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. Copyright (c) 2006 S. Karger AG, Basel

Predictive and prognostic value of circulating nucleosomes and serum biomarkers in patients with metastasized colorectal cancer undergoing Selective Internal Radiation Therapy

Background Selective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and prognosis are needed for the individual management of those patients undergoing SIRT. Methods Blood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival. Results Circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model. Conclusion Panels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy

Relevance of circulating nucleosomes and oncological biomarkers for predicting response to transarterial chemoembolization therapy in liver cancer patients

<p>Abstract</p> <p>Background</p> <p>Transarterial chemoembolization (TACE) therapy is an effective locoregional treatment in hepatocellular cancer (HCC) patients. For early modification of therapy, markers predicting therapy response are urgently required.</p> <p>Methods</p> <p>Here, sera of 50 prospectively and consecutively included HCC patients undergoing 71 TACE therapies were taken before and 3 h, 6 h and 24 h after TACE application to analyze concentrations of circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), alpha fetoprotein (AFP), C-reactive protein (CRP) and several liver biomarkers, and to compare these with radiological response to therapy.</p> <p>Results</p> <p>While nucleosomes, CYFRA 21-1, CRP and some liver biomarkers increased already 24 h after TACE, percental changes of nucleosome concentrations before and 24 h after TACE and pre- and posttherapeutic values of AFP, gamma-glutamyl-transferase (GGT) and alkaline phosphatase (AP) significantly indicated the later therapy response (39 progression versus 32 no progression). In multivariate analysis, nucleosomes (24 h), AP (24 h) and TACE number were independent predictive markers. The risk score of this combination model achieved an AUC of 81.8% in receiver operating characteristic (ROC) curves and a sensitivity for prediction of non-response to therapy of 41% at 97% specificity, and of 72% at 78% specificity.</p> <p>Conclusion</p> <p>Circulating nucleosomes and liver markers are valuable tools for early estimation of the efficacy of TACE therapy in HCC patients.</p

Colorectal carcinoma: nucleosomes, carcinoembryonic antigen and ca 19-9 as apoptotic markers; a comparative study

<p>Abstract</p> <p>Background</p> <p>Colorectal carcinoma is a common and often fatal disease in which methods of early detection and monitoring are essential. The present study was conducted for measuring serum levels of nucleosomes, carcinoembryonic antigen (CEA) and CA 19-9 in patients newly diagnosed with colorectal carcinoma and confirmed by clinicopathological study.</p> <p>Method</p> <p>Thirty subjects were included in the current study: six normal subjects as a control group with mean age (45.6 ± 7.9) and twenty four colorectal carcinoma patients with mean age (46.9 ± 15.6), which were classified pathologically according to the degree of malignant cell differentiation into well differentiated (group I), moderately differentiated (group II) and poorly differentiated (group III). Fasting venous blood samples were collected preoperative.</p> <p>Results</p> <p>The results revealed a significant increase in serum level of nucleosomes in patients with poorly differentiated tumors versus patients with well differentiated tumors (p = 0.041). The levels of CEA and CA19-9 showed no significant increase (p = 0.569 and 0.450, respectively).</p> <p>Conclusion</p> <p>In conclusion, serum level of nucleosomes provides a highly sensitive and specific apoptotic marker for colorectal carcinoma.</p

Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer

In pancreatic cancer ( PC) accurate determination of treatment response by imaging often remains difficult. Various efforts have been undertaken to investigate new factors which may serve as more appropriate surrogate parameters of treatment efficacy. This review focuses on the role of carbohydrate antigen 19- 9 ( CA 19- 9) as a prognostic tumor marker in PC and summarizes its contribution to monitoring treatment efficacy. We undertook a Medline/ PubMed literature search to identify relevant trials that had analyzed the prognostic impact of CA 19- 9 in patients treated with surgery, chemoradiotherapy and chemotherapy for PC. Additionally, relevant abstract publications from scientific meetings were included. In advanced PC, pretreatment CA 19- 9 levels have a prognostic impact regarding overall survival. Also a CA 19- 9 decline under chemotherapy can provide prognostic information for median survival. A 20% reduction of CA 19- 9 baseline levels within the first 8 weeks of chemotherapy appears to be sufficient to define a prognostic relevant subgroup of patients ('CA 19- 9 responder'). It still remains to be defined whether the CA 19- 9 response is a more reliable method for evaluating treatment efficacy compared to conventional imaging. Copyright (c) 2006 S. Karger AG, Basel

