Approaches to management of cardiovascular morbidity in adult cancer patients - cross-sectional survey among cardio-oncology experts.

BACKGROUND: In cardio-oncology, a range of clinical dilemmas can be identified where high-quality evidence for management is still lacking. The aim of this project was to study clinical practices and expert approaches to several clinical cardio-oncological dilemmas regarding prediction, prevention and treatment of cardiovascular disease in adult cancer patients. METHODS: A cross-sectional online survey was sent out to internationally renowned experts in the field of cardio-oncology. Participants were selected based on being first or last authors of papers in the field of cardio-oncology, or principal investigators to trials in this field. RESULTS: Topics discussed include, among others, the use of biomarkers for subclinical cardiovascular toxicity, approaches towards primary prevention and follow-up with medication and life-style recommendations, and management of fluoropyrimidine-vasospasm, QTc-prolongation and asymptomatic declines in left ventricular ejection fraction. CONCLUSION: The answers provided in this survey have shed light on expert-based practices in cardio-oncologic dilemmas. Attitudes towards, as well as discrepancies in those dilemmas are presented. Existing discrepancies clearly indicate the need for generation of high-quality data that allows for more evidence-based recommendations in the future.

Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy.

BACKGROUND: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, high-risk patients should be identified. The aim of this study was to assess BEP-chemotherapy induced vascular damage and to find risk factors for early vascular events. PATIENTS AND METHODS: A prospective cohort study was performed in (B)EP treated TC patients. Development of venous and arterial vascular events was assessed. Vascular damage markers (von Willebrand factor [vWF], coagulation factor VIII [FVIII], intima media thickness [IMT]) and cardiovascular risk factors were assessed before and until 1 year after chemotherapy. Before start of chemotherapy a vascular fingerprint was estimated. Presence of ≥3 risk factors was defined as high-risk vascular fingerprint: body mass index >25 kg/m(2), current smoking, blood pressure >140/90 mm Hg, total cholesterol >5.1 and/or low-density lipoprotein >2.5 mmol/L or glucose ≥7 mmol/L. RESULTS: Seventy-three patients were included. Eight (11%) developed vascular events (four arterial events, four pulmonary embolisms). vWF and FVIII increased during chemotherapy, especially in patients with vascular events. Sixteen patients (22%) had a high-risk vascular fingerprint before start of chemotherapy. These patients had arterial events more often (3/16 [19%] versus 1/57 [2%]; p = 0.031) and higher vWF levels and IMT. CONCLUSIONS: Endothelial activation and upregulation of procoagulant activity seem important mechanisms involved in early (B)EP-chemotherapy-induced vascular events. Before chemotherapy, a quarter already had cardiovascular risk factors. A vascular fingerprint could identify patients at risk for arterial events. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies.

Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors.

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1-13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC1-3 years) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3-15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T1/2 was 3.7 (range 2.5-5.2) years. Pt AUC1-3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1-3 years (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC1-3 years. CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure.

Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009.

SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, integrated, well-resourced TB service where all patients are offered culture-confirmed diagnosis by a central reference laboratory. OBJECTIVE: To assess the treatment outcomes of MDR-TB patients over a period of 10 years in The Netherlands. DESIGN: Demographic, clinical and microbiological features of all patients with MDR-TB who started treatment in 2000-2009 in the Netherlands were analysed from national registry and patient records. RESULTS: Characteristics of the 113 MDR-TB patients were as follows: male/female ratio 1.57, 96% foreign born, median age 29 years, 96 (85%) pulmonary TB, 56 (50%) smear-positive, 14 (12%) human immunodeficiency virus (HIV) co-infected. Of the 104 (92%) patients who started MDR-TB treatment, 86% had a successful outcome using a median of six active drugs; eight underwent pulmonary surgery. HIV negativity was associated with successful outcome (adjusted OR 2.1, 95%CI 1.1-3.8). CONCLUSION: High success rates for MDR-TB treatment were achieved with close collaboration of all stakeholders, reaching the targets set for drug-susceptible TB. HIV remained an independent risk factor for unsuccessful treatment outcome.

