Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Predictors of adherence to exercise interventions during and after cancer treatment: A systematic review.

OBJECTIVE: Exercise interventions benefit cancer patients. However, only low numbers of patients adhere to these interventions. This review aimed to identify predictors of exercise intervention adherence in patients with cancer, during and after multimodality cancer treatment. METHODS: A literature search was performed using electronic databases (PubMed, Embase, and Cochrane) to identify relevant papers published before February 1, 2017. Papers reporting randomized controlled trials, conducted in adult cancer patients who participated in an exercise intervention during and/or after multimodality cancer treatment, and providing outcome of factors predicting exercise adherence were included. Papers were assessed for methodological quality by using the Physiotherapy Evidence Database scale. RESULTS: The search identified 720 potentially relevant papers, of which 15 fulfilled the eligibility criteria. In these 15 studies, 2279 patients were included and 1383 of these patients were randomized to an exercise intervention. During cancer treatment, the factors predicting exercise adherence were as follows: location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. After cancer treatment, factors that predicted adherence were as follows: less extensive surgery, low alcohol consumption, high previous exercise adherence, family support, feedback by trainers, and knowledge and skills of exercise. Methodological quality of the included papers was rated "high". CONCLUSIONS: The most prominent predictors of adherence to exercise interventions were location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. To increase the number of cancer patients who will benefit, these results should be considered into the development and implementation of future exercise interventions.

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.

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.

Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer.

Testicular cancer is the most frequent solid malignant tumour type in men 20-40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin-induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers.

Risk and prognostic significance of metachronous contralateral testicular germ cell tumours.

BACKGROUND: Testicular germ cell tumour (TGCT) patients are at increased risk of developing a contralateral testicular germ cell tumour (CTGCT). It is unclear whether TGCT treatment affects CTGCT risk. METHODS: The risk of developing a metachronous CTGCT (a CTGCT diagnosed ≥6 months after a primary TGCT) and its impact on patient's prognosis was assessed in a nationwide cohort comprising 3749 TGCT patients treated in the Netherlands during 1965-1995. Standardised incidence ratios (SIRs), comparing CTGCT incidence with TGCT incidence in the general population, and cumulative CTGCT incidence were estimated and CTGCT risk factors assessed, accounting for competing risks. RESULTS: Median follow-up was 18.5 years. Seventy-seven metachronous CTGCTs were diagnosed. The SIR for metachronous CTGCTs was 17.6 (95% confidence interval (95% CI) 13.9-22.0). Standardised incidence ratios remained elevated for up to 20 years, while the 20-year cumulative incidence was 2.2% (95% CI 1.8-2.8%). Platinum-based chemotherapy was associated with a lower CTGCT risk among non-seminoma patients (hazard ratio 0.37, 95% CI 0.18-0.72). The CTGCT patients had a 2.3-fold (95% CI 1.3-4.1) increased risk to develop a subsequent non-TGCT cancer and, consequently, a 1.8-fold (95% CI 1.1-2.9) higher risk of death than patients without a CTGCT. CONCLUSION: The TGCT patients remain at increased risk of a CTGCT for up to 20 years. Treatment with platinum-based chemotherapy reduces this risk.

Shared-care survivorship program for testicular cancer patients: safe and feasible.

BACKGROUND: Testicular cancer survivors are at risk for cardiovascular disease, often preceded by early development of cardiovascular risk factors due to chemotherapeutic treatment. Therefore, close collaboration between oncologists and primary care physicians (PCPs) is needed during follow-up to monitor and manage cardiovascular risk factors. We designed a shared-care survivorship program, in which testicular cancer patients visit both their oncologist and their PCP. The objective of this study was to test the safety and feasibility of shared-care follow-up after treatment for metastatic testicular cancer. PATIENTS AND METHODS: The study was designed as an observational cohort study with a stopping rule to check for the safety of follow-up. Safety boundaries were defined for failures in the detection of signals indicating cancer recurrence. Secondary outcomes were the proportion of carried out cardiovascular risk assessments, psychosocial status and patient preferences measured with an evaluation questionnaire. RESULTS: One hundred and sixty-two patients were enrolled (69% of eligible testicular cancer patients). Almost all (99%, n = 150) PCPs of the enrolled patients agreed to participate in the study. In total, 364 primary care visits took place. No failures occurred in the detection of relapsed testicular cancer. Four follow-up visits were considered as failures because of organizational issues, without activation of the stopping rule. Eventually, the safe boundary was crossed indicating that this shared-care model is a safe alternative for follow-up after testicular cancer. Patients were satisfied with the knowledge level of PCPs. PCPs were willing to further extend their role in follow-up care after cancer. CONCLUSIONS: Shared-care follow-up is safe and feasible in this patient population. Patients benefit from personalized care, partly close to their home. Within shared care, PCPs can have an important role in cardiovascular risk management and psychosocial survivorship issues.