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen / Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

Immunogene Zelltodmarker sind eine inhomogene Gruppe von Molekülen, die während Zelltodprozessen wie Apoptose, Nekrose oder weiteren Formen freigesetzt werden. Je nach Zusammensetzung des extrazellulären Milieus können diese „Danger associated molecular patterns“ (DAMPs) wie das „High mobility group box 1“ (HMGB1) Protein das Immunsystem stimulierend oder inhibierend beeinflussen. Bei Tumorerkrankungen scheint eine kontinuierliche Freisetzung von HMGB1, u.a. über eine Vermittlung durch den zellulären Bindungspartner „Receptor of advanced glycation end products“ (RAGE), zu einer Förderung des Tumorwachstums zu führen, während die pulsatile Freisetzung während zytotoxischer Therapie zu einer verbesserten antitumorösen Immunantwort beitragen könnte. Lösliches RAGE (sRAGE) kann hingegen die Effekte von extrazellulärem HMGB1 abpuffern. In diesem Review werden die strukturellen und funktionalen Charakteristika dieser immunogenen Zelltodmarker sowie ihre Rolle in der Pathophysiologie von nicht-malignen und malignen Erkrankungen vorgestellt; sodann wird ihre Relevanz als Serum-Biomarker für die Diagnose, die Prognoseabschätzung, die Prädiktion und das Monitoring des Ansprechens einer zytotoxischen Therapie bei Tumorpatienten beleuchtet. Bei Patienten mit verschiedenen Tumorerkrankungen wurden im Vergleich zu gesunden Personen erhöhte Serumkonzentrationen von HMGB1 und niedrigere sRAGE-Werte gefunden. Zudem waren hohe HMGB1- und niedrige sRAGE-Serumwerte vor und während einer zytotoxischen Therapie mit einem unzureichenden Ansprechen auf die Behandlung und einem kürzeren Überleben assoziiert. Diese Ergebnisse weisen die immunogenen Zelltodmarker HMGB1 und sRAGE als neue, vielversprechende Biomarker zur Abschätzung der Prognose, Stratifikation der Patienten und zum Therapiemonitoring bei Tumorpatienten aus.Immunogenic cell death markers are an inhomogeneous group of molecules which are released from apoptotic, necrotic or otherwise dying cells. Once in the extracellular milieu, these danger associated molecular patterns (DAMPs) such as the high mobility group box 1 protein (HMGB1) are able to exert activating and suppressive effects on the immunity system. On the one hand, continuously released HMGB1 – via interaction with its cellular binding partner receptor of advanced glycation end products (RAGE) – can promote tumor growth, whereas, on the other hand, pulsatile release of HMGB1 during cytotoxic therapies may activate the immunity system against tumor cells. Soluble RAGE (sRAGE), however, can act as a decoy receptor, balancing the extracellular effects of HMGB1. Here, we review the structural and functional characteristics of these immunogenic cell death markers and their role in the pathophysiology of diverse benign and malignant diseases. Further, we report on their relevance as serum biomarkers for the diagnosis, estimation of prognosis, as well as the prediction and monitoring of response to cytotoxic therapy in cancer patients. Elevated levels of HMGB1 and lower levels of sRAGE were found to be present in blood of patients suffering from various tumor entities as compared with healthy controls. Furthermore, high HMGB1 and low sRAGE serum levels of cancer patients before or during cytotoxic therapy were associated with poor treatment response and shortened overall survival. These results indicate that immunogenic cell death markers such as HMGB1 and sRAGE are promising new biomarkers for prognosis, patients’ stratification and therapy monitoring in cancer patients