Early development of the metabolic syndrome after chemotherapy for testicular cancer.

BACKGROUND: The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of gonadal function. METHODS: TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3-20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function. RESULTS: In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, [95% confidence interval (CI) 1.5-3.3] compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels <15 nmol/l (22%) have an increased risk of the MS (OR 4.1, 95% CI 1.8-9.3). CONCLUSIONS: The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer.

BACKGROUND: Cross-sectional studies showed that treatment with cisplatin chemotherapy for testicular cancer is associated with an increased incidence of cardiac dysfunction. We investigated longitudinal progression of and contributing factors to cardiac dysfunction in testicular cancer survivors. PATIENTS AND METHODS: Cardiac assessments were carried out before 10 months (range 7-15 months) and 6.9 years (range 4.9-9.7 years) after start of cisplatin-based chemotherapy, consisting of echocardiography [systolic function (left ventricular ejection fraction, LVEF), diastolic function (myocardial tissue velocities; tissue velocity imaging of early diastole, TVI Et)] and plasma biomarkers (N-Terminal pro brain natriuretic peptide, NT-proBNP; galectin-3). RESULTS: In 37 patients [median age 34 years (range 24-51 years)], the incidence of abnormal TVI Et increased from 0% at baseline and 4.5% at 10 months (in 27 patients) to 16.7% at 6.9 years post-chemotherapy (P = 0.03). One patient developed LVEF <50%; no other systolic abnormalities occurred. Hypertension, obesity and age were associated with larger decreases in TVI Et. Changes in NT-proBNP and galectin-3 were not related to echocardiographic abnormalities. CONCLUSIONS: In this longitudinal cohort study, we observed a gradual decline in diastolic parameters after cisplatin-based chemotherapy for testicular cancer, whereas the rate of systolic dysfunction remains low. The association of larger declines in diastolic parameters with hypertension and obesity stresses the need to monitor and treat cardiovascular risk factors.

Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer.

Long-term cardiovascular morbidity is increasingly observed in chemotherapy-treated testicular cancer survivors, but little is known of early sub-clinical changes in cardiac function. We prospectively evaluated cardiac function in testicular cancer patients by echocardiography. Systolic (Wall Motion Score Index) and diastolic (E/A-ratio and Tissue Velocity Imaging (TVI)) parameters, and serum levels of N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) were assessed before the start of chemotherapy and 1 year later. Echocardiography data were compared with an age-matched group of healthy controls. Forty-two patients treated with bleomycin, etoposide and cisplatin were evaluated (median age 27 years, range 18-50). Systolic function and E/A-ratio did not change, whereas the median TVI decreased (12.0 vs 10.0 cms(-1); P=0.002). Median levels of NT-proBNP increased (5 vs 18 pmoll(-1), P=0.034). Compared with controls, TVI before the start of chemotherapy was not significantly different. In conclusion, we found that at a median of 10 months after cisplatin-based treatment for testicular cancer, TVI decreased significantly, indicating a deterioration of diastolic cardiac function. Serum levels of NT-proBNP increased. The prognostic significance of these changes for future cardiovascular morbidity is not clear.

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.

Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.

Indications for percutaneous endoscopic gastrostomy in complex tuberculosis patients.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) is a widely used method for providing long-term administration of tube feeding. Different indications in relation to diseases, impairments and nutritional factors for PEG placement have been mentioned in guidelines. Treatment with PEG has not been described previously for tuberculosis (TB). Our aim was to identify and describe indications and contributing factors for PEG placement in TB patients. METHODS: A retrospective medical record review was conducted of 32 TB patients who required PEG from March 1996 to April 2004. Indications and contributing factors for PEG placement were analysed. RESULTS: PEG placement was based on three different indications. In 18 patients, PEG was used to administer tube feeding, in 4 patients anti-tuberculosis drugs were administered and in 10 patients both tube feeding and antituberculosis drugs were administered. Contributing factors for PEG placement were swallowing disabilities, weakness, anti-tuberculosis drugs and their side effects, pain of neuralgic origin, hiccups and refusal of food and drugs. CONCLUSIONS: In TB, imminent and overt malnutrition, as well as the administration of drugs with a curative aim, are new indications for PEG placement. The use of PEG can overcome various problems in TB treatment and prevent treatment default.