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.

Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors.

BACKGROUND: Patients with elevated human chorionic gonadotrophin (HCG) can have hyperthyroidism. We assessed the prevalence of hyperthyroidism in patients presenting with disseminated non-seminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: In all patients with metastatic NSGCT who started chemotherapy at our center from April 2001 to April 2007, thyroid function was analyzed. The association between thyroid function and HCG level was examined and the frequency of hyperthyroidism in patients with low (<5000 IU/l), intermediate (> or = 5000 but <50 000 IU/l) and high (> or = 50 000 IU/l) serum HCG was assessed. RESULTS: For 144 of 148 eligible patients, thyroid function tests were available. Five patients with hyperthyroidism (3.5%) were identified, who all had high-serum HCG (mean 1 325 147 IU/l). Fifty percent of the patients with high HCG levels had hyperthyroidism versus 0% of the patients with HCG <50 000 IU/l (P < 0.001). Free thyroxin levels normalized within 26 days after starting chemotherapy in all patients. CONCLUSIONS: Hyperthyroidism frequently accompanies NSGCT with highly elevated HCG. Since its symptoms overlap with those of extensive metastatic disease, it may not be recognized. Thyroid function should be assessed in patients with high HCG levels and symptomatic hyperthyroidism should be treated temporarily with beta-blockade or antithyroidal medication.

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.

Insulin-like growth factors and insulin-like growth factor-binding proteins in relation to disease status and incidence of hypoglycaemia in patients with a gastrointestinal stromal tumour.

OBJECTIVE: Patients with a gastrointestinal stromal tumour (GIST) suffering from non-islet cell tumour-induced hypoglycaemia (NICTH), being associated with increased plasma levels of pro-insulin-like growth factor (IGF)-IIE[68-88], have been reported occasionally. We studied the clinical relevance of pro-IGF-IIE[68-88] and other IGF-related proteins in GIST patients. PATIENTS AND METHODS: Twenty-four patients were included. Plasma samples were collected before 1 week and median 5 months after start of treatment with imatinib, and levels of IGF-I, total IGF-II, pro-IGF-IIE[68-88], insulin-like growth factor-binding protein (IGFBP)-2, -3 and -6 were determined. GIST specimens from 17 patients and tumour cyst fluid from two patients were analysed for IGF-II and IGFBP-2. RESULTS: Before treatment and/or during follow-up, 3 of 24 (13%) patients showed increased plasma levels of pro-IGF-IIE[68-88]. All three developed NICTH. Overall, patients with metastatic disease, elevated serum lactate dehydrogenase activity or total tumour size >12 cm had the highest pro-IGF-IIE[68-88] levels. Most patients had increased plasma IGFBP-2 levels and these levels were significantly higher in patients with progressive disease. (Pro-)IGF-II was expressed in 82% of GISTs and IGFBP-2 only in one case. CONCLUSION: We identified pro-IGF-IIE[68-88] as a marker that may be used in the surveillance of GIST.

Insulin-like factor 3, luteinizing hormone and testosterone in testicular cancer patients: effects of ß-hCG and cancer treatment.

BACKGROUND: Primary hypogonadism (low testosterone and high luteinizing hormone, LH) is present in approximately 20% of testicular cancer (TC) survivors after orchidectomy with or without chemotherapy. OBJECTIVES: We investigated insulin-like factor 3 (INSL3), a novel marker of Leydig cell function, in TC patients. MATERIALS AND METHODS: We analyzed: (I) a cross-sectional cohort of TC patients after orchidectomy with or without chemotherapy (1988-1999) at long-term follow-up (median 36 and 35 years of age at follow-up, respectively) and healthy men of similar age; (II) a longitudinal cohort of chemotherapy-treated TC patients (2000-2008), analyzed before and 1 year after chemotherapy (median 29 years of age at chemotherapy). INSL3, testosterone, and LH were compared between groups and over time and related to pre-chemotherapy ß-hCG levels. RESULTS: In the cross-sectional cohort, TC patients at median 7 years after orchidectomy and chemotherapy (n = 79) had higher LH (p < 0.001), lower testosterone (p = 0.001), but similar INSL3 as controls (n = 40). After orchidectomy only (n = 25), higher LH (p = 0.02), but no differences in testosterone or INSL3 were observed compared to controls. In the longitudinal cohort, patients with normal pre-chemotherapy ß-hCG (≤5 mU/L, n = 35) had increased LH 1 year after chemotherapy compared to pre-chemotherapy (p = 0.001), and no change in testosterone or INSL3. In contrast, patients with high ß-hCG pre-chemotherapy (n = 42) had suppressed LH, markedly elevated testosterone, and low INSL3 at start of chemotherapy, with increased LH, decreased testosterone, and increased INSL3 1 year later (all p < 0.001). DISCUSSION: Changes in LH show that gonadal endocrine function is disturbed before chemotherapy, 1 year later, and at long-term follow-up in chemotherapy-treated TC patients. CONCLUSION: Pre-chemotherapy, ß-hCG-producing tumors affect the gonadal endocrine axis, demonstrated by increased testosterone and decreased LH. INSL3 did not uniformly follow the pattern of testosterone.

Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity.

BACKGROUND: Recently, case reports of patients treated with imatinib (imatinib mesylate; Gleevec; Glivec) indicated that this tyrosine kinase inhibitor may induce cardiomyopathy. Consequently, careful cardiac monitoring was advocated for clinical studies. The purpose of this study was to prospectively evaluate whether imatinib (Gleevec) induces early, subclinical, cardiac toxicity. PATIENTS AND METHODS: History and physical examination were carried out with special attention for symptoms of heart failure. Additionally, assessments of serial plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) and serum cardiac troponin T (cTnT) measurement before and 1 and 3 months after the start of imatinib treatment (400-800 mg daily) were done in patients with advanced and/or metastatic gastrointestinal stromal tumours (GIST). RESULTS: A total of 55 GIST patients were enrolled. Only one patient, with a normal pretreatment NT-proBNP, showed an increase in NT-proBNP to above age-specific normal values during imatinib treatment and developed symptomatic heart failure due to pre-existent cardiac valvular disease. cTnT levels remained stable. CONCLUSIONS: In our study population, imatinib treatment for GIST was not associated with an increase in plasma NT-proBNP levels, indicating that the risk of subclinical cardiac toxicity is limited with the use of this agent. These results do not support the current strategy to standard cardiac monitoring in all patients. This may be restricted to GIST patients with a history of cardiac disease.

Prognostic versus predictive value of biomarkers in oncology.

Numerous options are currently available for tumour typing. This has raised intense interest in the elucidation of prognostic and predictive markers. A prognostic biomarker provides information about the patients overall cancer outcome, regardless of therapy, whilst a predictive biomarker gives information about the effect of a therapeutic intervention. A predictive biomarker can be a target for therapy. Amongst the genes that have proven to be of relevance are well-known markers such as ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in chronic myeloid leukaemia, c-KIT mutations in GIST tumours and EGFR1 mutations in NSCLC. Several reasons for the difficult elucidation of new markers will be addressed including the involvement of cellular pathways in tumour biology instead of single genes and interference in disease outcome as a result of anticancer therapies. Future perspectives for the development of prognostic and predictive markers will be given.

[Diagnostics and treatment of cholangiocarcinoma]. / Diagnostiek en behandeling van het cholangiocarcinoom.

--Cholangiocarcinoma is a rare malignancy originating from the biliary epithelium. The disease can arise anywhere in the biliary tract: intrahepatic, perihilar or distal. The overall prognosis for cholangiocarcinoma is poor. --The treatment necessitates a multidisciplinary approach. --Radical resection of the extrahepatic bile ducts, usually in combination with concomitant partial liver resection, remains the only curative treatment. --Liver transplantation in combination with neoadjuvant chemoradiation therapy seems to be promising in a highly selected group of patients. --Palliative treatment should be targeted at adequate biliary drainage, preferably by stenting. --Radiotherapy and systemic chemotherapy are not standard treatment and should be applied in an experimental setting only. --New options such as photodynamic therapy and tyrosine kinase inhibitors are promising, but still experimental treatments.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Changes in body composition after childhood cancer treatment: impact on future health status--a review.

PURPOSE: To describe data on changes in body composition in childhood cancer survivors. Underlying mechanisms in development of obesity are addressed, in order to discuss intervention strategies. METHODS: A systematic literature search was undertaken with a number of search terms. RESULTS: Female survivors of ALL and brain tumours, especially if treated with cranial irradiation, showed a higher prevalence of obesity compared with the general population, while survivors of other malignancies had a higher prevalence of underweight. Influences of corticosteroid treatment and cytostatics on body composition are uncertain. Diminished physical activity, early adiposity rebound (<5 years of age) and/or hypothalamic involvement of tumour or treatment, and subsequent growth hormone deficiency, may play a role in the development of obesity in childhood cancer survivors. CONCLUSION: Longitudinal prospective studies in more extensive cohorts are necessary to estimate actual prevalence and facilitate the unravelling of the underlying mechanisms in change of body composition.