Gabriela Kornek

Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients.

Summary.  Background:  Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF‐positive microparticles (MPs) may contribute to venous thromboembolism (VTE).

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality

Objective Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. Methods We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. Results During a median follow-up of 25 (IQR 16–31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. Conclusions Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Incidence of dermatitis in head and neck cancer patients treated with primary radiotherapy and cetuximab

Purpose:To retrospectively assess the incidence of radiation dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who received primary radiotherapy in combination with cetuximab in a curative intent.Patients and Methods:A total of 112 consecutively treated patients who received cetuximab in combination with radiotherapy at the Departments of Radiotherapy at the Medical University in Vienna and the Hospital Hietzing (Vienna) were analyzed. Radiotherapy was administered either as conventional radiotherapy (70 Gy in 7 weeks) or using a concomitant boost protocol (72 Gy in 6 weeks). The incidence of dermatitis and mucositis within the radiation portals in 103 eligible patients was compared with a historical control group treated at the Medical University of Vienna as well as with published data.Results:The incidence of grade 1/2, 3, and 4 dermatitis was 57%, 29%, and 1% in the radiotherapy plus cetuximab treated collective. The incidence of grade 1/2, 3, and 4 mucositis was 37%, 47%, and 4%, respectively. The incidence of grade 3 dermatitis during concurrent radiotherapy plus cetuximab was 29% in our patient collective. Only one case of grade 4 dermatitis was observed.Conclusion:These results do not statistically differ significantly from the incidence reported in the Bonner trial and indicate that cetuximab in combination with radiotherapy is well tolerated.Ziel:Retrospektive Prüfung der Inzidenz der Strahlendermatitis bei Patienten mit lokal fortgeschrittenen nicht-resektablen Tumoren der Kopf-Hals-Region, die eine primäre Radiotherapie in Kombination mit Cetuximab in kurativer Intention erhielten.Patienten und Methodik:Insgesamt wurden 112 konsekutiv behandelte Patienten analysiert, die Cetuximab in Kombination mit Radiotherapie an den Abteilungen für Strahlentherapie der Medizinischen Universität Wien und des Krankenhauses Hietzing (Wien) erhielten. Die Strahlentherapie bestand entweder aus einer konventionellen Radiotherapie (70 Gy in 7 Wochen) oder aus einem konkomitanten Boost-Protokoll (72 Gy in 6 Wochen). Die Inzidenz an Dermatitis und Mukositis innerhalb der Bestrahlungsfelder wurde von 103 auswertbaren Patienten ermittelt und mit einer historischen Kontrollgruppe der Medizinischen Universität Wien wie auch mit publizierten Daten verglichen.Ergebnisse:Die Inzidenz von Grad-1/2-, -3- und -4-Dermatitis betrug jeweils 57%, 29% und 1% in der Radiotherapie-plus-Cetuximab-Gruppe. Die Inzidenz an Grad-1/2-, -3- und -4-Mukositis betrug jeweils 37%, 47% und 4%. Die Inzidenz von Grad-3-Dermatitis während einer konkomitanten Radiotherapie und Cetuximab betrug 29% in unserem Patientenkollektiv. Nur ein Fall einer Grad-4-Dermatitis wurde beobachtet.Schlussfolgerung:Die Ergebnisse unterscheiden sich in statistischer Weise nicht signifikant von der in der Bonner-Studie publizierten Inzidenz und weisen darauf hin, dass Cetuximab in Kombination mit Bestrahlung gut vertragen wird.

Autoimmune hemolytic anemia as a paraneoplastic phenomenon in solid tumors: A critical analysis of 52 cases reported in the literature