[Underdiagnosis of HIV in patients with tuberculosis]. / Onderdiagnostiek naar hiv bij patiënten met tuberculose.

HIV/AIDS and tuberculosis impose a large infectious burden world wide. The conditions mutually interact, both epidemiologically and biologically. The course and treatment of tuberculosis are importantly complicated by HIV co-infection. A recent study showed that in newly detected tuberculosis patients, HIV sero-testing has been consistently low in the Netherlands. Two random samples of TB cases from the national registry were analysed--1993 and 2003--before and after the introduction of effective therapy for HIV/AIDS became available. There was no significant increase in HIV sero-testing. Guidelines for the treatment of tuberculosis should include routine HIV testing.

[Pulmonary infection caused by non-tuberculous mycobacteria in two patients with bronchiectasis]. / Infectie met niet-tuberculeuze mycobacteriën bij 2 patiënten met bronchiëctasieën.

Two patients, a woman aged 67 years and a man aged 80 years, had chronic cough among other respiratory symptoms. In the woman, chest radiograph and CT-scan revealed partial atelectasis of the middle lobe and bronchiectasis. In the man, an interstitial pattern was seen on chest radiograph, and CT scan showed diffuse bronchiectasis. In both the man and the woman, non-tuberculous mycobacteria were identified (Mycobacterium avium complex and Mycobacterium abscessus, respectively). Treatment was successful in both patients. Non-tuberculous mycobacteria can cause considerable pulmonary infection in patients with bronchiectasis.

[Two patients with tuberculous pleurisy]. / Pleuritis tuberculosa bij 2 patiënten.

Tuberculous pleurisy was diagnosed in two patients, a 21-year-old Somali woman and a 19-year-old Surinam man. The first patient suffered from a paradoxical (immunological) reaction and the other had an infectious reaction. Both patients recovered after treatment with tuberculostatic agents and pleural drainage. The pathophysiology of the paradoxical reaction is still largely unclear. Culture continues to be the gold standard in diagnosing tuberculous pleuritis but, in many cases, bacteriological confirmation is not obtained. The (probable) diagnosis is then often made on the basis of a combination of the patient's history, estimation of the risk, physical examination, radiology and histology, and on the basis of a (trial) treatment with tuberculostatic agents. In the diagnostic process, a PCR on the Mycobacterium tuberculosis complex can be helpful. The routine determination of adenosine deaminase and interferon gamma in patients with tuberculous pleurisy is not useful in low-incidence countries such as The Netherlands. The measurement of the in-vitro T-cell reactivity against M. tuberculosis-specific antigens may be of more value in the future. The pharmacotherapy of tuberculous pleurisy is the same as that of pulmonary tuberculosis. Rinsing the pleural cavity is recommended in the case of an infectious reaction. Drainage of pleural fluid is indicated in the case of a paradoxical reaction if there are mechanical difficulties.

Non-respiratory tuberculosis with Mycobacterium tuberculosis after penetrating lesions of the skin: five case histories.

Tuberculosis is primarily transmitted from person to person via the respiratory route. We describe five cases of patients who developed tuberculosis at the site of a skin injury: three after being treated repeatedly with local corticosteroids via intramuscular injections, and two who cut themselves accidentally with a knife. All cultures yielded normal-sensitive Mycobacterium tuberculosis, and all patients responded well to anti-tuberculosis treatment. These unusual manifestations of non-respiratory tuberculosis may support the assumption that persistent, painful, reddish and/or fistulous areas of the skin might also indicate an infection caused by M. tuberculosis, via either reactivation of pulmonary tuberculosis or primary infection with M. tuberculosis by cutaneous transmission.

Relation between beta-lactamase producing bacteria and patient characteristics in chronic obstructive pulmonary disease (COPD).

