W.T.A. van der Graaf

Cardiovascular Morbidity in Long-Term Survivors of Metastatic Testicular Cancer

PURPOSE To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy. PATIENTS AND METHODS Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were </= 50 years at the time of analysis were evaluated for the occurrence of cardiovascular events. Sixty-two of 87 patients were additionally evaluated for cardiac damage and cardiovascular risk factors. Their cardiovascular risk profile was compared with that of 40 patients with comparable age and follow-up duration treated with orchidectomy only for stage I disease. RESULTS Major cardiac events were found in five (6%) of the 87 patients (age at time of event, 30 to 42 years; time after chemotherapy, 9 to 16 years): two with myocardial infarction and three with angina pectoris with proven myocardial ischemia. An increased observed-to-expected ratio of 7.1 (95% confidence interval, 1.9 to 18.3) for coronary artery disease, as compared with the general male Dutch population, was found. In addition, one patient experienced a cerebrovascular accident. Exercise ECG did not reveal cases of subclinical coronary artery disease. Echocardiography showed normal systolic left ventricular function in most patients, but diastolic left ventricular function was disturbed in 33% of the patients. Of 62 chemotherapy patients, 79% had hypercholesterolemia, 39% had hypertension, 25% still experienced Raynauds phenomenon, and 22% had microalbuminuria. Compared with patients with stage I disease, the chemotherapy patients had higher blood pressure and higher total cholesterol and triglyceride levels and were more insulin-resistant. CONCLUSION In long-term survivors of metastatic testicular cancer, we observed a significantly increased risk for occurrence of cardiac events accompanied by a persisting unfavorable cardiovascular risk profile. Accurate follow-up, focused on cardiovascular complications and aimed at intervention in these young cancer survivors, seems to be important.

Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal; University Hospital Essen, Essen, Germany; Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy; Klinikum Stuttgart-Olgahospital, Stuttgart, Germany; Institut Curie, Paris, France; NORDIX, Athens, Greece; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria; Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain; Centro di Riferimento Oncologico di Aviano, Aviano; Ospedale Regionale di Treviso “S.Maria di Cà Foncello”, Treviso, Italy; Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain; Sarcoma Unit, University College London Hospitals, London, UK; Skane University Hospital-Lund, Lund, Sweden; N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; Institute of Scientific Hospital Care (IRCCS), Regina Elena National Cancer Institute, Rome; Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; Istituto Ortopedico Rizzoli, Bologna; Azienda Ospedaliera Universitaria Careggi Firenze, Florence, Italy; Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands; Institut Jules Bordet, Brussels, Belgium; Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy; Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam and Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands; Turku University Hospital (Turun Yliopistollinen Keskussairaala), Turlu, Finland; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Mannheim University Medical Center, Mannheim; Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Helsinki University Central Hospital (HUCH), Helsinki, Finland; Royal Marsden Hospital, London; The Institute of Cancer Research, London, UK; University Medical Center Groningen, Groningen; Radboud University Medical Center, Nijmegen, The Netherlands; University Hospital Motol, Prague; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Gustave Roussy Cancer Campus, Villejuif, France; Maria Skłodowska Curie Institute, Oncology Centre, Warsaw, Poland; Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel; Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland; Azienda Ospedaliera, Universitaria, Policlinico S Orsola-Malpighi Università di Bologna, Bologna; Azienda Ospedaliero, Universitaria Cita della Salute e della Scienza di Torino, Turin, Italy; Fundacio de Gestio Sanitaria de L’hospital de la SANTA CREU I Sant Pau, Barcelona, Spain; Helios Klinikum Berlin Buch, Berlin, Germany; YCRC Department of Clinical Oncology, Weston Park Hospital NHS Trust, Sheffield, UK; Aarhus University Hospital, Aarhus, Finland; Leuven Cancer Institute, Leuven, Belgium; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Institute of Oncology of Ljubljana, Ljubljana, Slovenia; Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands; University College Hospital, London, UK; Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany; Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Centre Leon Bernard and UCBL1, Lyon, France

Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility

This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.