ZusammenfassungDie autoimmunhämolytische Anämie ist ein wohlbekanntes paraneoplastisches Phänomen bei lymphoproliferativen Erkrankungen. Es gibt aber auch eine Reihe von Fallberichten einer Assoziation einer autoimmunhämolytischen Anämie mit soliden Tumoren. Wir haben 52 publizierte Fälle einer solchen Assoziation analysiert. Eine autoimmunhämolytische Anämie kann vor klinischer Diagnose, gleichzeitig mit der klinischen Diagnose des Tumors oder nach Beendigung der Tumorbehandlung, entweder als Zeichen eines Rezidivs oder auch in kompletter Remission, auftreten. 70 % der Patienten hatten Wärme-Antikörper, 30 % Kälte-Antikörper. Einige Patienten hatten zusätzliche Antikörper wie gegen Plättchen (Evans Syndrom), Phospholipide (Lupus Antikoagulans) oder C1-Esterase Inhibitor. Eine autoimmunhämolytische Anämie trat bei nahezu allen Typen von Karzinomen auf, war aber relativ am häufigsten bei Nierenzellkarzinom und Kaposi Sarkom. Bei mehreren Karzinomen im Frühstadium, besonders bei Nierenzellkarzinomen, führte eine kurative Resektion des Tumors innerhalb von Wochen zu einer kompletten, potenziell anhaltenden Remission der autoimmunhämolytischen Anämie. Die Resektion des Tumors hatte auch günstige Effekte auf die autoimmunhämolytische Anämie bei metastasierenden Tumoren. Patienten, die auf eine Resektion des Tumors ansprachen, waren oft refraktär gegenüber Steroidbehandlung vor der Operation. Ein Ansprechen auf Steroide wurde hingegen öfters bei Patienten mit metastasierendem Tumor beobachtet. Eine Untersuchung von Patienten mit Autoimmunerkrankungen bei Tumoren könnte wichtige Einblicke in die Biologie von Tumoren geben.SummaryAutoimmune hemolytic anemia (AIHA) is a well known paraneoplastic phenomenon in lymphoproliferative disorders but there are also a number of case reports of such an association with solid tumors. We have analysed 52 cases of this association reported in the literature. We found that AIHA may occur prior to, concurrent with cancer or well after end of treatment, either as a sign of recurrence or in complete remission of the cancer. 70% of the patients had warm antibody and 30% cold antibody AIHA. Some patients had additional antibodies such as platelet antibodies (Evans syndrome), lupus anticoagulants or antibodies to C1 esterase inhibitor. AIHA occurred in almost all types of cancers, but it was relatively more common in renal cell cancer and Kaposi sarcoma compared to other cancers. In early stage cancers, in particular in renal cell cancers, curative resection of the cancers led to complete, often sustained remission of AIHA within a short time in a number of patients. Resection of the tumor had also beneficial effects in some metastatic cancers. Patients who had a response to resection of the tumor were often refractory to steroid treatment before surgery, while some responses to steroids were observed in patients with metastatic cancer. The study of cancer patients with autoimmune diseases may provide important insights into the biology of tumors.

Microparticle-associated tissue factor activity in patients with metastatic pancreatic cancer and its effect on fibrin clot formation

Highly elevated microparticle (MP)-associated tissue factor (TF) activity was found in patients with pancreatic cancer, one of the most prothrombotic malignancies. It remains to be elucidated whether MP-TF activity reflects the prothrombotic state in these patients. MP-TF activity levels and the TF-dependent and -independent effect of MPs on fibrin clot formation were determined in patients with metastatic pancreatic cancer (n = 27), in healthy individuals (n = 10) and in plasma samples from lipopolysaccharide (LPS)-stimulated blood (LPS-plasma), which is rich in monocyte-derived TF-bearing MPs. The median MP-TF activity was 1.06 pg/mL (range, from 0.19 to 10.34 pg/mL) in patients with pancreatic cancer, 0.61 pg/mL (range, from 0.36 to 0.79 pg/mL) in LPS-plasma, and 0.18 pg/mL (range, from 0.04 to 0.39 pg/mL) in healthy individuals. MPs derived from LPS-plasma had the strongest impact on fibrin clot formation time (median, 157.6 seconds; range, from 149.5 to 170.4 seconds). Fibrin clot formation occurred significantly later in MPs derived from patients with pancreatic cancer (median, 273.4 seconds; range, from 146.6 to 354.4 seconds; P < 0.001) and in healthy individuals (median, 299.0 seconds; range, from 261.1 to 417.9 seconds; P < 0.001). Only in MPs derived from LPS-plasma the fibrin clot formation time dependent strongly on TF (median prolongation after TF blockade: 68% in LPS-plasma, 10% in patients with pancreatic cancer, and 4% in healthy individuals). In conclusion, highly elevated MP-TF activity was found in patients with metastatic pancreatic cancer, but TF-bearing MPs had a small effect on fibrin clot formation. TF-bearing MPs might not be the main mediators of the prothrombotic state associated with pancreatic cancer. However, the small but significant increase in coagulation potential by TF-bearing MPs might contribute to the multifactorial pathogenesis of venous thromboembolism in pancreatic cancer.