Carboplatin: molecular mechanisms of action associated with chemoresistance

A carboplatina é um derivado da cisplatina, possuindo mecanismo de ação similar, diferindo em estrutura e toxicidade. Este fármaco foi aprovado pelo FDA em meados de 1980 e, desde então, tem sido amplamente usado no tratamento de diversos tipos de tumores. Este agente é caracterizado por sua habilidade em gerar lesões no DNA através da formação de adutos com a platina, inibindo a replicação e a transcrição, levando à morte celular. Entretanto, seu uso pode levar a graves inconvenientes, advindos do desenvolvimento de resistência que alguns pacientes adquirem durante o tratamento, limitando o alcance de seu potencial. Até então, os mecanismos bioquímicos relacionados ao problema da resistência não são precisamente conhecidos. Dessa forma, o conhecimento das vias associadas à resistência causada pela exposição à carboplatina pode prover valiosas informações para o planejamento racional de fármacos com base em platina mais eficiente e para o desenvolvimento de novas estratégias terapêuticas. Nesta revisão narrativa, serão discutidos alguns mecanismos de resistência a fármacos com base em platina, especialmente ao antitumoral carboplatina.Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin

Nukleosomen im Serum von Tumorpatienten unter Radiochemotherapie

Diese Promotionsschrift versucht zu klären, ob die Freisetzung von Nukleosomen innerhalb der ersten Tage einer Radiochemotherapie frühzeitig die Effizienz der Therapie und damit das progressionsfreie Intervall erkennen lässt. Dazu wurden 32 Patienten mit einem Karzinom der Bauchspeicheldrüse und 25 Patienten mit einem Malignom des Dickdarms in eine prospektive Studie eingeschlossen. Mehrere Serumproben wurden im Verlauf der Therapie abgenommen und darin die Konzentration an Nukleosomen gemessen und mit den etablierten biologischen Markern CEA, CA 19-9 und CYFRA 21-1 sowie den Resultaten bildgebender Verfahren korreliert. Patienten mit postoperativer Radiochemotherapie nach kompletter Resektion (R0-Resektion) eines kolorektalen Karzinoms wiesen niedrige Nukleosomenwerte mit geringer Schwankungsbreite auf. Signifikant höhere Konzentrationen der Nukleosomen wurden bei Patienten mit noch vorhandenen Tumormassen gemessen, die sich einer präoperativen oder Rezidiv-Radiochemotherapie unterzogen. Dieses Ergebnis korrelierte auch mit anderen biologischen Markern wie CEA, CA 19-9 und CYFRA 21-1. Bei kolorektalen Malignomen konnte in der Gruppe der präoperativ behandelten Patienten frühzeitig das Therapieansprechen vorhergesagt werden. Hier korrelierte eine kleine Fläche unter der Kurve (area under the curve, AUC) mit fehlender Progression, eine hohe AUC mit Progression der Tumorerkrankung unter Therapie. Bei Patienten mit Pankreaskarzinom während Radiochemotherapie konnte anhand der Nukleosomenkonzentrationen im Serum frühzeitig das progressionsfreie Intervall abgeschätzt werden. Eine kleine Fläche unter der Kurve korrelierte dabei mit einem langen progressionsfreien Intervall. Dagegen erlitten Patienten mit einer großen AUC frühzeitig eine Progression. Biologische Marker und bildgebende Verfahren ermöglichen oft erst nach Wochen bis Monaten die Beurteilung einer Therapie. Nukleosomen dagegen, insbesondere die AUC, ergeben frühzeitig wertvolle prognostische Hinweise für das Ansprechen von Pankreas- und kolorektalen Karzinomen auf eine Radiochemotherapie. Nukleosomen stellen somit einen einfach und günstig zu bestimmenden Laborparameter dar, der sich zum Therapiemonitoring während Radiochemotherapien eignet. Werden die hier vorliegenden Daten in umfangreicheren, prospektiven, klinischen Studien bestätigt, könnten Nukleosomen als wertvolles laborchemisches Instrument dienen, um das therapeutische Vorgehen bei Patienten mit einer Tumorerkrankung individuell zu optimieren