Prospective Evaluation of Early Cardiac Damage Induced by Epirubicin-Containing Adjuvant Chemotherapy and Locoregional Radiotherapy in Breast Cancer Patients

PURPOSE To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. PATIENTS AND METHODS Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. RESULTS No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV. CONCLUSION Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography

1 Homozygously mdr1a gene disrupted mice (mdr1a(−/−) mice) and wild type mice (mdr1a(+/+) mice) were used to develop a method for P‐glycoprotein (P‐gp) function imaging non‐invasively and to study the effect of a P‐gp reversal agent on its function in vivo. 2 [11C]verapamil (0.1 mg/kg) was administered and the changes in tissue concentrations were determined ex vivo by organ extirpation and in vivo with PET. To block P‐gp function, cyclosporin A was administered. 3 Biodistribution studies revealed 9.5‐fold (P<0.001) and 3.4‐fold (P<0.001) higher [11C]verapamil in the brain and testes of mdr1a(−/−) mice than in mdr1a(+/+) mice. Cyclosporin A (25 mg/kg) increased [11C]verapamil levels in the brain and testes of mdr1a(+/+) mice in both cases 3.3‐fold (P<0.01 (brain); P<0.001 (testes)). Fifty mg/kg cyclosporin A increased [11C]verapamil in the brain 10.6‐fold (P<0.01) and in the testes 4.1‐fold (P<0.001). No increases were found in the mdr1a(−/−) mice. This indicates complete inhibition of P‐gp mediated [11C]verapamil efflux. 4 Positron camera data showed lower [11C]verapamil levels in the brain of mdr1a(+/+) mice compared to those in mdr1a(−/−) mice. [11C]verapamil accumulation in the brain of mdr1a(+/+) mice was increased by cyclosporin A to levels comparable with those in mdr1a(−/−) mice, indicating that reversal of P‐gp mediated efflux can be monitored by PET. 5 We conclude that cyclosporin A can fully block the P‐gp function in the blood brain barrier and the testes and that PET enables the in vivo measurement of P‐gp function and reversal of its function non‐invasively.

Visualization of multidrug resistance in vivo

Abstract. Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.

Spinal extradural metastasis: review of current treatment options.

Bone metastases, especially to the spine, are frequently encountered during the course of a malignancy. Due to a worldwide increase of cancer incidence and to a longer life expectancy of patients with cancer, a rise in incidence of bone metastases is observed. A brief historical overview is the base of a review of current treatment options. Despite new developments in the surgical and radiotherapeutic fields, as well as in medical oncology, external beam radiotherapy is the cornerstone of the treatment of spinal metastases. In selected cases, surgical treatment is a proven option. Vertebroplasty or kyphoplasty can also be considered. Supportive medical care does not differ from that given for symptomatic lesions to the skeletal system elsewhere in the body. After discussing the treatment options, an algorithm is given.

Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy.

The development of targeted therapies is a major breakthrough in the treatment of cancer. By evoking necrosis and cavitation, evaluation based on tumour size alone, as is done in the RECIST criteria, is no longer an adequate method. New molecular and functional imaging techniques are developed. This review focuses on the use of new imaging modalities for the evaluation of treatment response of pathway based targeted therapies. First, the basic principles of functional and molecular imaging modalities are briefly discussed. Thereafter, their clinical application in targeted therapies is correlated to the underlying biological mechanism. In this way, the best method for response evaluation for a new agent can be identified.

Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables

OBJECTIVE To investigate left ventricular dysfunction in patients who had been treated with anthracycline based chemotherapy. METHODS Autonomic function was compared with left ventricular diastolic function in 20 asymptomatic women with normal systolic function (left ventricular ejection fraction (LVEF) > 0.50) treated for breast cancer with high dose anthracycline based chemotherapy, and 20 age matched healthy controls. Left ventricular diastolic function was assessed echocardiographically by measuring the early peak flow velocity to atrial peak flow velocity ratio, isovolumic relaxation time, and deceleration time. Heart rate variability analysis was assessed for time domain and frequency domain parameters. RESULTS The mean (SD) age of the patients was 45 (7) years and the mean LVEF was 0.59 (0.06). The time interval after the end of chemotherapy was 29 (27) months. One or more diastolic variables were abnormal in 50% of the patients. Heart rate variability was abnormal in 85% of patients. Mean values of both time domain and frequency domain parameters were decreased (p < 0.05), in particular the parasympathetic indices. CONCLUSIONS Autonomic impairment occurs in a large proportion of asymptomatic patients with normal systolic left ventricular function after high dose anthracycline based chemotherapy. In particular, heart rate variability analysis may be a sensitive tool to identify the first signs of cardiotoxicity in these patients.

Susceptibility to development of Mycobacterium ulcerans disease: review of possible risk factors

Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance‐associated macrophage protein‐1 (NRAMP‐1), HLA‐DR, vitamin D3 receptor, mannose binding protein, interferon‐gamma (IFN‐γ) receptor, tumour necrosis factor alpha (TNF‐α), interleukin (IL)‐1α, 1β and their receptor antagonists; and IL‐12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fuelled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th‐2 pattern, away from a Th‐1 preponderant protection against mycobacterial infection. If the latter hypothesis is confirmed, enhanced schistosomiasis control should impact on BU.