Survival of patients with HPV-positive oropharyngeal cancer after radiochemotherapy is significantly enhanced

ZusammenfassungHINTERGRUND: Der Zweck dieser retrospektiven Studie war, die Inzidenz und klinische Signifikanz von Infektionen mit HPV (Humanes Papillomavirus) in Patienten mit Kopf-Hals-Tumoren, die eine Strahlentherapie erhalten hatten, zu evaluieren. PATIENTEN AND METHODEN: Bei 88 Patienten mit Karzinomen des Kopf-Hals-Bereiches wurde eine Untersuchung zur Identifizierung von high-risk HPV mittels Immunhistochemie, PCR (Polymerase Chain Reaction) und in-situ Hybridisierung durchgeführt. 26 Patienten hatten ein Karzinom der Mundhöhle, 45 des Oropharynx, sieben ein Larynx- und 10 ein Hypopharnyxkarzinom. 29 der 45 Patienten mit einem Plattenepithelkarzinom des Oropharynx erhielten entweder eine alleinige Strahlentherapie oder eine Kombination mit Cisplatin oder Cetuximab. ERGEBNISSE: Von den 29 untersuchten Patienten, die zur Therapie ihres Oropharynxkarzinoms eine konservative Therapie erhielten, hatten 11 Patienten einen HPV positiven und 18 einen HPV negativen Tumor. Den Patienten wurde eine Strahlentherapie ± Cisplatin oder Cetuximab verabreicht, wobei die Patienten mit einem HPV positiven Tumor ein signifikant besseres Ansprechen auf die Therapie zeigten (p = 0.015). Auch das krankheits-spezifische Überleben war deutlich besser in HPV positiven Patienten (p = 0.001). SCHLUSSFOLGERUNG: Patienten mit einem Oropharynxkarzinom und einem positiven HPV Status sprechen deutlich besser auf eine Radiochemotherapie an als Patienten mit einem HPV negativen Tumor. Das HPV Screening ist eine sehr einfache Prozedur und kann einfach routinemässig in die Standard Operational Procedures inkludiert werden.SummaryBACKGROUND: The purpose of this study was to evaluate the incidence and clinical significance of HPV (Human papilloma virus) infection in patients with head and neck cancer who had received radiotherapy in Eastern Austria. PATIENTS AND METHODS: 88 patients with head and neck cancer including 26 patients with oral cavity cancer, 45 patients with oropharyngeal cancer, seven patients with laryngeal carcinoma and ten patients with carcinoma of the hypopharynx were screened for high risk HPV by immunohistochemistry, PCR (Polymerase Chain Reaction) and in-situ hybridization. 29 out of 45 patients with a squamous cell carcinoma of the oropharynx received radiotherapy alone, radiotherapy in combination with cisplatin or cetuximab. RESULTS: Of the investigated 29 patients with oropharyngeal cancer receiving conservative treatment, 11 had a HPV-positive and 18 a HPV-negative tumor. Patients received radiation ± cisplatin or cetuximab, where the HPV-positive patients had a significant better response to treatment and overall survival (p = 0.015) as well as disease-free survival (p = 0.001) after therapy. CONCLUSION: Patients with oropharyngeal carcinoma and a positive HPV status respond considerably better to radiochemotherapy than patients with HPV-negative tumors. HPV screening is a simple procedure and can easily be implemented in routine pathology investigations and should be included in standard operational procedures for the diagnosis and therapy of head and neck cancer patients.

Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab

Cancer progression is often associated with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a major regulator of vascular permeability and has been implicated as mediator of tumor progression.

Significance of p16 expression in head and neck cancer patients treated with radiotherapy and cetuximab

