during the following weeks and at the end of radiochemotherapy. The response to therapy was defined according to the kinetics of CA 19-9: a decrease of CA 19-9 > or =50% after radiochemotherapy was considered as 'remission'; an increase of > or =100% (which was confirmed by two following values) was defined as 'progression'. Patients with 'stable disease' ranged intermediately. Most of the examined patients showed a decrease of the concentration of nucleosomes within 6 h after the first dose of radiation. Afterwards, nucleosome levels increased rapidly, reaching their maximum during the following days. Patients receiving postsurgery, primary or relapse therapies did not show significant differences in nucleosome values during the time of treatment. Single nucleosome values, measured at 6, 24 and 48 h after the application of therapy, could not discriminate significantly between patients with no progression and those with progression of disease. However, the area under the curve of the first 3 days, which integrated all variables of the initial therapeutic phase, showed a significant correlation with the progression-free interval (p=0.008). Our results indicate that the area under the curve of nucleosomes during the initial phase of radiochemotherapy could be valuable for the early prediction of the progression-free interval.

Heparin-mediated extracorporeal LDL precipitation treating a peripheral arterial disease patient suffering from repeated postoperative bypass occlusion.

Acute occlusion of a peripheral artery is a serious complication in peripheral arterial disease (PAD). Traditionally open surgical intervention in combination with antithrombotic therapy is the choice for treatment but the beneficial effects of both strategies are limited often by the patient's situation and therapeutic side effects. Heparin-mediated extracorporeal low-density lipoprotein precipitation (H.E.L.P.) apheresis efficiently removes circulating atherogenic lipoproteins, fibrinogen and C-reactive proteins as well as various proinflammatory and procoagulatory factors. We first report H.E.L.P. apheresis treating a PAD patient suffering from repeated postoperative femoropopliteal bypass graft occlusion, first, intensively, followed by weekly intervals. Limb amputation was avoided and the patient is doing well now. Angiography revealed bypass graft remained patent half a year after operation. This case report might help to design the regime for preventing postoperative bypass occlusion in patients with hyperlipidemia or hyperfibrinogenemia.

Circulating nucleosomes predict the response to chemotherapy in patients with advanced non-small cell lung cancer.

PURPOSE: We investigated the potential of circulating, nucleosomal DNA for the early prediction of the efficacy of chemotherapy in patients with advanced lung cancer. EXPERIMENTAL DESIGN: In serum of 212 patients with newly diagnosed non-small cell lung cancer (stages III and IV) undergoing chemotherapy, nucleosomes (ELISA, Roche) were measured at days 1, 3, 5, and 8 of the first cycle and before each new therapeutic cycle. Additionally, carcinoembryonic antigen and cytokeratin 19 fragments (CYFRA 21-1; Elecsys, Roche) were determined before each cycle. The therapeutic success was classified by computed tomography before start of the third cycle according to the World Health Organization criteria. RESULTS: In univariate analysis, responders (patients with remission) showed significantly (P < 0.05) lower values for the area under the curve of days 1 to 8 (AUC 1-8) of nucleosomes, the pretherapeutic baseline values of cycle 2 (BV2) and cycle 3 (BV3) of nucleosomes, and higher decreases of the baseline values from cycle 1 to 2 (BV1-2) and from cycle 1 to 3 (BV1-3) compared with nonresponders (patients with stable or progressive disease). Additionally, CYFRA 21-1 (BV1, BV2, BV3, BV1-2, BV1-3) and carcinoembryonic antigen (BV1-2) discriminated significantly between both groups. In multivariate analysis including all parameters available until end of the first therapeutic cycle, nucleosomes (AUC 1-8), CYFRA 21-1 (BV1), stage, and age were independent predictors of therapy response with nucleosomes (AUC 1-8) having the strongest impact. CONCLUSION: Circulating nucleosomes in combination with oncological biomarkers are valuable for the early estimation of the efficacy of chemotherapy in patients with lung cancer.