BACKGROUND: In addition to bronchodilator and anti-inflammatory therapy, exacerbations in patients with chronic obstructive pulmonary disease (COPD) are often treated with antibiotics. Haemophilus influenzae and Moraxella (Branhamella) catarrhalis, two important respiratory pathogens, may produce beta-lactamase which makes them resistant to ampicillin. Surveillance studies conducted in various countries have shown an increasing incidence of these beta-lactamase producing bacteria. Although this may simply be a consequence of the increasing use of antibiotics, it is possible that other factors are important. A study was undertaken to investigate whether clinical factors are related to the presence of beta-lactamase forming bacteria in the sputum of patients with COPD. METHODS: One hundred patients with COPD aged over 40 years were sequentially selected from an outpatient clinic on the basis of sputum culture results. Fifty had beta-lactamase positive (beta L+) and 50 had beta-lactamase negative (beta L-) bacteria in their sputum. Patients were included only if sputum culture results yielded one pathogen. The files of these patients were investigated for possible causative factors present during the two preceding years. RESULTS: Both groups were almost identical in terms of lung function, maintenance medication, and smoking history. The total number of antibiotic courses in the beta L+ group was higher, as were individual courses of cephalosporins, tetracyclines, and macrolides. The number of patients admitted to hospital was higher in the beta L+ group, but admissions were of equal duration in both groups. Patients admitted to hospital had poorer lung function. Risk factors for beta-lactamase producing bacteria were identified by logistic regression analysis which revealed an odds ratio for one course of antibiotics of 1.15 (95% CI 1.04 to 1.28). CONCLUSIONS: An increased number of antibiotic courses is related to a higher incidence of beta-lactamase producing bacteria and more patients had hospital admissions in the beta L+ group. beta-lactamase stable antibiotics were used more frequently in the beta L+ group, probably because prescribing was adapted to the presence of beta-lactamase producing bacteria. No other differences were found between the beta L+ and beta L- groups.

Respiratory resistance measured by flow-interruption in a normal population.

Data on reference values of total respiratory resistance (Rint) in healthy people are limited. The aim of this study was to examine the relationship between Rint and gender, height, weight, age and smoking habits. The instrument used was the Jaeger Pneumoscope with a flow interruption device. The method is based on transient interruption of airflow at the mouth for a brief period during which alveolar pressure equilibrates with mouth pressure. Measurement of mouth pressure is used to estimate alveolar pressure prior to interruption. The ratio of this to the flow prior to interruption gives airway resistance. The Rint data were correlated with height, weight, age, gender and smoking habits in 172 healthy subjects. They had a normal lung function (VC, FEV1) and no signs of pulmonary disease. The important determining factor for the value of the Rint were height and age. The mean Rint of 172 subjects was 0.38 +/- 0.17 kPa.1-1.s. The average within-subject variability of repeated measurements of Rint expressed as coefficient of variation was 14.4 +/- 6.9%. Reference equation and normal values for Rint in a healthy population are related to height and age. The measurements were obtained with a commercially available interruption technique.

Comparison of histamine and acetylcholine for use in bronchial challenge testing in atopic and nonatopic subjects with chronic airways obstruction: a review of 180 cases.

A retrospective study was performed to evaluate the diagnostic yield for bronchial hyperresponsiveness from histamine and acetylcholine challenge tests. The records of 180 cases from the last 10 years were analysed. They were selected because their hyperresponsiveness to inhaled histamine or acetylcholine was equal or less than 32 mg.ml-1. Increasing doses of histamine and acetylcholine were given up to a maximum of 32 mg.ml-1 according to the method of de Vries et al. [3]. The challenges were accomplished on two separate days. The provocative dose of agonist causing a 20% fall in FEV1 (PC20) was noted. The interrelationships between smoking history, objective markers of allergy, patient's complaints, histamine and acetylcholine responsiveness were examined. Separate statistical analyses are presented for atopic and nonatopic subjects with chronic airways obstruction. More subjects had a measurable PC20 with acetylcholine than with histamine (43 vs. 16 subjects, p < 0.0001). Using the chi 2 test, the relationship between PC20 histamine and PC20 acetylcholine was similar in smokers and nonsmokers, and in atopics and nonatopics. It is concluded that for an equal molar basis, acetylcholine evokes a higher frequency of bronchus obstruction than histamine in patients.