BackgroundHPV-infection, p16 positivity, and EGFR expression have been correlated with favorable responses of head and neck cancer patients treated with radiotherapy (RT) with or without chemotherapy. However, a possible correlation of HPV/p16 and EGFR status on the effect of RT in combination with cetuximab has not been sufficiently investigated.Materials and methodsWe analyzed tumor samples for p16 and EGFR expression and correlated these variables with treatment outcome. Cox-proportional-hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. Survival was estimated by the Kaplan–Meier method. Results were compared with an institutional historical control group treated without cetuximab and with published data.ResultsExpression of p16 was predominantly found in oropharyngeal squamous cell cancer patients (OPSCC; 36.6 % positivity; 92 % of all cases), while EGFR was expressed at high levels in all tumor subsites (82 %). p16 expression was associated with improved overall survival in irradiated OPSCC patients (2-year overall survival of 80 % in p16-positive vs. 33 % overall survival in p16-negative patients). In a multivariable analysis covering all tumor sites, nodal stage (> N2a vs. ≤ N2a) and tumor site (OPSSC vs. non-OPSCC) had an impact on overall survival.ConclusionOur results show that p16 positivity is associated with a favorable outcome in OPSCC patients treated with RT and cetuximab.ZusammenfassungHintergrundHPV-Infektion, p16-Positivität und EGFR-Expression wurden bei Kopf-Hals-Tumorpatienten, die mit einer Strahlentherapie (RT) mit oder ohne Chemotherapie behandelt wurden, mit einem besseren Ergebnis in Verbindung gebracht. Bis jetzt wurde eine solche Korrelation bei Patienten, die mit einer RT in Kombination mit Cetuximab therapiert wurden, nicht untersucht.Material und MethodenEs wurden die p16- und die EGFR-Expression in Tumormaterial untersucht und die Daten mit dem Behandlungsergebnissen korreliert. Um die Sterberisiken zu vergleichen, wurden Cox-Regressionsmodelle angewendet und die Patienten nach Risikofaktoren stratifiziert. Das Überleben wurde nach der Kaplan-Mayer-Methode bewertet. Die Resultate wurden mit einer historischen Vergleichsgruppe aus unserem Institut und der Literatur verglichen.ErgebnisseDie p16-Expression wurde vorrangig in Oropharynxkarzinompatienten gefunden (OPSCC; 36,6 % positiv; 92 % aller positiven Fälle), während EGFR in allen Tumorlokalisationen stark exprimiert war (82 %). Die p16-Expression war in OPSCC-Patienten mit einem verbesserten Gesamtüberleben (OS) assoziiert (2-Jahres-OS von 80 % in p16-positiven vs. 33 % in p16-negativen Patienten). In einer multivariablen Analyse, die sämtliche Tumorlokalisationen umfasste, zeigten der Lymphknotenstatus (> N2a vs. ≤ N2a) und die Tumorlokalisation (OPSSC vs. non-OPSCC) einen Einfluss auf das OS.SchlussfolgerungUnsere Resultate zeigen, dass eine p16-Expression mit einem besseren Outcome von OPSCC-Patienten, die mit einer Kombination aus RT und Cetuximab behandelt wurden, assoziiert ist.

Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer

Carcinoembryonic antigen (CEA) affects tumorigenesis by enhancing tumor cell survival and by inducing tumor angiogenesis. This study aimed to evaluate baseline CEA serum levels to predict bevacizumab‐based therapy effect and survival in patients with metastatic colorectal cancer (mCRC). Two hundred and ninety eight mCRC patients receiving chemotherapy plus either bevacizumab or cetuximab were analyzed in a retrospective study. Disease control (DC), progression‐free survival (PFS), and overall survival were assessed and related to pretreatment CEA serum levels. Patients with baseline CEA serum levels below the statistical median of 26.8 ng/mL (group I) were compared with patients with higher CEA levels (group II). The cetuximab‐based treatment cohort was analyzed for specificity assessment of CEA to predict the anti‐vascular endothelial growth factor effect in mCRC. Baseline CEA serum levels inversely correlated with therapeutic response in patients receiving bevacizumab‐based treatment (disease control rate, 84% vs 60%), inversely correlated with median PFS leading to a median PFS benefit of 2.1 months for patients in group I when compared with group II, as well as inversely correlated with median overall survival (37.5 months vs 21.4 months). In an independent cohort of 129 patients treated with cetuximab‐based therapy, no association of therapeutic response or PFS with CEA serum levels was found. As expected, baseline CEA levels were prognostic for mCRC. These data give first evidence that baseline serum CEA levels might constitute an important predictor for the efficacy of first‐line bevacizumab‐based therapy in patients with mCRC.

Safety and feasibility of every-other-week maintenance cetuximab after first-line chemotherapy in patients with recurrent or metastatic head and neck squamous cell cancer

In patients with recurrent and/or metastatic head and neck squamous cell cancer (HNSCC), there are no data about an every‐other‐week cetuximab maintenance schedule after chemotherapy plus cetuximab as first‐line treatment.